43 results on '"Yvette Latchman"'
Search Results
2. Abstract PD4-09: Preclinical studies support the development of SBT6050, an anti-HER2 antibody conjugated to a potent TLR8 agonist, for treatment of moderate and high HER2-expressing tumors that lack pre-existing T cell infiltrate
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Ty Brender, Jamie Brevik, Li-Qun Fan, Phil Tan, Valerie Odegard, Jeffrey Adamo, Damion Winship, Sean W. Smith, Yvette Latchman, Kara Moyes, Heather E. Metz, Monica Childs, Jenny R Chang, Ben Setter, Hengyu Xu, Peter R. Baum, and Robert F. Dubose
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Antibody-dependent cell-mediated cytotoxicity ,Cancer Research ,Myeloid ,biology ,business.industry ,T cell ,Dendritic cell ,Epitope ,medicine.anatomical_structure ,Immune system ,Oncology ,Trastuzumab ,medicine ,biology.protein ,Cancer research ,Antibody ,skin and connective tissue diseases ,business ,medicine.drug - Abstract
Despite advances in treatment options for patients with HER2-expressing tumors, significant unmet medical need remains. Of note, checkpoint inhibition (CPI) therapy has been largely ineffective in HER2-expressing tumors, likely due to the absence of T cell infiltrate. We show here, however, that a large fraction of HER2-expressing tumors is replete with resident myeloid cells despite lacking T cells. Intratumoral activation of myeloid cells could be beneficial in breast cancer, as suggested by clinical studies with demonstrated responses in cutaneous breast cancer metastases after topical application of imiquimod, a relatively weak TLR agonist. Local administration, the typical delivery route used for innate immune/myeloid cell agonists, is limited by tumor accessibility and a dependence on abscopal responses. SBT6050 is a HER2-directed monoclonal antibody conjugated to a potent TLR8 agonist, allowing for systemic delivery of a myeloid cell agonist with activity localized to HER2-expressing tumor sites. SBT6050 is designed to activate human myeloid cells only in the presence of HER2-positivetumor cells with moderate (2+ by IHC) or high (3+ by IHC) expression levels. As previously described, SBT6050 is designed to drive tumor immunity through intratumoral pan-myeloid activation by inducing direct macrophage-mediated killing of tumor cells, repolarizing suppressive myeloid cell populations to a pro-immunogenic phenotype, augmenting dendritic cell priming of tumor-specific CTL responses, and facilitating tumor recruitment and infiltration of immune cell types, including T cells. Here, we present preclinical studies that provide additional support for the clinical evaluation of SBT6050 as a monotherapy as well as in combination with trastuzumab. SBT6050 is proficient at ADCC and ADCP and binds to an epitope distinct from trastuzumab. An SBT6050 mouse surrogate shows robust single agent efficacy in several tumor models, including an EMT6 breast cancer model, known to be CPI refractory due to low T cell infiltrate, engineered to express huHER2. Tumor-bearing mice treated with the SBT6050 surrogate had durable cures and were resistant to tumor rechallenge, indicating development of immunological memory. The SBT6050 surrogate was also more efficacious than unconjugated anti-HER2 mAb in HER2-positive xenograft models conducted in T cell deficient, but myeloid competent, mouse strains. These data demonstrate the benefit of tumor-directed myeloid cell activation, even in the absence of T cells. As trastuzumab and SBT6050 bind to distinct epitopes on HER2, we evaluated the combination of trastuzumab with SBT6050 in vitro or SBT6050 surrogate in vivo for enhanced activity. In vitro, SBT6050 did not impede trastuzumab’s blockade of HER2 signaling as evidenced by cell death of HER2-positive tumor cell lines. Furthermore, SBT6050 potently activates myeloid cells in a HER2-dependent manner in the presence of trastuzumab. In vivo studies assessing the combination of the SBT6050 surrogate with trastuzumab in HER2- positive xenograft models will support evaluating the combination in the clinic. SBT6050 is currently in preclinical development and is projected to enter the clinic in 2020. Citation Format: Valerie H Odegard, Kara Moyes, Monica Childs, Jamie Brevik, Damion Winship, Ty Brender, Heather Metz, Jenny R Chang, Jeffrey Adamo, Ben Setter, Hengyu Xu, Li-Qun Fan, Sean W Smith, Phil Tan, Robert DuBose, Yvette Latchman, Peter Baum. Preclinical studies support the development of SBT6050, an anti-HER2 antibody conjugated to a potent TLR8 agonist, for treatment of moderate and high HER2-expressing tumors that lack pre-existing T cell infiltrate [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-09.
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- 2020
3. 712 SBT6290, a systemically administered Nectin-4-directed TLR8 ImmunoTAC (TM) therapeutic, is a potent human myeloid cell agonist for the treatment of Nectin-4-expressing tumors
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Damion Winship, Ray Carrillo, Brenda L. Stevens, Jonathan Grey, Hengyu Xu, Ben Setter, Robert F. Dubose, Peter R. Baum, Jenny C. Chang, Heather Metz, Li-Qun Fan, Ty Brender, Jeffrey Adamo, Sean W. Smith, Jamie Brevik, Yvette Latchman, Michael R. Comeau, Monica Childs, Phil Tan, and Valerie Odegard
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Cell type ,Chemokine ,Myeloid ,biology ,business.industry ,T cell ,medicine.medical_treatment ,Inflammasome ,Human leukocyte antigen ,Immunotherapy ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,medicine.anatomical_structure ,Immune system ,Cancer research ,biology.protein ,Medicine ,business ,medicine.drug - Abstract
Background SBT6290 is a novel therapeutic comprised of a selective TLR8 agonist conjugated to a Nectin-4-specific monoclonal antibody, designed for systemic delivery and tumor-localized activation of myeloid cells. Nectin-4 is a cell surface adhesion molecule that is overexpressed in multiple solid tumor types including triple negative breast, head and neck, lung, and urothelial cancers, with limited expression in normal tissues. Many solid tumors, including those expressing Nectin-4, are resistant to immunotherapy due to immune-suppressive mechanisms, loss of HLA, low neoantigen availability, and/or minimal T cell infiltrates. These tumors, however, are often replete with myeloid cells. Activation of these cells has emerged as a promising approach in overcoming resistance mechanisms to current cancer immunotherapies. TLR8 is highly expressed in myeloid cell types prevalent in human tumors, including conventional DCs and macrophages. Agonism of TLR8 in human myeloid cells activates a broad spectrum of anti-tumor immune mechanisms, including proinflammatory cytokine production, repolarization of suppressive myeloid cells, and the priming of CTL responses. Here, we show that SBT6290 potently activates human myeloid cells in a Nectin-4-dependent manner and that a mouse surrogate confers single agent anti-tumor activity in preclinical studies. These data support the development of SBT6290 for the treatment of patients with Nectin-4-expressing tumors. Methods SBT6290 activity was characterized in vitro using co-culture systems consisting of human immune cells and Nectin-4-expressing tumor cells. The in vivo efficacy of the SBT6290 surrogate was evaluated as a single agent in mouse tumor models expressing Nectin-4. Results Studies with human immune cells show that SBT6290 potently induces multiple anti-tumor immune activities including proinflammatory cytokine and chemokine production, inflammasome activation, direct activation of DCs and indirect T and NK cell cytolytic activity. This activity requires the presence of Nectin-4 expressing tumor cells and the engagement of Fc gamma receptors on the surface of the myeloid cells by the conjugate to facilitate delivery of SBT6290 into myeloid cells. Notably, SBT6290 is >100 fold more potent than the free, unconjugated TLR8 agonist. Systemic administration of a SBT6290 surrogate in mice results in robust single agent efficacy in tumor models intrinsically resistant to checkpoint blockade, including the EMT6 model engineered to express human Nectin-4. Conclusions The preclinical data described here show the potential for SBT6290 to drive robust, single agent anti-tumor responses and support the clinical development of SBT6290 for patients with Nectin-4 expressing tumors.
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- 2020
4. Abstract 1858: SBT6290, a systemically administered Nectin4-directed TLR8 ImmunoTAC™ product candidate, is designed for tumor-localized activation of myeloid cells
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Michael R. Comeau, Ben Setter, Marcus Rhodehamel, Brenda L. Stevens, Valerie Odegard, Monica Childs, Jamie Brevik, Jenny C. Chang, Yvette Latchman, Damion Winship, Ray Carillo, Elsa Hay, Jeffrey Adamo, Phil Tan, Hengyu Xu, Peter R. Baum, Jonathan Grey, Robert F. Dubose, Li-Qun Fan, Sean W. Smith, and Heather E. Metz
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Cancer Research ,Tumor microenvironment ,Chemokine ,Myeloid ,biology ,business.industry ,medicine.medical_treatment ,T cell ,Inflammasome ,medicine.anatomical_structure ,Immune system ,Oncology ,Cancer immunotherapy ,TIGIT ,medicine ,biology.protein ,Cancer research ,business ,medicine.drug - Abstract
SBT6290 is a novel product candidate comprised of a selective TLR8 agonist conjugated to a Nectin4-specific monoclonal antibody, designed for systemic delivery and tumor-localized activation of myeloid cells. Nectin4 is a cell surface adhesion molecule that is overexpressed in multiple solid tumor types including bladder, triple negative breast, squamous head and neck, and non-small cell lung cancers, with limited expression in normal tissues. Nectin4-expressing solid tumors display substantial myeloid cell infiltrate. Activation of these myeloid cells in the tumor microenvironment has emerged as a promising approach in overcoming resistance mechanisms to current cancer immunotherapies. TLR8 is highly expressed in myeloid cell types prevalent in human tumors, including conventional dendritic cells (DCs) and macrophages. TLR8 agonism in human myeloid cells activates a broad spectrum of anti-tumor immune mechanisms, including proinflammatory cytokine production, repolarization of suppressive myeloid cells, and the priming of CTL responses. Here, we show that SBT6290 activates human myeloid cells by SBT6290 in a Nectin4-dependent manner and that a SBT6290 mouse surrogate confers single agent anti-tumor activity in preclinical studies. In vitro studies with human immune cells demonstrate that SBT6290 induces multiple anti-tumor immune mechanisms including proinflammatory cytokine and chemokine production, inflammasome activation, direct activation of DCs and indirect activation of T and NK cell cytolytic activity. This activity is Nectin4-specific and requires SBT6290 engagement of Fcγ receptors on the surface of myeloid cells to facilitate uptake of the conjugate into myeloid cells. Notably, SBT6290 is >100-fold more active than free, unconjugated TLR8 agonist and demonstrates activity on tumor cells with Nectin4 overexpression that correlates with levels found in primary tumor samples. Nectin4 was recently described to be a ligand for T cell immunoreceptor with Ig and ITIM domains (TIGIT), an inhibitory receptor considered to be a promising new target for cancer immunotherapy (J Immunother Cancer. 2020; 8(1): e000266). The SBT6290 binding domain blocks the interaction between TIGIT and Nectin4, potentially contributing to the T and NK cell activation induced by SBT6290. Systemic administration of a SBT6290 surrogate in mice bearing Nectin4-expressing tumors results in intra-tumoral myeloid and T cell activation and increased overall survival. The preclinical data described here demonstrate the potential for SBT6290 to drive anti-tumor responses and support continued preclinical development of SBT6290 for Nectin4-expressing tumors. Citation Format: Michael R. Comeau, Heather Metz, Brenda Stevens, Damion Winship, Jamie Brevik, Marcus Rhodehamel, Monica Childs, Elsa Hay, Jenny Chang, Li-Qun Fan, Hengyu Xu, Jonathan Grey, Jeffrey Adamo, Ben Setter, Ray Carillo, Sean W. Smith, Phil Tan, Robert Dubose, Yvette Latchman, Peter Baum, Valerie Odegard. SBT6290, a systemically administered Nectin4-directed TLR8 ImmunoTAC™ product candidate, is designed for tumor-localized activation of myeloid cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1858.
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- 2021
5. Transfusion-related immunomodulation: gamma irradiation alters the effects of leukoreduction on alloimmunization
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Sherrill J. Slichter, Paul Warner, Terry Gernsheimer, Devi Gunasekera, Karen Nelson, Yvette Latchman, Doug Bolgiano, Ayala Tamir, and Gabriel S. Aldea
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Blood transfusion ,Allosensitization ,medicine.medical_treatment ,Immunology ,Human leukocyte antigen ,030204 cardiovascular system & hematology ,T-Lymphocytes, Regulatory ,Transfusion-related immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,HLA Antigens ,Isoantibodies ,medicine ,Immune Tolerance ,Immunology and Allergy ,Humans ,Blood Transfusion ,biology ,business.industry ,FOXP3 ,Immunosuppression ,Hematology ,Leukoreduction ,Gamma Rays ,biology.protein ,Natural Killer T-Cells ,Antibody ,Leukocyte Reduction Procedures ,business ,030215 immunology - Abstract
Background Adverse events following blood transfusion include allosensitization and generalized immunosuppression, collectively referred to as transfusion-related immune modulation. We evaluated the immunological effects of red blood cell (RBC) and platelet transfusions on alloantibody responses and on immunoregulatory cells in nonimmunosuppressed patients undergoing cardiovascular surgery. Study design and methods Patients were randomized to receive standard unmodified (STD), leukoreduced (LR), or leukoreduced and γ-irradiated (LRγ) RBCs. Patients received only apheresis platelets that were in-process LR and were γ-irradiated for the third arm. Nontransfused patients served as controls for the effects of surgery itself on immunologic changes. Antibodies to HLA were assessed with use of solid-phase assays. The effects of transfusion on adaptive and innate immunity were evaluated by assessing T regulatory cells (Tregs) and invariant natural killer T (iNKT) cells. Results LR of blood products reduced the development of human leukocyte antigen (HLA) alloantibodies, but only in patients without preexisting HLA antibodies. However, if LR blood products were γ-irradiated, HLA antibody production was not reduced. Compared to nontransfused patients, recipients of STD or LR transfusions showed a significant increase in CD4+CD25hi T cells expressing FoxP3 or CTLA4 and also of iNKT cells producing interleukin-4. In contrast, recipients of LRγ blood products showed markedly lower increases in all three cellular assays. Conclusion LR decreased HLA alloantibody production in naive recipients, but did not reduce the immunosuppressive effects of transfusion. LRγ reduced immunosuppression and was not associated with decreased HLA alloantibody production.
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- 2019
6. Abstract 4537: SBT6050, a HER2-directed TLR8 ImmunoTAC™therapeutic, is a potent human myeloid cell agonist that provides opportunity for single agent clinical activity
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Sean W. Smith, Hengyu Xu, Peter R. Baum, Yvette Latchman, Jamie Brevik, Ty Brender, Phil Tan, Jeffrey Adamo, Valerie Odegard, Michael R. Comeau, Li-Qun Fan, Monica Childs, Jenny C. Chang, Ben Setter, Robert F. Dubose, Damion Winship, Heather Metz, and Brenda L. Stevens
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Agonist ,Cancer Research ,Innate immune system ,Myeloid ,business.industry ,medicine.drug_class ,T cell ,medicine.medical_treatment ,Immunotherapy ,Epitope ,chemistry.chemical_compound ,medicine.anatomical_structure ,Immune system ,Oncology ,chemistry ,medicine ,Cancer research ,Resiquimod ,business - Abstract
SBT6050, a novel therapeutic comprised of a potent toll-like receptor (TLR) 8 agonist conjugated to a HER2-directed monoclonal antibody that binds an epitope distinct from trastuzumab, is designed for systemic delivery and tumor-localized activation of human myeloid cells in the presence of moderate and high HER2-expressing tumor cells. Many solid tumors, including those expressing HER2, are refractory to immunotherapy due to immune-suppressive mechanisms, loss of HLA, low neoantigen availability, and/or minimal T cell infiltrates. These tumors frequently contain abundant populations of tumor-associated myeloid cells. Activation of these cells through TLR agonism has emerged as a promising approach in overcoming resistance mechanisms to current cancer immunotherapies. Unlike other endosomal TLRs such as TLR7 and TLR9, TLR8 is highly expressed in human myeloid cells known to be prevalent in human tumors such as conventional DCs and macrophages. TLR8's restricted myeloid cell expression removes the risk of inducing T cell death or tumor cell proliferation as described for other innate immune activators such as STING. Agonism of TLR8 in human myeloid cells activates a broad spectrum of anti-tumor immune mechanisms, including proinflammatory cytokine production, repolarization of suppressive myeloid cells and the priming of CTL responses. These functions cannot be replicated by a potent TLR7 agonist or with clinical agents such as resiquimod that agonize TLR7 and only weakly engage TLR8. Here we present data demonstrating the superiority of SBT6050 at activating human myeloid cells compared to HER2 antibody conjugates that use either a selective TLR7 agonist or resiquimod. In vitro studies with human immune cells show that SBT6050 potently induces multiple anti-tumor immune activities, including proinflammatory cytokine and chemokine production, inflammasome activation, direct activation of DCs and indirect T and NK cell cytolytic activity. Our data indicate the favorable profile of SBT6050 is likely due to efficient engagement of TLR8 in conjugate form and TLR8's unique expression profile, and not due to differences in the potency of the small molecule payloads. Using an SBT6050 mouse surrogate we show in vivo evidence for intratumoral TLR agonist activation of several myeloid driven anti-tumor pathways leading to curative single agent efficacy in both a T cell-excluded syngeneic tumor model and a xenograft model lacking T, B and NK cells. Collectively, these data demonstrate that SBT6050 displays an attractive functional profile unachievable with agonist-based antibody conjugates directed against other innate immune receptors. These data also highlight the potential for SBT6050 to be clinically active as a monotherapy. SBT6050 is projected to enter the clinic in 2020 for patients with moderate or high HER2-expressing tumors. Citation Format: Michael R. Comeau, Ty Brender, Monica Childs, Jamie Brevik, Damion Winship, Heather Metz, Jenny Chang, Jeffrey Adamo, Ben Setter, Hengyu Xu, Li-Qun Fan, Brenda Stevens, Sean W. Smith, Phil Tan, Robert DuBose, Yvette Latchman, Peter Baum, Valerie Odegard. SBT6050, a HER2-directed TLR8 ImmunoTAC™therapeutic, is a potent human myeloid cell agonist that provides opportunity for single agent clinical activity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4537.
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- 2020
7. SBT6050, a HER2-directed TLR8 therapeutic, as a systemically administered, tumor-targeted human myeloid cell agonist
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Sean W. Smith, Jeffrey Adamo, Damion Winship, Yvette Latchman, Valerie Odegard, Kara Moyes, Heather Metz, Jenny C. Chang, Ty Brender, Phil Tan, Michael R. Comeau, Jamie Brevik, Robert F. Dubose, Monica Childs, Li-Qun Fan, Hengyu Xu, Peter R. Baum, and Ben Setter
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Agonist ,Cancer Research ,Myeloid ,business.industry ,medicine.drug_class ,Cell ,TLR8 ,Tumor targeted ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Myeloid cells ,Cancer research ,Medicine ,business ,030215 immunology - Abstract
3110 Background: Solid tumors are replete with myeloid cells which, when activated, drive potent anti-tumor responses. Clinical development of systemically administered myeloid cell agonists, however, has been hindered by acute toxicities due to peripheral activation of the targeted cell types. Intratumoral administration, the route of delivery typically used for innate immune/myeloid cell agonists, is limited by tumor accessibility and a dependence on abscopal responses. A systemically delivered myeloid cell agonist with tumor-localized activity has the potential to overcome challenges encountered with other innate immune/myeloid cell agonists in clinical development. Methods: SBT6050 is a novel therapeutic comprised of a potent toll-like receptor (TLR) 8 agonist payload conjugated to a HER2-directed monoclonal antibody. Delivery of the payload into the endosome of human myeloid cells, where TLR8 resides, requires the co-engagement of HER2 on tumor cells and Fc gamma receptor on human myeloid cells. Thus, SBT6050 is designed for systemic delivery and tumor-targeted activation of human myeloid cells. Results: Studies with human immune cells show that SBT6050 potently induces, in a HER2-dependent manner, multiple anti-tumor immune activities due to its direct activation of myeloid cells and the subsequent induction of T and NK cell cytolytic activity. SBT6050 is designed to activate human myeloid cells only in the presence of HER2-positive tumor cells with moderate (2+ by IHC) or high (3+ by IHC) expression levels. Tumor-localized activity has been demonstrated in mouse models using a SBT6050 mouse surrogate. Systemic delivery results in robust single agent efficacy in multiple mouse tumor models, even those engineered to lack T cells, without accompanying peripheral cytokine production. Trastuzumab and SBT6050 bind to distinct epitopes on HER2 and enhanced activity is observed when the two agents are combined. Conclusions: SBT6050 is a systemically administered, tumor-targeted myeloid cell agonist that demonstrates single agent efficacy in multiple mouse tumor models without peripheral cytokine production. A first-in-human study with SBT6050 is expected to begin this year for patients with HER2-expressing solid tumors.
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- 2020
8. The generation and analyses of a novel combination of recombinant adenovirus vaccines targeting three tumor antigens as an immunotherapeutic
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Christopher R. Heery, Massimo Fantini, Frank R. Jones, Claudia Palena, Ravi A. Madan, James L. Gulley, Joseph P. Balint, Justin M. David, Adrian Rice, James W. Hodge, Elizabeth Gabitzsch, Jeffrey Schlom, Kwong Y. Tsang, Yvette Latchman, and Anna R. Kwilas
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T-Lymphocytes ,viruses ,medicine.medical_treatment ,Genetic Vectors ,Gene delivery ,medicine.disease_cause ,Cancer Vaccines ,Adenoviridae ,Interferon-gamma ,Mice ,Immune system ,Carcinoembryonic antigen ,Antigen ,Adenovirus Vaccines ,Antigens, Neoplasm ,Neoplasms ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,biology ,business.industry ,Dendritic Cells ,Immunotherapy ,biochemical phenomena, metabolism, and nutrition ,Flow Cytometry ,Xenograft Model Antitumor Assays ,Virology ,Adenovirus E2 Proteins ,digestive system diseases ,Carcinoembryonic Antigen ,3. Good health ,Mice, Inbred C57BL ,Vaccination ,tumor antigens ,Oncology ,biology.protein ,Adenovirus E1 Proteins ,Female ,Immunization ,immunotherapy ,brachyury ,business ,CD8 ,Research Paper - Abstract
Phenotypic heterogeneity of human carcinoma lesions, including heterogeneity in expression of tumor-associated antigens (TAAs), is a well-established phenomenon. Carcinoembryonic antigen (CEA), MUC1, and brachyury are diverse TAAs, each of which is expressed on a wide range of human tumors. We have previously reported on a novel adenovirus serotype 5 (Ad5) vector gene delivery platform (Ad5 [E1-, E2b-]) in which regions of the early 1 (E1), early 2 (E2b), and early 3 (E3) genes have been deleted. The unique deletions in this platform result in a dramatic decrease in late gene expression, leading to a marked reduction in host immune response to the vector. Ad5 [E1-, E2b-]-CEA vaccine (ETBX-011) has been employed in clinical studies as an active vaccine to induce immune responses to CEA in metastatic colorectal cancer patients. We report here the development of novel recombinant Ad5 [E1-, E2b-]-brachyury and-MUC1 vaccine constructs, each capable of activating antigen-specific human T cells in vitro and inducing antigen-specific CD4+ and CD8+ T cells in vaccinated mice. We also describe the use of a combination of the three vaccines (designated Tri-Ad5) of Ad5 [E1-, E2b-]-CEA, Ad5 [E1-, E2b-]-brachyury and Ad5 [E1-, E2b-]-MUC1, and demonstrate that there is minimal to no “antigenic competition” in in vitro studies of human dendritic cells, or in murine vaccination studies. The studies reported herein support the rationale for the application of Tri-Ad5 as a therapeutic modality to induce immune responses to a diverse range of human TAAs for potential clinical studies.
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- 2015
9. Leukofiltration plus pathogen reduction prevents alloimmune platelet refractoriness in a dog transfusion model
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Esther Pellham, S. Lawrence Bailey, Lakshmi K. Gaur, Todd Christoffel, Irena Gettinger, Sherrill J. Slichter, Doug Bolgiano, Karen Nelson, and Yvette Latchman
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Blood Platelets ,medicine.medical_specialty ,Isoantigens ,Blood transfusion ,medicine.medical_treatment ,Immunology ,030204 cardiovascular system & hematology ,Biochemistry ,Antibodies ,03 medical and health sciences ,0302 clinical medicine ,Dogs ,Internal medicine ,medicine ,Immune Tolerance ,Leukocytes ,Animals ,Platelet ,Blood Transfusion ,Whole blood ,Hematology ,Microbial Viability ,business.industry ,Platelet-Rich Plasma ,Alloimmunity ,Cell Biology ,Donor Lymphocytes ,Survival Analysis ,Platelet transfusion refractoriness ,Platelet transfusion ,Models, Animal ,Immunization ,business ,Filtration ,030215 immunology - Abstract
Human lymphocyte antigen alloimmunization to filter leukoreduced (F-LR) platelets occurs in about 18% of immunosuppressed thrombocytopenic hematology/oncology patients and represents a significant challenge for effective chemotherapy. In a dog platelet transfusion model, we have evaluated other methods of preventing alloimmune platelet refractoriness and demonstrated that successful methods in our dog model are transferable to man. In the present study, donor/recipient pairs were dog lymphocyte antigen DR-B incompatible (88% of the pairs), and recipient dogs received up to 8 weekly treated transfusions from a single donor (a highly immunogenic stimulus), or until platelet refractoriness. Continued acceptance of F-LR platelets occurred in 6 of 13 recipients (46%), but neither γ-irradiation (γ-I; 0 of 5) nor Mirasol pathogen reduction (MPR; 1 of 7) treatment of donor platelets prevented alloimmune platelet refractoriness. Combining γ-I with F-LR was associated with only 2 of 10 (20%) recipients accepting the transfused platelets. Surprisingly, F-LR platelets that then underwent MPR were accepted by 21 of 22 (95%) recipients (P < .001 vs F-LR + γ-I recipients). Furthermore, 7 of 21 (33%) of these accepting recipients demonstrated specific tolerance to 8 more weekly donor transfusions that had not been treated. In addition, platelet concentrates prepared from F-LR + MPR whole blood were also nonimmunogenic; that is, 10 of 10 (100%) recipients accepted donor platelets. Overall, 31 of 32 (97%) recipients accepted F-LR + MPR platelets; none developed antibodies to donor lymphocytes. These data are the highest rate of acceptance for platelet transfusions reported in either animals or man. This approach to platelet transfusion may be particularly important when supporting patients with intact immune systems, such as in myelodysplastic syndromes.
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- 2016
10. Suppression of the Immune Response to FVIII in Hemophilia A Mice by Transgene Modified Tolerogenic Dendritic Cells
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Jackie Roy, Yvette Latchman, Neil C. Josephson, Angela Epp, Junli Feng, Xiaoping Wu, Doug Bolgiano, and Rui-Jun Su
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Pharmacology ,Factor VIII ,Regulatory T cell ,Transgene ,T cell ,Antigen presentation ,Original Articles ,Dendritic Cells ,Biology ,Hemophilia A ,T-Lymphocytes, Regulatory ,Viral vector ,Mice ,Immune system ,medicine.anatomical_structure ,Immunology ,Drug Discovery ,Splenocyte ,medicine ,Genetics ,Animals ,Molecular Medicine ,Transgenes ,Molecular Biology ,Ex vivo - Abstract
Current methods for eradicating clinically significant inhibitory antibodies to human factor VIII (hFVIII) in patients with hemophilia A rely on repeated delivery of high doses of factor concentrates for a minimum of many months. We hypothesize that tolerance can be induced more efficiently and reliably through hFVIII antigen presentation by tolerogenic dendritic cells (tDCs). In this study, we generated tDCs from hemophilia A mice and modified them with a foamy virus vector expressing a bioengineered hFVIII transgene. Naive and preimmunized mice infused with hFVIII expressing tDCs showed suppression of the T cell and inhibitor responses to recombinant hFVIII (rhFVIII). Treatment with hFVIII expressing tDCs was also associated with a higher percentage of splenocytes demonstrating a regulatory T cell phenotype in immunized mice. Furthermore, CD4(+) T cells harvested from recipients of hFVIII expression vector-modified tDCs were able to mediate antigen-specific immune suppression in naive secondary recipients. We also demonstrated a trend for improved suppression of inhibitor formation by coexpressing interleukin-10 (IL-10) and hFVIII from a bicistronic vector. These preclinical results demonstrate the potential for employing vector modified ex vivo generated tDCs to treat high titer inhibitors in patients with hemophilia A.
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- 2011
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11. The SLAM family member CD48 (Slamf2) protects lupus-prone mice from autoimmune nephritis
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Anna E. Koh, Elahna Paul, Robert B. Colvin, Marianela Feliu, Alexis Cook, Martin K. Selig, Yvette Latchman, Sarah W. Njoroge, and Arlene H. Sharpe
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Mice, Inbred MRL lpr ,Mice, 129 Strain ,Kidney Glomerulus ,Immunology ,Lupus nephritis ,Autoimmunity ,Genes, Recessive ,Antigen-Antibody Complex ,CD48 Antigen ,Biology ,medicine.disease_cause ,Article ,Mice ,Glomerulonephritis ,Antigens, CD ,medicine ,Animals ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Mice, Knockout ,Autoimmune disease ,Mice, Inbred BALB C ,Systemic lupus erythematosus ,Glomerular basement membrane ,Autoantibody ,medicine.disease ,Lupus Nephritis ,Disease Models, Animal ,medicine.anatomical_structure ,Female ,Nephritis - Abstract
Polymorphisms in the SLAM family of leukocyte cell surface regulatory molecules have been associated with lupus-like phenotypes in both humans and mice. The murine Slamf gene cluster lies within the lupus-associated Sle1b region of mouse chromosome 1. Non-autoreactive C57BL/6 (B6) mice that have had this region replaced by syntenic segments from other mouse strains (i.e. 129, NZB and NZW) are B6 congenic strains that spontaneously produce non-nephritogenic lupus-like autoantibodies. We have recently reported that genetic ablation of the SLAM family member CD48 (Slamf2) drives full-blown autoimmune disease with severe proliferative glomerulonephritis (CD48GN) in B6 mice carrying 129 sequences of the Sle1b region (B6.129CD48(-/-)). We also discovered that BALB/c mice with the same 129-derived CD48-null allele (BALB.129CD48(-/-)) have neither nephritis nor anti-DNA autoantibodies, indicating that strain specific background genes modulate the effects of CD48 deficiency. Here we further examine this novel model of lupus nephritis in which CD48 deficiency transforms benign autoreactivity into fatal nephritis. CD48GN is characterized by glomerular hypertrophy with mesangial expansion, proliferation and leukocytic infiltration. Immune complexes deposit in mesangium and in sub-endothelial, sub-epithelial and intramembranous sites along the glomerular basement membrane. Afflicted mice have low-grade proteinuria, intermittent hematuria and their progressive renal injury manifests with elevated urine NGAL levels and with uremia. In contrast to the lupus-like B6.129CD48(-/-) animals, neither BALB.129CD48(-/-) mice nor B6 × BALB/c F1.129CD48(-/-) progeny have autoimmune traits, indicating that B6-specific background genes modulate the effect of CD48 on lupus nephritis in a recessive manner.
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- 2011
12. Targeting NKT cells and PD-L1 pathway results in augmented anti-tumor responses in a melanoma model
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Yvette Latchman, Paul Warner, Kevin Durgan, and Mohamed Ali
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Cancer Research ,Immunology ,CD1 ,Enzyme-Linked Immunosorbent Assay ,Galactosylceramides ,Mice, Transgenic ,Cell Separation ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,Cancer Vaccines ,B7-H1 Antigen ,Article ,Mice ,Interleukin 21 ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,IL-2 receptor ,Antigen-presenting cell ,Melanoma ,Membrane Glycoproteins ,CD40 ,biology ,Dendritic Cells ,Flow Cytometry ,Natural killer T cell ,Adoptive Transfer ,Cell biology ,Mice, Inbred C57BL ,Chemotaxis, Leukocyte ,Disease Models, Animal ,Oncology ,B7-1 Antigen ,biology.protein ,Interleukin 12 ,Cytokines ,Natural Killer T-Cells ,Peptides ,Signal Transduction - Abstract
Invariant or Type 1 NKT cells (iNKT cells) are a unique population of lymphocytes that share characteristics of T cells and natural killer (NK) cells. Various studies have shown that positive costimulatory pathways such as the CD28 and CD40 pathways can influence the expansion and cytokine production by iNKT cells. However, little is understood about the regulation of iNKT cells by negative costimulatory pathways. Here, we show that in vivo activation with α-GalCer results in increased cytokine production and expansion of iNKT cells in the absence of programmed cell death ligand-1 (PD-L1, B7-H1, and CD274). To study whether PD-L1 deficiency on NKT cells would enhance antigen-specific T-cell responses, we utilized CD8(+) OT-1 OVA transgenic T cells. α-GalCer enhanced the expansion and cytokine production of OT-1 CD8(+) cells after adoptive transfer into wild-type recipients. However, this expansion was significantly enhanced when OT-1 CD8(+) T cells were adoptively transferred into PD-L1(-/-) recipients. To extend these results to a tumor model, we used the B16 melanoma system. PD-L1(-/-) mice given dendritic cells loaded with antigen and α-GalCer had a significant reduction in tumor growth and this was associated with increased trafficking of antigen-presenting cells and CD8(+) T cells to the tumors. These data demonstrate that abrogating PDL1:PD-1 interactions during the activation of iNKT cells amplifies an anti-tumor response when coupled with DC vaccination.
- Published
- 2011
13. Suppression of FVIII Inhibitor Formation in Hemophilic Mice by Delivery of Transgene Modified Apoptotic Fibroblasts
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Yvette Latchman, Steven W. Pipe, Rui-Jun Su, Angela Epp, Doug Bolgiano, and Neil C. Josephson
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CD4-Positive T-Lymphocytes ,Adoptive cell transfer ,congenital, hereditary, and neonatal diseases and abnormalities ,T cell ,Transgene ,animal diseases ,Cell- and Tissue-Based Therapy ,Apoptosis ,Spleen ,Hemophilia A ,T-Lymphocytes, Regulatory ,Immune tolerance ,Mice ,Immune system ,Antigen ,hemic and lymphatic diseases ,Drug Discovery ,medicine ,Genetics ,Animals ,IL-2 receptor ,Molecular Biology ,Cells, Cultured ,Mice, Knockout ,Pharmacology ,Factor VIII ,business.industry ,Interleukin-2 Receptor alpha Subunit ,Original Articles ,Fibroblasts ,medicine.anatomical_structure ,Immunology ,Molecular Medicine ,business - Abstract
The development of inhibitory antibodies to factor VIII (FVIII) is currently the most significant complication of FVIII replacement therapy in the management of patients with severe hemophilia A. Immune tolerance protocols for the eradication of inhibitors require daily delivery of intravenous FVIII for at least 6 months and are unsuccessful in 20–40% of treated patients. We hypothesize that tolerance can be induced more efficiently and reliably by delivery of FVIII antigen within autologous apoptotic cells (ACs). In this study, we demonstrated suppression of the T cell and inhibitor responses to FVIII by infusion of FVIII expression vector modified apoptotic syngeneic fibroblasts in both naive and preimmunized hemophilia A mice. ACs without FVIII antigen exerted modest generalized immune suppression mediated by anti-inflammatory signals. However, FVIII expressing apoptotic syngeneic fibroblasts produced much stronger antigen-specific immune suppression. Mice treated with these fibroblasts generated CD4+ T cells that suppressed the immune response to FVIII after adoptive transfer into naive recipients and antigen-specific CD4+CD25+ regulatory T cells (Tregs) that inhibited the proliferation of FVIII responsive effector T cells in vitro. These preclinical results demonstrate the potential for using FVIII vector modified autologous ACs to treat high-titer inhibitors in patients with hemophilia A.
- Published
- 2010
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14. Ly6Clow Monocytes Differentiate into Dendritic Cells and Cross-Tolerize T Cells through PDL-1
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Yvette Latchman, Keith B. Elkon, and YuFeng Peng
- Subjects
Ovalbumin ,T cell ,Cellular differentiation ,Immunology ,CD11c ,Apoptosis ,Mice, Transgenic ,Spleen ,Biology ,B7-H1 Antigen ,Monocytes ,Article ,Immune tolerance ,Immature Monocyte ,Mice ,Mice, Congenic ,Cross-Priming ,Immune system ,T-Lymphocyte Subsets ,Immune Tolerance ,medicine ,Animals ,Antigens, Ly ,Immunology and Allergy ,Mice, Knockout ,Membrane Glycoproteins ,Cell Differentiation ,Dendritic Cells ,Molecular biology ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,B7-1 Antigen ,Peptides - Abstract
Monocyte-derived dendritic cells are active participants during the immune response against infection, but whether they play a role in maintaining self-tolerance under steady-state conditions is not known. Here we investigated the differentiation of monocytes, their ability to ingest apoptotic cells, and their potential functionality in vivo. We observed that Ly6C (Gr-1)low mature monocytes up-regulate their MHC II level in the spleen, express high levels of PDL-1 (programmed death ligand 1), and are more efficient than Ly6Chigh immature monocytes in the ingestion of apoptotic cells in vivo. Sorted circulating Ly6Clow monocytes were able to cross-present both apoptotic cell-associated OVA and soluble OVA protein. Monocytes containing apoptotic cells can further differentiate into CD11c+CD8α−MHC II+ splenic dendritic cells that maintained high expression of PDL-1. Since wild-type but not PDL-1-deficient peripheral blood monocytes containing apoptotic cell-associated OVA suppressed the response to OVA immunization, PDL-1 expression was required for monocyte-mediated T cell tolerance. These observations demonstrate that Ly6Clow mature monocytes can promote tolerance to self Ag contained in apoptotic cells through a PDL-1-dependent mechanism.
- Published
- 2009
15. Further studies to evaluate methods of leucoreduction to prevent alloimmune platelet refractoriness and induce tolerance in a dog platelet transfusion model
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Yvette Latchman, Todd Christoffel, Irena Gettinger, S. Lawrence Bailey, Doug Bolgiano, Sherrill J. Slichter, Esther Pellham, Kraig Abrams, Lakshmi K. Gaur, and Karen Nelson
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Centrifugation ,Histocompatibility Testing ,Buffy coat ,Platelet Transfusion ,030204 cardiovascular system & hematology ,Antibodies ,03 medical and health sciences ,Leukocyte Count ,0302 clinical medicine ,Dogs ,Leukocytes ,Medicine ,Animals ,Platelet ,Platelet refractoriness ,biology ,business.industry ,Platelet-Rich Plasma ,Hematology ,General Medicine ,Flow Cytometry ,Thrombocytopenia ,Chromium Radioisotopes ,Tolerance induction ,Platelet transfusion ,Platelet-rich plasma ,Immunology ,Models, Animal ,biology.protein ,Female ,Antibody ,business ,Filtration ,030215 immunology - Abstract
Objectives Three leucoreduction filters were evaluated – when used alone or combined with centrifuge leucoreduction (C-LR) – to prevent alloimmune platelet refractoriness in a dog platelet transfusion model. Materials and Methods Donor platelet-rich plasma (PRP) or buffy coat (BC) platelets were either filter leucoreduced (F-LR) or F-LR/C-LR, 51Cr radiolabelled and transfused. Weekly transfusions were given for up to 8 weeks or until platelet refractoriness. Recipients who accepted treated transfusions were then given non-leucoreduced (non-LR) platelets to determine whether donor-specific tolerance had been induced. Results Acceptance of F-LR PRP transfusions ranged from 29% to 66%. F-LR/C-LR transfusions prepared from PRP were accepted by 92%, from BC by 63% and from pooled PRP by 75% of recipients (p=NS); overall acceptance rate of F-LR/C-LR transfusions was 83%. Tolerance to subsequent non-LR transfusions occurred in 45% of the F-LR-/C-LR-accepting recipients unrelated to DR-B compatibility between donors and recipients (P = 0·18). Conclusion In a dog platelet transfusion model, acceptance of donor platelets required combining F-LR with C-LR as apparently each process removes different immunizing WBCs.
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- 2015
16. Extended evaluation of a Phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late stage colorectal cancer
- Author
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Joseph P. Balint, Michael A. Morse, Frank R. Jones, Adrian Rice, Yvette Latchman, Arvind Chaudhry, Elizabeth Gabitzsch, Younong Xu, and Gerald L. Messerschmidt
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Adult ,Cytotoxicity, Immunologic ,Male ,Cancer Research ,Colorectal cancer ,medicine.medical_treatment ,T cell ,Immunology ,chemical and pharmacologic phenomena ,Cancer Vaccines ,T-Lymphocytes, Regulatory ,Article ,Adenoviridae ,Interferon-gamma ,Carcinoembryonic antigen ,Immune system ,T-Lymphocyte Subsets ,medicine ,Immunology and Allergy ,Humans ,Neoplasm Metastasis ,Survival analysis ,Cells, Cultured ,Aged ,Neoplasm Staging ,Sequence Deletion ,biology ,business.industry ,Immunogenicity ,Immunotherapy ,Middle Aged ,medicine.disease ,Survival Analysis ,Adenovirus E2 Proteins ,medicine.anatomical_structure ,Oncology ,biology.protein ,Adenovirus E1 Proteins ,Female ,Immunization ,business ,Colorectal Neoplasms ,Oligopeptides ,CD8 ,Follow-Up Studies - Abstract
A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T regulatory (Treg) to T effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMCs), and determination of HLA-A2 status. An overall survival of 20 % (median survival 11 months) was observed during long-term follow-up, and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations, and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA)-specific CMI activity decreased from their peak values during follow-up in five patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post-immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed, and samples from three of five patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations.
- Published
- 2015
17. Tissue expression of PD-L1 mediates peripheral T cell tolerance
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Lee A. Albacker, Arlene H. Sharpe, Yvette Latchman, Maria Koulmanda, Spencer Liang, Indira Guleria, Mary E. Keir, A. Qipo, Gordon J. Freeman, and Mohamed H. Sayegh
- Subjects
Programmed Cell Death 1 Ligand 2 Protein ,T-Lymphocytes ,medicine.medical_treatment ,T cell ,Immunology ,Biology ,Lymphocyte Activation ,Article ,Immune tolerance ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,IL-2 receptor ,Antigen-presenting cell ,030304 developmental biology ,0303 health sciences ,Articles ,Molecular biology ,Cell biology ,Haematopoiesis ,Cytokine ,medicine.anatomical_structure ,030215 immunology - Abstract
Programmed death 1 (PD-1), an inhibitory receptor expressed on activated lymphocytes, regulates tolerance and autoimmunity. PD-1 has two ligands: PD-1 ligand 1 (PD-L1), which is expressed broadly on hematopoietic and parenchymal cells, including pancreatic islet cells; and PD-L2, which is restricted to macrophages and dendritic cells. To investigate whether PD-L1 and PD-L2 have synergistic or unique roles in regulating T cell activation and tolerance, we generated mice lacking PD-L1 and PD-L2 (PD-L1/PD-L2−/− mice) and compared them to mice lacking either PD-L. PD-L1 and PD-L2 have overlapping functions in inhibiting interleukin-2 and interferon-γ production during T cell activation. However, PD-L1 has a unique and critical role in controlling self-reactive T cells in the pancreas. Our studies with bone marrow chimeras demonstrate that PD-L1/PD-L2 expression only on antigen-presenting cells is insufficient to prevent the early onset diabetes that develops in PD-L1/PD-L2−/− non-obese diabetic mice. PD-L1 expression in islets protects against immunopathology after transplantation of syngeneic islets into diabetic recipients. PD-L1 inhibits pathogenic self-reactive CD4+ T cell–mediated tissue destruction and effector cytokine production. These data provide evidence that PD-L1 expression on parenchymal cells rather than hematopoietic cells protects against autoimmune diabetes and point to a novel role for PD-1–PD-L1 interactions in mediating tissue tolerance.
- Published
- 2006
18. Programmed Death-1 (PD-1):PD-Ligand 1 Interactions Inhibit TCR-Mediated Positive Selection of Thymocytes
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Arlene H. Sharpe, Gordon J. Freeman, Mary E. Keir, and Yvette Latchman
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Thymocyte ,Programmed Cell Death 1 Ligand 2 Protein ,Immunology ,T-cell receptor ,Immunology and Allergy ,CD28 ,Biology ,Receptor ,Molecular biology ,B7-H1 Antigen ,CD8 ,Clonal deletion - Abstract
Positive selection during thymocyte development is driven by the affinity and avidity of the TCR for MHC-peptide complexes expressed in the thymus. In this study, we show that programmed death-1 (PD-1), a member of the B7/CD28 family of costimulatory receptors, inhibits TCR-mediated positive selection through PD-1 ligand 1 (PD-L1):PD-1 interactions. Transgenic mice that constitutively overexpress PD-1 on CD4+CD8+ thymocytes display defects in positive selection in vivo. Using an in vitro model system, we find that PD-1 is up-regulated following TCR engagement on CD4+CD8+ murine thymocytes. Coligation of TCR and PD-1 on CD4+CD8+ thymocytes with a novel PD-1 agonistic mAb inhibits the activation of ERK and up-regulation of bcl-2, both of which are downstream mediators essential for positive selection. Inhibitory signals through PD-1 can overcome the ability of positive costimulators, such as CD2 and CD28, to facilitate positive selection. Finally, defects in positive selection that result from PD-1 overexpression in thymocytes resolve upon elimination of PD-L1, but not PD-1 ligand 2, expression. PD-L1-deficient mice have increased numbers of CD4+CD8+ and CD4+ thymocytes, indicating that PD-L1 is involved in normal thymic selection. These data demonstrate that PD-1:PD-L1 interactions are critical to positive selection and play a role in shaping the T cell repertoire.
- Published
- 2005
19. Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses
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Arlene H. Sharpe, Spencer C Liang, Yvette Latchman, Janet E. Buhlmann, Michal Tomczak, Bruce H. Horwitz, and Gordon J. Freeman
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medicine.medical_specialty ,Encephalomyelitis, Autoimmune, Experimental ,Encephalomyelitis ,Programmed Cell Death 1 Receptor ,Immunology ,CHO Cells ,Thymus Gland ,Nod ,Biology ,Transfection ,medicine.disease_cause ,B7-H1 Antigen ,Autoimmune Diseases ,Autoimmunity ,Mice ,Mice, Inbred NOD ,Cricetinae ,PD-L1 ,Internal medicine ,medicine ,Animals ,Immunology and Allergy ,STAT4 ,NOD mice ,Mice, Inbred BALB C ,Membrane Glycoproteins ,Pancreatic islets ,Experimental autoimmune encephalomyelitis ,NF-kappa B ,Blood Proteins ,Germinal Center ,Programmed Cell Death 1 Ligand 2 Protein ,medicine.disease ,Molecular biology ,Up-Regulation ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,Antigens, Surface ,B7-1 Antigen ,Trans-Activators ,biology.protein ,Apoptosis Regulatory Proteins ,Peptides ,STAT6 Transcription Factor ,Spleen - Abstract
Newer members of the B7-CD28 superfamily include the receptor PD-1 and its two ligands, PD-L1 and PD-L2. Here, we characterize the expression of PD-1, PD-L1, and PD-L2 in tissues of naive miceand in target organs from two models of autoimmunity, the pancreas from non-obese diabetic (NOD) mice and brain from mice with experimental autoimmune encephalomyelitis (EAE). In naive mice, proteiexpression of PD-1, PD-L1, and PD-L2 was detected in the thymus, while PD-1 and PD-L1 were detected in the spleen. PD-L1, but not PD-L2, was also detected at low levels on cardiac endothelium, pancreatic islets, and syncyciotrophoblasts in the placenta. In pre-diabetic NOD mice, PD-1 and PD-L1 were expressed on infiltrating cells in the pancreatic islets. Furthermore, PD-L1 was markedly up-regulated on islet cells. In brains from mice with EAE, PD-1, PD-L1, and PD-L2 were expressed on infiltrating inflammatory cells, and PD-L1 was up-regulated on endothelium within EAE brain. The distinct expression patterns of PD-L1 and PD-L2 led us to compare their transcriptional regulation in STAT4(-/-), STAT6(-/-), or NF-kappaB p50(-/-)p65(+/-) dendritic cells (DC).PD-L2, but not PD-L1, expression was dramatically reduced in p50(-/-)p65(+/-) DC. Thus, PD-L1 and PD-L2 exhibit distinct expression patterns and are differentially regulated on the transcriptional level.
- Published
- 2003
20. Negative co-receptors on lymphocytes
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Yvette Latchman, Arlene H. Sharpe, and Rebecca J. Greenwald
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Antigens, Differentiation, T-Lymphocyte ,Immunoconjugates ,T-Lymphocytes ,T cell ,Programmed Cell Death 1 Receptor ,Immunology ,chemical and pharmacologic phenomena ,Biology ,B7-H1 Antigen ,Abatacept ,Inducible T-Cell Co-Stimulator Protein ,Immune system ,CD28 Antigens ,Antigen ,Downregulation and upregulation ,Antigens, CD ,medicine ,Animals ,Humans ,Immunology and Allergy ,CTLA-4 Antigen ,Receptor ,Membrane Glycoproteins ,T-cell receptor ,hemic and immune systems ,Blood Proteins ,Programmed Cell Death 1 Ligand 2 Protein ,Antigens, Differentiation ,Cell biology ,medicine.anatomical_structure ,Antigens, Surface ,B7-1 Antigen ,Intercellular Signaling Peptides and Proteins ,Apoptosis Regulatory Proteins ,Peptides - Abstract
The past year has seen significant advances in our understanding of critical roles of negative immunoregulatory signals delivered through the B7-CD28 superfamily in regulating T cell activation and tolerance. Structural data on CTLA-4 have provided novel insights into the inhibitory functions of CTLA-4. Initial characterization of the PD-1-PD-1-ligand pathway has revealed that this pathway can downregulate TCR- and CD28-mediated signals. Recent studies indicate that ICOS exerts distinct effects at different phases of an immune response: ICOS can inhibit as well as stimulate T cell responses.
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- 2002
21. PD-L2 is a second ligand for PD-1 and inhibits T cell activation
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Irene Chernova, Gordon J. Freeman, Yvette Latchman, Hiroyuki Nishimura, Laura L. Carter, Andrew J. Long, Arlene H. Sharpe, Beatriz M. Carreno, Yoshiko Iwai, Julia A. Brown, Edward A. Greenfield, Madhuri Borde, Nelly Malenkovich, Karen Bourque, Clive Wood, Raquel A. Nunes, Taku Okazaki, Tatyana Chernova, Vassiliki A. Boussiotis, Divya Chaudhary, and Tasuku Honjo
- Subjects
Programmed Cell Death 1 Ligand 2 Protein ,T-Lymphocytes ,T cell ,Molecular Sequence Data ,Programmed Cell Death 1 Receptor ,Immunology ,Receptors, Antigen, T-Cell ,Apoptosis ,CHO Cells ,Biology ,Ligands ,Lymphocyte Activation ,Transfection ,B7-H1 Antigen ,Jurkat Cells ,Mice ,CD28 Antigens ,Antigens, CD ,Cricetinae ,medicine ,Animals ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Amino Acid Sequence ,IL-2 receptor ,Antigen-presenting cell ,Cells, Cultured ,Mice, Inbred BALB C ,Membrane Glycoproteins ,Sequence Homology, Amino Acid ,T-cell receptor ,CD28 ,Blood Proteins ,Cell biology ,medicine.anatomical_structure ,Antigens, Surface ,B7-1 Antigen ,Cytokines ,Intercellular Signaling Peptides and Proteins ,Apoptosis Regulatory Proteins ,Peptides - Abstract
Programmed death I (PD-I)-deficient mice develop a variety of autoimmune-like diseases, which suggests that this immunoinhibitory receptor plays an important role in tolerance. We identify here PD-1 ligand 2 (PD-L2) as a second ligand for PD-1 and compare the function and expression of PD-L1 and PD-L2. Engagement of PD-1 by PD-L2 dramatically inhibits T cell receptor (TCR)-mediated proliferation and cytokine production by CD4+ T cells. At low antigen concentrations, PD-L2-PD-1 interactions inhibit strong B7-CD28 signals. In contrast, at high antigen concentrations, PD-L2-PD-1 interactions reduce cytokine production but do not inhibit T cell proliferation. PD-L-PD-1 interactions lead to cell cycle arrest in G0/G1 but do not increase cell death. In addition, ligation of PD-1 + TCR leads to rapid phosphorylation of SHP-2, as compared to TCR ligation alone. PD-L expression was up-regulated on antigen-presenting cells by interferon gamma treatment and was also present on some normal tissues and tumor cell lines. Taken together, these studies show overlapping functions of PD-L1 and PD-L2 and indicate a key role for the PD-L-PD-1 pathway in regulatingT cell responses.
- Published
- 2001
22. CD48-deficient mice have a pronounced defect in CD4+T cell activation
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Jesús González-Cabrero, Arlene H. Sharpe, Catherine J. Wise, Hans Reiser, Gordon J. Freeman, and Yvette Latchman
- Subjects
CD4-Positive T-Lymphocytes ,CD3 Complex ,Lymphoid Tissue ,T cell ,Thymus Gland ,CD48 Antigen ,Lymphocyte Activation ,Mice ,Interleukin 21 ,Antigens, CD ,medicine ,Animals ,Cytotoxic T cell ,IL-2 receptor ,Cells, Cultured ,Interleukin 3 ,Mice, Knockout ,Multidisciplinary ,CD40 ,biology ,Stem Cells ,ZAP70 ,Homozygote ,Antibodies, Monoclonal ,CD28 ,Biological Sciences ,Molecular biology ,medicine.anatomical_structure ,biology.protein ,Lymph Nodes ,Spleen - Abstract
We have generated mice deficient in the expression of the lymphocyte cell surface antigen CD48 (Blast-1, BCM1, sgp-60) by gene targeting in embryonic stem cells. Mice homozygous for the CD48 mutation (CD48−/−mice) are severely impaired in CD4+T cell activation. Proliferative responses to mitogens, anti-CD3 mAb, and alloantigen are all reduced. Experiments in which T cells and antigen-presenting cells from either wild-type or CD48−/−mice were cocultured reveal that CD48 is important on both T cells and antigen-presenting cells. The most dramatic impairment was observed in experiments in which highly purified T cells were stimulated through the T cell receptor in the presence of the phorbol ester, phorbol 12-myristate 13-acetate. The results of these experiments raise the possibility that CD48 plays a role in signaling through the T cell receptor.
- Published
- 1999
23. Enhanced murine CD4+ T cell responses induced by the CD2 ligand CD48
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Hans Reiser and Yvette Latchman
- Subjects
CD4-Positive T-Lymphocytes ,Cytotoxicity, Immunologic ,T cell ,Immunology ,CD2 Antigens ,CHO Cells ,CD48 Antigen ,Biology ,Ligands ,Lymphocyte Activation ,Transfection ,Mice ,Interleukin 21 ,Antigens, CD ,Cricetinae ,medicine ,Animals ,Immunology and Allergy ,Cytotoxic T cell ,IL-2 receptor ,Antigen-presenting cell ,ZAP70 ,CD28 ,Molecular biology ,Cell biology ,medicine.anatomical_structure ,CD80 ,Signal Transduction - Abstract
The physiological functions of murine CD2 and its ligand CD48 are uncertain. We have examined the role of the CD2-CD48 interaction in murine T cell activation using a series of Chinese hamster ovary (CHO) cell transfectants. CHO cells expressing I-Ad together with CD48 induced more potent activation of OVA-specific, I-Ad -restricted DO11.10-transgenic T cells than CHO cells expressing I-Ad alone. CD48 augmented proliferation and IL-2 production in response to antigen. The enhancing effect of CD48 was of the same magnitude as that seen for CD80 (B7-1). Conjugate assays revealed the ability of CD48 to increase adhesion between T cells and CHO transfectants. The enhancing effects of CD48 on T cell-antigen-presenting cell adhesion and T cell activation were inhibited by anti-CD2 monoclonal antibody. This report provides the first evidence that the CD2 ligand CD48 contributes to the interactions of murine CD4+ T cells with antigen-presenting cells.
- Published
- 1998
24. Cutting Edge: Identification of the 2B4 Molecule as a Counter-Receptor for CD48
- Author
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Yvette Latchman, Paul F. McKay, and Hans Reiser
- Subjects
Immunology ,Immunology and Allergy - Abstract
The CD48 molecule belongs to a subfamily of the Ig superfamily that also includes the CD2, CD58, 2B4, Signaling lymphocyte activation molecule (SLAM), and Ly-9 molecules. Receptor-ligand interactions are known to occur between several members of this family, and these interactions can strengthen cell to cell adhesion. In mice, the CD48 molecule can bind to CD2. To search for additional ligands of murine CD48, we have generated a chimeric fusion protein consisting of the extracellular domain of murine CD48 and the C region of human IgG1. The results of immunofluorescence and immunoprecipitation experiments in which this reagent was used identify the 2B4 molecule as a novel counter-receptor of CD48.
- Published
- 1998
25. Abstract 2363: Combinational therapy with specific immunization plus checkpoint inhibition results in enhanced tumor regression and survival benefit
- Author
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Frank R. Jones, Joseph P. Balint, Adrian Rice, Yvette Latchman, and Elizabeth Gabitzsch
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Survival benefit ,Immunization ,business.industry ,Internal medicine ,Immune checkpoint inhibitors ,medicine ,Tumor regression ,business - Abstract
Effective immunotherapeutic treatment of various cancers may require combinational approaches to induce specific immunity to the tumor as well as inhibition of immune check-points. We have developed a viral gene delivery platform to immunize against numerous tumor associated antigens (TAA) such as carcinoembryonic antigen (CEA), HER2/neu and HPV 16. We investigated the therapeutic benefit of the immunotherapeutics alone and in combination with check-point inhibitors such as programmed death-ligand 1 (PD-1) blockade and LAG3 blockade in murine tumor models. As single agents, immunization with the viral delivery platform encoding the TAA induced target-specific cell-mediated immunity and anti-tumor responses in the respective model. When the immunotherapies were combined with immune checkpoint blockade, an increased level of anti-tumor activity against was observed in addition to an improvement in survival. Tumor microenvironment analysis immunized mice revealed an increase in CD8+ tumor-infiltrating lymphocytes (TILs). In addition, we observed induction of suppressive mechanisms such as programmed death-ligand 1 (PD-L1) expression on tumor cells and an increase in PD-1+ TILs. When immunotherapy was combined with anti-PD-1 antibody, we observed CD8+ TILs at the same increased level but found that a smaller fraction of these were PD-1+. Furthermore, we observed a reduction in PD-L1 expression on tumor cells, providing a mechanism by which combination therapy favors tumor clearance and a rationale for pairing antigen-specific vaccines with checkpoint inhibitors in future clinical trials. Citation Format: Elizabeth Gabitzsch, Adrian Rice, Yvette Latchman, Joseph P. Balint, Frank Jones. Combinational therapy with specific immunization plus checkpoint inhibition results in enhanced tumor regression and survival benefit. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2363.
- Published
- 2016
26. Immunomodulatory Effects of Transfusion
- Author
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Paul Warner, Sherrill J. Slichter, Yvette Latchman, and Karen Nelson
- Subjects
biology ,business.industry ,medicine.medical_treatment ,ELISPOT ,Immunology ,Immunosuppression ,Cell Biology ,Hematology ,Human leukocyte antigen ,Natural killer T cell ,Biochemistry ,Peripheral blood mononuclear cell ,Isoantibodies ,Cytokine ,biology.protein ,Medicine ,Antibody ,business - Abstract
Immunomodulation following transfusion of cellular blood products presents as a generalized immunosuppression and/or production of alloantibody. The immunological effects of transfusion in immunocompetent subjects were evaluated in patients undergoing cardiac surgery with cardio-pulmonary by-pass. Subjects were consented for this IRB-approved study and were randomized to receive unmodified (STD) red blood cells (rbc), leukoreduced (LR) rbc or LR rbc that were g-irradiated (g-I). All platelet transfusions were collected LR and they were also g-I for the third arm. Patients were transfused only when clinically indicated. Subjects receiving no transfusions during the study served as a fourth control arm. Peripheral blood samples collected prior to surgery were controls for samples collected after surgery (day 10 +/- 4 and day 30 +/-5). HLA antibody production was evaluated in 245 subjects using single-antigen multiarray assays for antibody to both HLA class I and class II, a summary of results in shown in Table 1. For subjects with HLA antibody in their pre-surgery sample, these assays allowed evaluation of change in antibody specificity or levels. For these pre-sensitized subjects, there was no significant difference in HLA antibody production between the transfused study arms: even those not transfused showed an increase, most likely due to activation of memory responses. For subjects without HLA antibody in their pre-surgery sample, recipients of LR products showed little increase supporting prior studies showing the efficacy of LR in reducing antibody. However the protection afforded by LR was abrogated by g-I. This was an unexpected finding. We evaluated cellular and cytokine mediators of immunosuppression in the first 139 consecutive subjects of the 245 subjects enrolled in this study. This part of the study was powered for hypothesis generation, not statistical significance. Mononuclear cells (MNC) were isolated from each sample, frozen, and all samples from a subject assayed together. We assayed these cells for production of TGFB1 using ELISPOT. We used flow cytometry phenotyping for markers of CD4+25+ T regulatory cells (CTLA4, FoxP3) and for intracellular cytokines for CD4+ and CD4- NKT cells (IFNG, IL-4, IL-10). As shown in Table 2, recipients of standard rbc showed an increase (following transfusion and surgery) in TGFB1 producing mononuclear cells with a lower increase in recipients of LR rbc and those who were not transfused, but further reduced in the group receiving g-I LR products. Recipients of standard rbc or of LR rbc showed an increase of T lymphocytes expressing FoxP3 or CTLA4, and of CD4+ NKT cells producing IL-4. In contrast, subjects whose LR products were g-I showed a markedly lower increase in all three measures. These data identify an increase in mediators of immunosuppression in recipients of standard rbc and LR rbc that was reduced in recipients of g-I and LR rbc and platelets. Surgery and bypass alone increased the numbers of TGFB1+ MNC and IL4+ NKT cells suggesting a role for the innate immune system in immunosuppression following transfusion. This study is the first to exam the immunomodulatory effects of transfusion by combining measurement of immunosuppression in ex vivo surrogate assays and measurement of HLA antibody production inclusive of pre-sensitized subjects. Our observations of differences in responses to blood products prepared with g-I plus LR compared to LR alone were unexpected and require confirmation. It suggests that the reduction in immunosuppressive cells and cytokines in the recipients of g-I and LR products contributed to the increased allosensitization we observed in that arm compared to recipients of LR products. It may be possible to manipulate immunomodulation after transfusion to reach a desired goal for specific patient populations. Disclosures Slichter: Department of Defense: Research Funding; Terumo BCT: Research Funding; Cerus Corporation: Research Funding; Cellphire, Inc.: Research Funding; Genentech: Research Funding.
- Published
- 2015
27. Auto-antibody production and glomerulonephritis in congenic Slamf1-/- and Slamf2-/- [B6.129] but not in Slamf1-/- and Slamf2-/- [BALB/c.129] mice
- Author
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Ninghai Wang, Silvia Calpe, Arlene H. Sharpe, Cynthia Detre, Carolina V. Arancibia, Massimo Morra, Wilson Castro, Elahna Paul, Vijay K. Vanguri, Marton Keszei, Yvette Latchman, Daniel R. Brown, and Cox Terhorst
- Subjects
Mice, 129 Strain ,Immunology ,Mutant ,Congenic ,Receptors, Cell Surface ,Biology ,medicine.disease_cause ,BALB/c ,Mice ,Mice, Congenic ,Glomerulonephritis ,Signaling Lymphocytic Activation Molecule Family Member 1 ,Antigens, CD ,medicine ,Immunology and Allergy ,Animals ,Humans ,Lupus Erythematosus, Systemic ,Inbreeding ,Gene ,Autoantibodies ,Genetics ,Mice, Knockout ,Mutation ,Systemic lupus erythematosus ,General Medicine ,biology.organism_classification ,medicine.disease ,Molecular biology ,Immunohistochemistry ,Tolerance induction ,Knockout mouse ,Original Research Papers - Abstract
Several genes in an interval of human and mouse chromosome 1 are associated with a predisposition for systemic lupus erythematosus. Congenic mouse strains that contain a 129-derived genomic segment, which is embedded in the B6 genome, develop lupus because of epistatic interactions between the 129-derived and B6 genes, e.g. in B6.129chr1b mice. If a gene that is located on chromosome 1 is altered through homologous recombination in 129-derived embryonic stem cells (ES cells) and if the resultant knockout mouse is backcrossed with B6, interpretation of the phenotype of the mutant mouse may be affected by epistatic interactions between the 129 and B6 genomes. Here, we report that knockout mice of two adjacent chromosome 1 genes, Slamf1(-/-) and Slamf2(-/-), which were generated with the same 129-derived ES cell line, develop features of lupus, if backcrossed on to the B6 genetic background. By contrast, Slamf1(-/-) [BALB/c.129] and Slamf2(-/-) [BALB/c.129] do not develop disease. Surprisingly, Slamf1(-/-) [B6.129] mice develop both auto-antibodies and glomerulonephritis between 3 and 6 months of age, while disease fully develops in Slamf1(-/-) [B6.129] mice after 9-14 months. Functional analyses of CD4(+) T cells reveals that Slamf2(-/-) T cells are resistant to tolerance induction in vivo. We conclude that the Slamf2(-/-) mutation may have a unique influence on T-cell tolerance and lupus.
- Published
- 2011
28. PD-L1/PD-1 signal deficiency promotes allogeneic immune responses and accelerates heart allograft rejection
- Author
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James D. Perkins, Jorge D. Reyes, Weigang Wang, Frances R. Malone, Wei Li, Yaowen Fu, Katie Carper, and Yvette Latchman
- Subjects
CD4-Positive T-Lymphocytes ,Graft Rejection ,Time Factors ,medicine.medical_treatment ,T-Lymphocytes ,Programmed Cell Death 1 Receptor ,Enzyme-Linked Immunosorbent Assay ,CD8-Positive T-Lymphocytes ,Major histocompatibility complex ,Lymphocyte Activation ,B7-H1 Antigen ,Major Histocompatibility Complex ,Mice ,Immune system ,Antigen ,PD-L1 ,medicine ,Cytotoxic T cell ,Animals ,Transplantation, Homologous ,Heart transplantation ,Mice, Knockout ,Transplantation ,Mice, Inbred BALB C ,Mice, Inbred C3H ,Membrane Glycoproteins ,biology ,business.industry ,Peripheral tolerance ,Antigens, Differentiation ,Killer Cells, Natural ,Mice, Inbred C57BL ,Immunology ,biology.protein ,B7-1 Antigen ,Heart Transplantation ,Lymphocyte Culture Test, Mixed ,business ,Peptides ,Spleen - Abstract
Background PD-L1, a ligand for programmed death 1 (PD-1), delivers a negative costimulatory signal to T cells and plays a critical role in the regulation of peripheral tolerance. Methods We used PD-L1(-/-) mice to evaluate the role of the PD-L1 signal on allogeneic immune responses in vivo and the underlying mechanisms. Heart transplantation was performed from PD-L1(-/-) donors or recipients in major histocompatibility complex fully mismatched mouse combinations. The immunologic function of allograft recipients was evaluated ex vivo by enzyme-linked immunospot, mixed lymphocytes reaction, cytotoxic T lymphocyte, and flow cytometry. Results Our results demonstrated that PD-L1(-/-) T cells proliferated vigorously under alloantigen stimulation, and also that the antigen-presenting cells (APCs) from PD-L1(-/-) mice exhibited a stronger allostimulatory activity compared with that in wild-type mice. Heart allografts were rejected at an accelerated rate in both PD-L1(-/-) donors and recipients. This was associated with significantly augmented donor specific T-cell proliferation and antidonor cytotoxic T lymphocyte activities, and enhanced Th1- or Th2-type immune responses of heart allograft recipients. Conclusions Absence of PD-L1 input triggers a stimulatory signal to effector T cells and APCs, accelerating heart allograft rejection. Engagement of the PD-L1 signal on T cells or APCs may be necessary to induce transplant tolerance.
- Published
- 2008
29. Distinct changes in adult lymphopoiesis in Rag2-/- mice fully reconstituted by alpha4-deficient adult bone marrow cells
- Author
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Greg V. Priestley, Yi Jiang, Ena Ray Banerjee, Yvette Latchman, and Thalia Papayannopoulou
- Subjects
Cancer Research ,Integrin alpha4 ,T-Lymphocytes ,Thymus Gland ,Biology ,Article ,Mice ,Immune system ,Genetic model ,Genetics ,medicine ,Animals ,Lymphopoiesis ,Progenitor cell ,Molecular Biology ,Bone Marrow Transplantation ,Mice, Knockout ,B-Lymphocytes ,Cell Biology ,Hematology ,Immunohistochemistry ,Transplantation ,DNA-Binding Proteins ,medicine.anatomical_structure ,Radiation Chimera ,Immunology ,biology.protein ,Bone marrow ,Antibody ,Gene Deletion ,Spleen ,Homing (hematopoietic) - Abstract
alpha4 Integrins are major players in lymphoid cell trafficking and immune responses. However, their importance in lymphoid reconstitution and function, studied by antibody blockade or in genetic models of chimeric animals with alpha4(KO) embryonic stem (ES) cells, competitive repopulation experiments with fetal liver(KO) cells, or in beta1/beta7 doubly-deficient mice has yielded disparate conclusions.To study the role of alpha4 integrin (alpha4beta1, alpha4beta7) during adult life, we transplanted lethally irradiated Rag2(-/-) mice with alpha4(Delta/Delta) or alpha4(f/f) adult bone marrow (BM) cells and evaluated recipients at several points after transplantation.Lymphomyeloid repopulation (8 months later) was entirely donor-derived in all recipients, and novel insights regarding lymphoid reconstitution and function were revealed. Thymic repopulation was impaired in all alpha4(Delta/Delta) recipients, likely because of homing defects of BM-derived progenitors, although a role of alpha4 integrin in intrathymic expansion/maturation of T cells cannot be excluded; reconstitution of gut lymphoid tissue was also greatly diminished because of homing defects of alpha4(Delta/Delta) cells; impaired immunoglobulin (Ig) M and IgE, but normal IgG responses were seen, suggesting compromised initial B-/T-cell interactions, whereas interferon-gamma production from ovalbumin-stimulated cells was increased, possibly reflecting a bias against Th2 stimulation.These data complement previous observations by defending the role of alpha4 integrin in thymic and gut lymphoid tissue homing, and by strengthening evidence of attenuated B-cell responses in alpha4-deficient mice.
- Published
- 2008
30. Requirement of homotypic NK-cell interactions through 2B4(CD244)/CD48 in the generation of NK effector functions
- Author
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Kyung Mi Lee, Sumalatha Kuppireddi, Hideo Yagita, John P. Forman, Arlene H. Sharpe, Mohamed H. Sayegh, Susan E. Stepp, Christoph Wülfing, Seog Bae Oh, Chul-Kyu Park, Vinay Kumar, John D. Schatzle, Yvette Latchman, Megan E. McNerney, Porunelloor A. Mathew, and Dustin Guzior
- Subjects
Interleukin 2 ,Immunology ,CD2 Antigens ,Biology ,CD48 Antigen ,Lymphocyte Activation ,Biochemistry ,Natural killer cell ,Interleukin 21 ,Interferon-gamma ,Mice ,Antigens, CD ,Signaling Lymphocytic Activation Molecule Family ,Neoplasms ,medicine ,Animals ,Interferon gamma ,Calcium Signaling ,Receptors, Immunologic ,Immunobiology ,Mice, Knockout ,Lymphokine-activated killer cell ,Membrane Glycoproteins ,Janus kinase 3 ,Cell Biology ,Hematology ,CD48 ,Cell biology ,Killer Cells, Natural ,medicine.anatomical_structure ,Interleukin 12 ,Interleukin-2 ,medicine.drug - Abstract
2B4 belongs to the CD2 subset of the IgG family of receptors. Members in this family have been shown to function as coreceptors via homophilic or heterophilic interactions. Both 2B4 and CD2 bind to CD48, another member of this family. Because all 3 molecules are expressed on natural killer (NK) cells, it raises a possibility that the binding of 2B4 and CD2 to CD48 among NK cells may have functional consequences. Using specific monoclonal antibodies and gene-deficient NK cells, we found that 2B4/CD48, but not CD2/CD48, interaction is essential for IL-2-driven expansion and activation of murine NK cells. In the absence of 2B4/CD48 interaction, NK cytotoxicity and IFN-gamma secretion on tumor target exposure is severely impaired. Impaired activation of NK cells in 2B4-deficient mice was also demonstrated by poor NK-mediated clearance of syngeneic tumor cells in these mice. Functional impairment of NK cells in the absence of 2B4/CD48 interactions was accompanied by defective calcium signaling, suggesting that the early signaling pathway of NK receptors is inhibited. Finally, homotypic interactions among NK cells through 2B4/CD48 was visualized by specific localization of GFP-tagged 2B4 onto NK-NK conjugation sites. Thus, these data identify a novel mechanism whereby NK effector function is regulated via homotypic 2B4/CD48 interactions.
- Published
- 2006
31. PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis
- Author
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Rebecca J. Greenwald, Yvette Latchman, Abhay R. Satoskar, Spencer C Liang, Gordon J. Freeman, Arlene H. Sharpe, and Lucia E. Rosas
- Subjects
Transgene ,Immunology ,Leishmania mexicana ,Leishmaniasis, Cutaneous ,Enzyme-Linked Immunosorbent Assay ,Mice, Transgenic ,Biology ,B7-H1 Antigen ,Mice ,Immune system ,Th2 Cells ,Cutaneous leishmaniasis ,Immunity ,PD-L1 ,parasitic diseases ,medicine ,Immunology and Allergy ,Animals ,Membrane Glycoproteins ,Cell Differentiation ,Th1 Cells ,Leishmania ,biology.organism_classification ,medicine.disease ,Programmed Cell Death 1 Ligand 2 Protein ,Blotting, Southern ,Immunoglobulin M ,Immunoglobulin G ,biology.protein ,B7-1 Antigen ,Female ,Peptides - Abstract
To compare the roles of programmed death 1 ligand 1 (PD-L1) and PD-L2 in regulating immunity to infection, we investigated responses of mice lacking PD-L1 or PD-L2 to infection with Leishmania mexicana. PD-L1(-/-) and PD-L2(-/-) mice exhibited distinct disease outcomes following infection with L. mexicana. In comparison to susceptible WT mice, PD-L1(-/-) mice showed resistance to L. mexicana, as demonstrated by reduced growth of cutaneous lesions and parasite burden. In contrast, PD-L2(-/-) mice developed exacerbated disease with increased parasite burden. Host resistance to L. mexicana is partly associated with the development of a Th1 response and down-regulation of the Th2 response. Both PD-L1(-/-) and PD-L2(-/-) mice produced levels of IFN-gamma similar to WT mice. However, the development of IL-4-producing cells was reduced in PD-L1(-/-) mice, demonstrating a role for PD-L1 in regulating Th cell differentiation. This inadequate Th2 response may explain the increased resistance of PD-L1(-/-) mice. Although no alterations in Th1/Th2 skewing were observed in PD-L2(-/-) mice, PD-L2(-/-) mice exhibited a marked increase in L. mexicana-specific antibody production. Increased Leishmania-specific IgG production may suppress the healing response through FcgammaR ligation on macrophages. Taken together, our results demonstrate that PD-L1 and PD-L2 have distinct roles in regulating the immune response to L. mexicana.
- Published
- 2005
32. CD48 controls T-cell and antigen-presenting cell functions in experimental colitis
- Author
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Atul K. Bhan, Arlene H. Sharpe, Hideo Yagita, Aimée Julien, Honbing Ji, William A. Faubion, Yvette Latchman, Ana C. Abadía–Molina, and Cox Terhorst
- Subjects
Adoptive cell transfer ,T cell ,T-Lymphocytes ,Antigen-Presenting Cells ,Biology ,CD48 Antigen ,Mice ,Antigen ,Antigens, CD ,medicine ,Animals ,Colitis ,Antigen-presenting cell ,Crosses, Genetic ,Mice, Knockout ,Mice, Inbred BALB C ,Hepatology ,Gastroenterology ,CD48 ,medicine.disease ,Molecular biology ,Disease Models, Animal ,medicine.anatomical_structure ,Immunology ,Interleukin 12 ,Mice, Inbred CBA ,Tumor necrosis factor alpha - Abstract
The cell-surface receptor CD48 is a lipid-anchored protein expressed on all antigen-presenting cells and T cells. CD2 and 2B4 are known ligands for CD48, which themselves are expressed on the surface of hematopoietic cells. Here we examine the effect of CD48 in the development of chronic experimental colitis and how CD48 affects adaptive and innate immune functions.The role of CD48 in experimental colitis was first assessed by transferring CD4(+)CD45RB(hi) cells isolated from either wild-type or CD48(-/-) mice into either Rag-2(-/-) or CD48(-/-) x Rag-2(-/-) mice. Development of chronic colitis in these adoptively transferred mice was assessed by disease activity index, histology, and production of interferon-gamma in mesenteric lymph nodes. Relevant functions of CD48(-/-)CD4(+) T cells and CD48(-/-) macrophages were examined using in vitro assays. In a second set of experiments, the efficacy of anti-CD48 in prevention or treatment of chronic colitis was determined.CD48(-/-)CD4(+) cells induced colitis when transferred into Rag-2(-/-) mice, but not when introduced into CD48(-/-) x Rag-2(-/-) recipients. However, both recipient mouse strains developed colitis upon adoptive transfer of wild-type CD4(+) cells. Consistent with a CD4(+) T-cell defect was the observation that in vitro proliferation of CD48(-/-)CD4(+) T cells was impaired upon stimulation with CD48(-/-) macrophages. In vitro evidence for a modest macrophage functional defect was apparent because CD48(-/-) macrophages produced less tumor necrosis factor alpha and interleukin 12 than wild-type cells upon stimulation with lipopolysaccharide. Peritoneal macrophages also showed a defect in clearance of gram-negative bacteria in vitro. Treatment of the CD4(+)CD45RB(hi)--Rag-2(-/-) mice or the wild-type BM--tg26 mice with anti-CD48 (HM48-1) ameliorated development of colitis, even after its induction.Both CD48-dependent activation of macrophages and CD48-controlled activation of T cells contribute to maintaining the inflammatory response. Consequently, T cell-induced experimental colitis is ameliorated only when CD48 is absent from both T cells and antigen-presenting cells. Because anti-CD48 interferes with these processes, anti-human CD48 antibody treatment may represent a novel therapy for inflammatory bowel disease patients.
- Published
- 2005
33. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells
- Author
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Raymond A. Sobel, Vijay K. Kuchroo, Arlene H. Sharpe, Gordon J. Freeman, Spencer Liang, Yvette Latchman, Martina Klemm, Yin Wu, and Tatyana Chernova
- Subjects
CD4-Positive T-Lymphocytes ,Encephalomyelitis, Autoimmune, Experimental ,T cell ,Antigen-Presenting Cells ,Biology ,CD8-Positive T-Lymphocytes ,Lymphocyte Activation ,B7-H1 Antigen ,Interleukin 21 ,Mice ,medicine ,Immune Tolerance ,Cytotoxic T cell ,Animals ,IL-2 receptor ,Antigen-presenting cell ,Mice, Knockout ,Multidisciplinary ,Membrane Glycoproteins ,ZAP70 ,CD28 ,Blood Proteins ,Biological Sciences ,Natural killer T cell ,Molecular biology ,Adoptive Transfer ,medicine.anatomical_structure ,Phenotype ,Immunology ,B7-1 Antigen ,Immunization ,Peptides - Abstract
Both positive and negative regulatory roles have been suggested for the B7 family member PD-L1(B7-H1). PD-L1 is expressed on antigen-presenting cells (APCs), activated T cells, and a variety of tissues, but the functional significance of PD-L1 on each cell type is not yet clear. To dissect the functions of PD-L1 in vivo , we generated PD-L1-deficient (PD-L1 –/– ) mice. CD4 + and CD8 + T cell responses were markedly enhanced in PD-L1 –/– mice compared with wild-type mice in vitro and in vivo . PD-L1 –/– dendritic cells stimulated greater wild-type CD4 + T cell responses than wild-type dendritic cells, and PD-L1 –/– CD4 + T cells produced more cytokines than wild-type CD4 + T cells in vitro , demonstrating an inhibitory role for PD-L1 on APCs and T cells. In vivo CD8 + T cell responses also were significantly enhanced, indicating that PD-L1 has a role in limiting the expansion or survival of CD8 + T cells. Studies using the myelin oligodendrocyte model of experimental autoimmune encephalomyelitis showed that PD-L1 on T cells and in host tissues limits responses of self-reactive CD4 + T cells in vivo . PD-L1 deficiency converted the 129S4/SvJae strain from a resistant to experimental autoimmune encephalomyelitis-susceptible strain. Transfer of encephalitogenic T cells from wild-type mice into PD-L1 –/– recipients led to exacerbated disease. Disease was even more severe in PD-L1 –/– recipients of PD-L1 –/– T cells. These results demonstrate that PD-L1 on T cells, APCs, and host tissue inhibits naïve and effector T cell responses and plays a critical role in T cell tolerance.
- Published
- 2004
34. PD-L1 Signal on Liver Dendritic Cells Is Critical for Foxp3+CD4+CD25+ Treg and Liver Tolerance Induction
- Author
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Hongyu Liu, R. Bakthavatsala, Z. Meng, James D. Perkins, Wei Li, Yvette Latchman, and Jorge Reyes
- Subjects
Transplantation ,Tolerance induction ,Cd4 cd25 ,biology ,Chemistry ,PD-L1 ,biology.protein ,Cancer research ,FOXP3 ,Signal on - Published
- 2012
35. Prevention of Alloimmune Platelet (Plt) Refractoriness In a Dog Model Requires Both Removal and Inactivation of Contaminating Donor White Blood Cells (WBCs)
- Author
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Esther Pellham, Yvette Latchman, Sherrill J. Slichter, Todd Christoffel, Lakshmi K. Gaur, Karen Nelson, S. Lawrence Bailey, and Doug Bolgiano
- Subjects
medicine.medical_specialty ,Refractory period ,business.industry ,Immunology ,Alloimmunity ,Urology ,Pathogen reduction ,Cell Biology ,Hematology ,Biochemistry ,Dog model ,Combined approach ,Ultraviolet B radiation ,Leukoreduction ,Medicine ,Platelet ,business - Abstract
Abstract 3343 Background: The TRAP Trial (NEJM 1997;337:1861) evaluated filtration leukocyte-reduction (F-LR) and UV-B irradiation (UV-BI) to prevent plt alloimmunization in AML patients (pts) receiving chemotherapy. Inclusion of UV-BI was based on a 45% rate of preventing plt alloimmunization in our dog plt tx model. UV-BI was 79% successful in the TRAP Trial. The lower success rate in the dog was probably because we use normal immunocompetent recipient dogs versus chemotherapy-induced immunosuppressed pts. The residual rate of alloimmunization in the TRAP Trial using either F-LR or UV-BI was still 17% to 21%, suggesting that better prevention methods are needed. Methods: In our dog plt tx model, we evaluated two leukoreduction filters to remove antigen presenting WBCs (APCs) and γ-irradiation (γ-I) or UV-I combined with riboflavin (Mirasol pathogen reduction technology) to inactivate APCs. Crossmatch-negative, DLA-DRB incompatible donor/recipient pairs were used. Txs from the same donor were given weekly for up to 8 weeks or until the donor's 51Cr-labeled plts were rejected based on two sequential txs with donor plt recoveries ≤5% at 20 hours post-tx. Results: Residual WBC counts for standard, γ-l, or Mirasol-treated plts averaged 2,860/μl ± 1,800/μl, and, for F-LR plts using the PL1-B or the PLS-5A filter, they were 80/μl ± 10/μl and 110/μl ± 270/μl, respectively. Residual WBCs were significantly reduced after F-LR compared to non-leukoreduced plts (p Conclusions: Except for the results with the PLS-5A filter, a single modification of the donor dog's plts is only minimally successful. Although residual WBC counts were similar for both filters, the better results achieved with the PLS-5A filter compared to the PL1-B filter (66% versus 20% success rate, respectively) suggest that the types of WBCs removed may be as important as simply a quantitative reduction in WBCs. Unfortunately, adding γ-l to F-LR did not improve the results using either filter. In contrast, Mirasol treatment markedly improved the results with both filters, suggesting that the effects of F-LR and Mirasol treatment are synergistic with F-LR removing APCs, while Mirasol treatment inactivates residual APCs. The effect is particularly striking for the PL1-B filter that is only minimally effective when used alone. The fact that a combined F-LR Mirasol treatment approach is so successful in our immunocompetent dog model using both good and poor performing filters may suggest two things: 1) the combined approach will be equally successful in both immunosuppressed as well as non-immunosuppressed pts; and 2) using any available leukoreduction filter combined with Mirasol treatment will give results similar to the two filters already tested. Based on our prior experience with UV-BI, data from our dog model may be directly transferable to man. Disclosures: Slichter: CaridianBCT Biotechnologies, LLC; Lakewood, CO: Research Funding; US Army Medical Research and Materiel Command/Dept of the Army – USAMRAA: Research Funding.
- Published
- 2010
36. CD48 Deficiency Precipitates Autoimmune Glomerulonephritis in Lupus Prone Mice
- Author
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Marianela Feliu, Elahna Paul, Anna Koh, Arlene H. Sharpe, Yvette Latchman, Andrew Kirby, Robert B. Colvin, Mark J. Daly, and Sarah W. Njoroge
- Subjects
Systemic lupus erythematosus ,business.industry ,Immunology ,Immunology and Allergy ,Medicine ,Glomerulonephritis ,CD48 ,business ,medicine.disease - Published
- 2010
37. Absence of α4 but not β2 integrins restrains development of chronic allergic asthma using mouse genetic models
- Author
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Yi Jiang, Ena Ray Banerjee, William R. Henderson, Thalia Papayannopoulou, and Yvette Latchman
- Subjects
Cancer Research ,Leukocyte migration ,Ovalbumin ,Integrin ,Inflammation ,Article ,Extracellular matrix ,Mice ,Transforming Growth Factor beta ,Genetic model ,Genetics ,medicine ,Animals ,Lung ,Molecular Biology ,Asthma ,Mice, Knockout ,Models, Genetic ,biology ,business.industry ,Integrin beta4 ,Cell Biology ,Hematology ,Transforming growth factor beta ,respiratory system ,medicine.disease ,Respiratory Function Tests ,respiratory tract diseases ,Chemotaxis, Leukocyte ,Phenotype ,CD18 Antigens ,Chronic Disease ,Immunology ,biology.protein ,Collagen ,medicine.symptom ,business ,Transforming growth factor - Abstract
Chronic asthma is characterized by ongoing recruitment of inflammatory cells and airway hyperresponsiveness leading to structural airway remodeling. Although alpha 4 beta 1 and beta2 integrins regulate leukocyte migration in inflammatory diseases and play decisive roles in acute asthma, their role has not been explored under the chronic asthma setting. To extend our earlier studies with alpha 4(Delta/Delta) and beta2(-/-) mice, which showed that both alpha 4 and beta2 integrins have nonredundant regulatory roles in acute ovalbumin (OVA)-induced asthma, we explored to what extent these molecular pathways control development of structural airway remodeling in chronic asthma.Control, alpha 4(Delta/Delta), and beta2(-/-) mouse groups, sensitized by intraperitoneal OVA as allergen, received intratracheal OVA periodically over days 8 to 55 to induce a chronic asthma phenotype. Post-OVA assessment of inflammation and pulmonary function (airway hyperresponsiveness), together with airway modeling measured by goblet cell metaplasia, collagen content of lung, and transforming growth factor beta1 expression in lung homogenates, were evaluated.In contrast to control and beta2(-/-) mice, alpha 4(Delta/Delta) mice failed to develop and maintain the composite chronic asthma phenotype evaluated as mentioned and subepithelial collagen content was comparable to baseline. These data indicate that beta2 integrins, although required for inflammatory migration in acute asthma, are dispensable for structural remodeling in chronic asthma.alpha 4 integrins appear to have a regulatory role in directing transforming growth factor beta-induced collagen deposition and structural alterations in lung architecture likely through interactions of Th2 cells, eosinophils, or mast cells with endothelium, resident airway cells, and/or extracellular matrix.
- Published
- 2009
38. Suppression of the Immune Responses to Factor VIII in the Hemophilia A Mice by Delivery of Transgene Modified Apoptotic Syngeneic Fibroblasts (89.36)
- Author
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Rui-Jun Su, Angela Epp, Yvette Latchman, and Neil Josephson
- Subjects
Immunology ,Immunology and Allergy - Abstract
The development of anti-FVIII inhibitory antibodies is a major obstacle to treatment of hemophilia A patients. Here, we employ the immunosuppressive properties of FVIII gene modified apoptotic syngeneic fibroblasts to reduce immune response to FVIII in hemophilic mice. We generated a fibroblast cell line from the 129Sv-FVIII KO mouse that expresses both FVIII and zeocin resistance gene. A cell line expressing only the zeocin resistance gene was also generated. Both vector modified cell lines were maintained under selective pressure and induced to apoptose just prior to infusion into 129Sv-FVIII KO mice. Mice treated with 2 intravenous infusions of FVIII expressing apoptotic fibroblasts showed up to a 79.5% reduction in Bethesda titers and significantly lower T cell responses after subsequent challenge with 4 doses of rhFVIII. Moreover, hemophilic mice pre-immunized with rhFVIII showed a 65% reduction in Bethesda titers following treatment with 4 infusions of FVIII expressing apoptotic cells. To investigate the antigen specificity of the induced immunosuppression, apoptotic fibroblast treated mice were challenged with an unrelated protein OVA. The immune response to OVA was not affected by the infusion of apoptotic cells. In adoptive transfer studies, a blunted immune response to rhFVIII could be induced in naïve mice by infusion of CD4+ splenocytes from FVIII expressing apoptotic cell treated animals. Moreover, in vitro Treg suppression assays showed that CD4+CD25+ regulatory T cells from FVIII expressing apoptotic cell treated mice were capable of inhibiting the T cell response to rhFVIII, but not to OVA. These data demonstrate that the CD4+CD25+ regulatory T cells in these mice direct antigen specific immune suppression to human FVIII.
- Published
- 2009
39. The PD-L1 Signal is Important to Liver Dendritic Cells in Induction of Foxp3+CD4+CD25+ Treg and Liver Transplant Tolerance (141.33)
- Author
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Wei Li, Ramasamy Bakthavatsalam, zihui Meng, James D Perkins, Yvette Latchman, and Jorge D Reyes
- Subjects
Immunology ,Immunology and Allergy - Abstract
Our previous studies have demonstrated that Foxp3+CD25+CD4+ regulatory T cells (Treg) play an important role in the induction of murine liver spontaneous transplant tolerance. How Treg are induced and what their mechanisms are in the regulation of liver transplant tolerance remain undefined. Here, we investigated the role of liver dendritic cells (DCs) on the induction of Treg and liver graft tolerance in vivo and in vitro. Fms-like tyrosine kinase 3 ligand (Flt3L) mutation mice, which have severe reduction in all types of DCs, and PD-L1 deficient mice were used to examine the role of liver DCs and the PD-L1 signal in Treg induction and liver transplant tolerance. Our results showed that liver DCs, which expressed a high number of PD-L1 molecules, induced more Foxp3+CD25+CD4+ Treg in vitro compared to spleen DCs. However, DCs from PD-L1 deficient mice failed to expand Foxp3+CD25+CD4+ Treg in vitro. Adoptive transfer of Foxp3+CD25+CD4+ Treg expanded from liver DCs prolonged heart allograft survival significantly more than in the CD4 treated controls. The liver grafts from Flt3L-/- and PD-L1-/- mice were rejected acutely in the C3H recipients. Foxp3+ cells were reduced, but IL-2, IL-10, and IFN-γ producing cells were significantly increased in the liver graft and recipient spleen sections of Flt3L-/- and PD-L1-/- donors. Thus, liver DCs play a critical role in the induction of Treg, which underpin spontaneous acceptance of liver allografts. The function of DCs on Treg induction appears to depend on the PD-L1 signal.
- Published
- 2009
40. THE ROLE OF THE PD-L1 SIGNAL IN THE REGULATION OF ALLOGENEIC IMMUNE RESPONSE
- Author
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Wei Li, K Carper, Jorge Reyes, Frances R. Malone, Yvette Latchman, Weigang Wang, and James D. Perkins
- Subjects
Transplantation ,Immune system ,biology ,business.industry ,PD-L1 ,Immunology ,biology.protein ,Medicine ,business ,Signal - Published
- 2008
41. Reduced levels of a regulatory DC subtype may be linked to the development of spontaneous autoimmune disease in aging CD48 deficient mice
- Author
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Ayala Tamir and Yvette Latchman
- Subjects
Autoimmune disease ,business.industry ,Immunology ,Genetics ,Deficient mouse ,Medicine ,CD48 ,business ,medicine.disease ,Molecular Biology ,Biochemistry ,Biotechnology - Published
- 2008
42. The role of liver NKT cells in the regulation of peripheral immune responses (42.9)
- Author
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Wei Li, Malcom Duthie, Weigang Wang, Katie Carper, Stuart Kahn, Yvette Latchman, Jorge Reyes, and James Perkins
- Subjects
Immunology ,Immunology and Allergy - Abstract
We have previously shown that the liver plays an important role in oral tolerance induction. The liver can transfer tolerance to OVA from OVA fed mice to naïve mice. In this study we employed an oral tolerance model by OVA feeding to further explore the mechanisms underlying the role of the liver in oral tolerance induction. OVA feeding, either high dose or low dose, expanded NKT cells in the liver which expressed higher levels of CD95L and PD-L1, a moderate level of PD-1 on the surface, peaked at the 2nd dose feeding in the high dose group and at the 3rd dose feeding in the low dose group. The Foxp3+CD4+CD25+ T regulatory cells (Treg) showed a slight increase in the livers and spleens in the low-fed group, but increased only in the livers in the high-fed group. OVA feeding inhibited NKT cell linked T cell proliferation in both low and high dose fed livers and spleens. Elispot assay revealed an increase in IL-4 and IFN-γ production in the low-fed mice, but increased IL-10 in the high-fed mice. Moreover, the DTH responses to OVA stimulation were increased markedly in the NKT−/− mice with high dose feeding, but showed no significant change in the PD-L1−/− mice compared to that in WT mice. Our results indicate that the liver NKT cells are important in OVA-induced oral tolerance, particularly in high dose feeding. The function of NKT cell appears to depend on CD95L and CD4+CD25+Treg, but not on the PD-1/PD-L1 pathway. IL-10 appears dominant in high dose feeding, while IL-4 and IFN-γ show importance in low dose feeding.
- Published
- 2007
43. The generation and analysis of a novel combination of recombinant adenovirus vaccines targeting three tumor antigens as an immunotherapeutic
- Author
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Ravi A. Madan, Romaine I. Fernando, Claudia Palena, James L. Gulley, Massimo Fantini, Jeffrey Schlom, Yvette Latchman, James W. Hodge, Christopher R. Heery, Joseph P. Balint, Adrian Rice, Caroline Jochems, Elizabeth Gabitzsch, Justin M. David, Kwong Y. Tsang, Anna R. Kwilas, and Frank R. Jones
- Subjects
Pharmacology ,Cancer Research ,Brachyury ,T cell ,Transgene ,Immunology ,Biology ,Gene delivery ,Virology ,Epitope ,medicine.anatomical_structure ,Immune system ,Oncology ,Antigen ,Poster Presentation ,medicine ,Molecular Medicine ,Immunology and Allergy ,MUC1 - Abstract
We have reported on a novel adenovirus serotype 5 (Ad5) vector gene delivery platform (Ad5 [E1-, E2b-]), in which regions of the early 1 (E1), early 2 (E2b), and early 3 (E3) genes have been deleted. The unique deletions in this platform result in a dramatic decrease in late gene expression, leading to a marked reduction in host immune response to the vector. CEA, MUC1, and brachyury are tumor-associated antigens (TAA) expressed on a wide range of human tumors. Ad5 [E1-, E2b-]–CEA vaccine (ETBX-011) has been employed in clinical studies as an active vaccine to induce immune responses to CEA in metastatic colorectal cancer patients. The Ad5 [E1-, E2b-]–CEA vector encodes the entire CEA sequence modified to express an enhancer T-cell epitope. We report here the development of novel Ad5 [E1-, E2b-]–brachyury and Ad5 [E1-, E2b-]–MUC-1 vaccine constructs. The Ad5 [E1-, E2b-]–brachyury vector was constructed to encode the entire brachyury gene devoid of 25 amino acids involved in DNA binding, and modified to express an enhancer T cell epitope. The Ad5 [E1-, E2b-]–MUC-1 vector was constructed to encode the entire MUC-1 transgene with eight agonist epitopes, including five in the C-terminus. Our results show that these constructs (CEA, MUC1 and brachyury) are capable of activation, as well as generation of antigen specific T cells in vitro, and of inducing antigen-specific T cells in vaccinated mice. We have also demonstrated that the use of a combination of the three vaccines (designated Tri-Ad5) displays little, if any, antigenic competition in in vitro studies of human dendritic cells for antigen-specific T cell activation and generation, or in murine vaccination studies. The studies reported here support the rationale for the application of Tri-Ad5 as a therapeutic modality to induce immune responses to a diverse range of human TAAs for potential clinical studies.
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