17 results on '"Derek A. Wainwright"'
Search Results
2. Tryptophan metabolism in brain tumors — IDO and beyond
- Author
-
Mirco Friedrich, Christiane A. Opitz, Michael Platten, Verena Panitz, and Derek A. Wainwright
- Subjects
0301 basic medicine ,medicine.medical_treatment ,Immunology ,Context (language use) ,Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Cancer immunotherapy ,Glioma ,Tumor Microenvironment ,medicine ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Immunology and Allergy ,Tumor microenvironment ,Brain Neoplasms ,Tryptophan ,medicine.disease ,Metabolic pathway ,030104 developmental biology ,Drug development ,Cancer research ,Immunotherapy ,Intracellular ,030215 immunology - Abstract
Metabolism of the essential amino acid tryptophan is a key metabolic pathway that restricts antitumor immunity and is a drug development target for cancer immunotherapy. Tryptophan metabolism is active in brain tumors including gliomas and promotes a malignant phenotype and contributes to the immunosuppressive tumor microenvironment. In recent years, improved understanding of the regulation and downstream function of tryptophan metabolism has been significantly expanded beyond the initial in vitro observation that the enzyme indoleamine-2,3-dioxygenase 1 (IDO1) promotes the depletion of intracellular tryptophan. Here, we revisit the specific roles of tryptophan metabolites in regulating brain functioning and neuronal integrity as well as in the context of brain tumors. This review summarizes recent developments in identifying key regulators, as well as the cellular and molecular effects of tryptophan metabolism with a particular focus on potential therapeutic targets in glioma.
- Published
- 2021
3. The Impact of Beta Blockers on Survival Outcomes in Patients With Non–small-cell Lung Cancer Treated With Immune Checkpoint Inhibitors
- Author
-
Alex Guzner, Young Kwang Chae, Michael S. Oh, Nisha Mohindra, Victoria M. Villaflor, Derek A. Wainwright, and Amir Behdad
- Subjects
Male ,0301 basic medicine ,Pulmonary and Respiratory Medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.drug_class ,medicine.medical_treatment ,Adrenergic beta-Antagonists ,Adenocarcinoma of Lung ,Article ,03 medical and health sciences ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Internal medicine ,medicine ,Humans ,Lung cancer ,Beta (finance) ,Immune Checkpoint Inhibitors ,Beta blocker ,Aged ,Retrospective Studies ,Proportional hazards model ,business.industry ,Hazard ratio ,Immunotherapy ,Prognosis ,medicine.disease ,Confidence interval ,Blockade ,Survival Rate ,030104 developmental biology ,030220 oncology & carcinogenesis ,Carcinoma, Squamous Cell ,Drug Therapy, Combination ,Female ,business ,Follow-Up Studies - Abstract
Background Beta blockers have been associated with anti-tumorigenic effects, potentially by reducing adrenergic-mediated stress responses. Preclinical studies have additionally shown that beta blockade may enhance the efficacy of cancer immunotherapy. We investigated patients with lung cancer who concomitantly used beta blockers and immune checkpoint inhibitors (ICIs), with the hypothesis that beta blockade would positively impact clinical outcomes. Patients and Methods We retrospectively reviewed the health records of 109 patients who were treated at Northwestern University from January 2014 through August 2018 with ICIs for non–small-cell lung cancer (NSCLC). Comparisons of overall survival and progression-free survival (PFS) were performed using Kaplan-Meier analysis with log-rank test, and a univariate regression analysis was performed with a Cox proportional hazards model. Results Among 109 patients treated with ICIs for NSCLC, 28 of them were concomitantly prescribed beta blockers. Use of beta blockers was associated with increased PFS, with a hazard ratio of 0.58 and 95% confidence interval of 0.36 to 0.93. There was not a significant increase in overall survival among patients who took beta blockers (hazard ratio, 0.66; 95% confidence interval, 0.38-1.17). In a regression model, beta blockers were identified as predictive of PFS, as were non-squamous histology, tumor programmed death-ligand 1 positivity, and lower line of treatment. Conclusions Our data suggests beta blocker use may be associated with improved PFS among patients treated with ICIs for NSCLC. This was a small study, and these findings should be further validated in prospective clinical studies.
- Published
- 2021
4. Identification and Characterization of a Novel Brain-Penetrant Indoleamine 2,3 Dioxygenase 1 Protein Degrader for Glioblastoma
- Author
-
Lakshmi Bollu, Prashant V. Bommi, Paige J. Monsen, Lijie Zhai, Kristen L. Lauing, April Bell, Miri Kim, Erik Ladomersky, Leonidas C. Platanias, Daniela E. Matei, Marcelo G. Bonini, Hidayatullah G. Munshi, Rintaro Hashizume, Jennifer D. Wu, Bin Zhang, C. David James, Peiwen Chen, Masha Kocherginsky, Craig Horbinski, Michael D. Cameron, Arabela A. Grigorescu, Bakhtiar Yamini, Rimas V. Lukas, Gary E. Schiltz, and Derek Alan Wainwright
- Published
- 2022
5. Management of glioblastoma in elderly patients
- Author
-
Katherine B. Peters, Bakhtiar Yamini, Rimas V. Lukas, Steven J. Chmura, Jacob S. Young, and Derek A. Wainwright
- Subjects
Oncology ,Treatment response ,medicine.medical_specialty ,medicine.medical_treatment ,Malignant brain tumor ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Aged ,Aged, 80 and over ,Chemotherapy ,Brain Neoplasms ,urogenital system ,business.industry ,Incidence (epidemiology) ,Optimal treatment ,Disease Management ,medicine.disease ,nervous system diseases ,Surgery ,Radiation therapy ,Clinical trial ,Neurology ,030220 oncology & carcinogenesis ,Neurology (clinical) ,Glioblastoma ,business ,030217 neurology & neurosurgery - Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults over 55 years of age. The median age of diagnosis for patients with GBM is 64 years old, with the incidence of patients between 75 and 85 increasing. The optimal treatment paradigm for elderly GBM patients continues to evolve due to the higher frequency of age-related and/or medical co-morbidities. Geriatric GBM patients have historically been excluded from larger, controlled clinical trials due to their presumed decreased likelihood of a sustained treatment response and/or a prolonged good outcome. Here, we highlight current treatment considerations of elderly GBM patients with respect to surgical, radiotherapeutic and systemic modalities, with considerations for improving future clinical outcomes for this patient population.
- Published
- 2017
6. Non-tumor cell IDO1 predominantly contributes to enzyme activity and response to CTLA-4/PD-L1 inhibition in mouse glioblastoma
- Author
-
Kathleen Swoap, Lijie Zhai, David C. Binder, Galina Gritsina, Derek A. Wainwright, Erik Ladomersky, Kristen L. Lauing, Meijing Wu, Leah K. Billingham, Robert H. McCusker, and Carlos R. Dostal
- Subjects
0301 basic medicine ,Immunology ,Cell ,Biology ,Article ,Mice ,03 medical and health sciences ,Behavioral Neuroscience ,chemistry.chemical_compound ,Glioma ,PD-L1 ,medicine ,Animals ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Kynurenine ,Mice, Knockout ,Brain Neoplasms ,Endocrine and Autonomic Systems ,Brain ,medicine.disease ,Immune checkpoint ,Blockade ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,Mechanism of action ,chemistry ,CTLA-4 ,biology.protein ,medicine.symptom ,Glioblastoma - Abstract
Glioblastoma (GBM) is the most common malignant brain tumor in adults with a median survival of 14.6 months. A contributing factor to GBM aggressiveness is the intratumoral expression of the potently immunosuppressive enzyme, indoleamine 2,3 dioxygenase 1 (IDO1). The enzymatic activity of IDO1 is associated with the conversion of tryptophan into downstream kynurenine (Kyn), which has previously been hypothesized to contribute toward the suppression of tumor immunity. Utilizing the syngeneic, immunocompetent, intracranial GL261 cell GBM model, we previously demonstrated that tumor cell, but not non-tumor cell IDO1, suppresses T cell-mediated brain tumor regression in mice. Paradoxically, we also showed that the survival advantage mediated by immune checkpoint blockade is abrogated by non-tumor cell IDO1 deficiency. Here, we have built on our past observations and confirm the maladaptive role of tumor cell IDO1 in a novel mouse GBM model. We also demonstrate that, non-tumor cells, rather than mouse GBM cells, are the dominant contributor to IDO1-mediated enzyme activity. Finally, we show the novel associations between maximally-effective immune-checkpoint blockade-mediated survival, non-tumor cell IDO1 and intra-GBM Kyn levels. These data suggest for the first time that, GBM cell-mediated immunosuppression is IDO1 enzyme independent, while the survival benefits of immune checkpoint blockade require non-tumor cell IDO1 enzyme activity. Given that current clinical inhibitors vary in their mechanism of action, in terms of targeting IDO1 enzyme activity versus enzyme-independent effects, this work suggests that choosing an appropriate IDO1 pharmacologic will maximize the effectiveness of future immune checkpoint blockade approaches.
- Published
- 2017
7. Advanced age negatively impacts survival in an experimental brain tumor model
- Author
-
Erik Ladomersky, Derek A. Wainwright, Lijie Zhai, C. David James, Meijing Wu, Galina Gritsina, Matthew Genet, and Kristen L. Lauing
- Subjects
Aging ,medicine.medical_treatment ,T cell ,Brain tumor ,Biology ,Article ,Mice ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Immune system ,Cell Line, Tumor ,Glioma ,Gene expression ,medicine ,Animals ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Kynurenine ,Brain Neoplasms ,General Neuroscience ,Tryptophan ,FOXP3 ,Immunosuppression ,medicine.disease ,Survival Analysis ,Phenotype ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Glioblastoma ,030217 neurology & neurosurgery - Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with an average age of 64 years at the time of diagnosis. To study GBM, a number of mouse brain tumor models have been utilized. In these animal models, subjects tend to range from 6 to 12 weeks of age, which is analogous to that of a human teenager. Here, we examined the impact of age on host immunity and the gene expression associated with immune evasion in immunocompetent mice engrafted with syngeneic intracranial GL261. The data indicate that, in mice with brain tumors, youth conveys an advantage to survival. While age did not affect the tumor-infiltrating T cell phenotype or quantity, we discovered that old mice express higher levels of the immunoevasion enzyme, IDO1, which was decreased by the presence of brain tumor. Interestingly, other genes associated with promoting immunosuppression including CTLA-4, PD-L1 and FoxP3, were unaffected by age. These data highlight the possibility that IDO1 contributes to faster GBM outgrowth with advanced age, providing rationale for future investigation into immunotherapeutic targeting in the future.
- Published
- 2016
8. The kynurenine to tryptophan ratio as a prognostic tool for glioblastoma patients enrolling in immunotherapy
- Author
-
Galina Gritsina, Alfred Rademaker, Rimas V. Lukas, Andrew T. Parsa, Lijie Zhai, Derek A. Wainwright, Orin Bloch, Robert H. McCusker, Carlos R. Dostal, Mahua Dey, Kristen L. Lauing, Rajwant Kaur, Jeffrey Raizer, and M. Kelly Nicholas
- Subjects
Male ,Oncology ,medicine.medical_treatment ,chemistry.chemical_compound ,Kynurenine ,Cancer ,Tumor ,Tryptophan ,Immunosuppression ,General Medicine ,Middle Aged ,Prognosis ,Treatment Outcome ,medicine.anatomical_structure ,Neurology ,Female ,Immunotherapy ,Adult ,medicine.medical_specialty ,Clinical Sciences ,Brain tumor ,Glioblastoma multiforme ,Blood–brain barrier ,Article ,Rare Diseases ,Physiology (medical) ,Glioma ,Internal medicine ,Biomarkers, Tumor ,medicine ,Humans ,Diagnostic ,Aged ,Chemotherapy ,Neurology & Neurosurgery ,business.industry ,Neurosciences ,medicine.disease ,Brain Disorders ,Brain Cancer ,Clinical trial ,Metabolism ,chemistry ,Immunology ,Surgery ,Neurology (clinical) ,Glioblastoma ,business ,Biomarkers - Abstract
We hypothesized that peripheral tryptophan (Trp) and/or kynurenine (Kyn) levels would provide prognostic value for physicians planning to enroll glioblastoma multiforme (GBM) patients in immunotherapy. GBM is the most common form of malignant glioma in adults. Despite aggressive surgical resection, irradiation and chemotherapy, patients with GBM have a median survival of only 14.6 months after diagnosis. This poor outcome has led to the search for more effective treatments, including immunotherapy. However, the identification of parameters that proactively stratify GBM patients who have the potential for therapeutic benefit has been challenging. Given recent observations demonstrating high indoleamine 2,3 dioxygenase 1 (IDO1) expression in GBM, the immunosuppressive impact of IDO1-mediated Trp catabolism, as well as active transport of Trp and the IDO1-downstream Trp catabolite, Kyn, across the blood brain barrier, we hypothesized that peripheral blood analysis of this pathway would provide diagnostic utility. When comparing individuals without tumors to GBM patients prior to surgical resection, or at the 48 hour (48 h) and ⩾10 week (10 w+) postoperative time points, Trp levels were significantly decreased (p
- Published
- 2015
9. CD4+ T cell-mediated neuroprotection is independent of T cell-derived BDNF in a mouse facial nerve axotomy model
- Author
-
Virginia M. Sanders, Craig J. Serpe, Nichole A. Mesnard, Derek A. Wainwright, Kathryn J. Jones, Thomas D. Alexander, Junping Xin, and Taylor Beahrs
- Subjects
CD4-Positive T-Lymphocytes ,Cell Survival ,medicine.medical_treatment ,T cell ,Blotting, Western ,Immunology ,Cell Count ,Biology ,Real-Time Polymerase Chain Reaction ,Neuroprotection ,Article ,Flow cytometry ,Mice ,Behavioral Neuroscience ,Neurotrophic factors ,Conditional gene knockout ,medicine ,Animals ,Facial Nerve Injuries ,Mice, Knockout ,Motor Neurons ,Brain-derived neurotrophic factor ,medicine.diagnostic_test ,Endocrine and Autonomic Systems ,Brain-Derived Neurotrophic Factor ,Axotomy ,Flow Cytometry ,Facial nerve ,medicine.anatomical_structure ,nervous system ,RNA ,Female ,Neuroscience - Abstract
The production of neurotrophic factors, such as BDNF, has generally been considered an important mechanism of immune-mediated neuroprotection. However, the ability of T cells to produce BDNF remains controversial.In the present study, we examined mRNA and protein of BDNF using RT-PCR and western blot, respectively, in purified and reactivated CD4(+) T cells. In addition, to determine the role of BDNF derived from CD4(+) T cells, the BDNF gene was specifically deleted in T cells using the Cre-lox mouse model system.Our results indicate that while both mRNA expression and protein secretion of BDNF in reactivated T cells were detected at 24 h, only protein could be detected at 72 h after reactivation. The results suggest a transient up-regulation of BDNF mRNA in reactivated T cells. Furthermore, in contrast to our hypothesis that the BDNF expression is necessary for CD4(+) T cells to mediate neuroprotection, mice with CD4(+) T cells lacking BDNF expression demonstrated a similar level of facial motoneuron survival compared to their littermates that expressed BDNF, and both levels were comparable to wild-type. The results suggest that the deletion of BDNF did not impair CD4(+) T cell-mediated neuroprotection.Collectively, while CD4(+) T cells are a potential source of BDNF after nerve injury, production of BDNF is not necessary for CD4(+) T cells to mediate their neuroprotective effects.
- Published
- 2012
10. Characterization and Immunotherapeutic Implications for a Novel Antibody Targeting Interleukin (IL)-13 Receptor α2
- Author
-
Derek A. Wainwright, Bart Thaci, Yu Han, Maciej S. Lesniak, Irina V. Balyasnikova, Gina Lee, and Elena Solomaha
- Subjects
Glycosylation ,Antibodies, Neoplasm ,medicine.drug_class ,Transplantation, Heterologous ,Antibody Affinity ,Clone (cell biology) ,Mice, Nude ,CHO Cells ,Monoclonal antibody ,complex mixtures ,Biochemistry ,Antibodies, Monoclonal, Murine-Derived ,Mice ,Cricetulus ,Antigen ,Cricetinae ,parasitic diseases ,medicine ,Animals ,Humans ,Receptor ,Molecular Biology ,Mice, Inbred BALB C ,Hybridomas ,biology ,HEK 293 cells ,Cell Biology ,Ligand (biochemistry) ,Molecular biology ,digestive system diseases ,HEK293 Cells ,Monoclonal ,Interleukin-13 Receptor alpha2 Subunit ,biology.protein ,Female ,Antibody ,Glioblastoma ,Neoplasm Transplantation - Abstract
The high affinity interleukin-13 receptor α2 (IL13Rα2) is selectively expressed at a high frequency by glioblastoma multiforme (GBM) as well as several other tumor types. One approach for targeting this tumor-specific receptor utilizes the cognate ligand, IL-13, conjugated to cytotoxic molecules. However, this approach lacks specificity because the lower affinity receptor for IL-13, IL13Rα1, is widely expressed by normal tissues. Here, we aimed to develop and characterize a novel monoclonal antibody (mAb) specific to IL13Rα2 for the therapeutic purpose of targeting IL13Rα2-expressing tumors. Hybridoma cell lines were generated and compared for binding affinities to recombinant human IL13Rα2 (rhIL13Rα2). Clone 47 demonstrated binding to the native conformation of IL13Rα2 and was therefore chosen for further studies. Clone 47 bound specifically and with high affinity (K(D) = 1.39 × 10(-9) M) to rhIL13Rα2 but not to rhIL13Rα1 or murine IL13Rα2. Furthermore, clone 47 specifically recognized wild-type IL13Rα2 expressed on the surface of CHO and HEK cells as well as several glioma cell lines. Competitive binding assays revealed that clone 47 also significantly inhibited the interaction between human soluble IL-13 and IL13Rα2 receptor. Moreover, we found that N-linked glycosylation of IL13Rα2 contributes in part to the interaction of the antibody to IL13Rα2. In vivo, the IL13Rα2 mAb improved the survival of nude mice intracranially implanted with a human U251 glioma xenograft. Collectively, these data warrant further investigation of this novel IL13Rα2 mAb with an emphasis on translational implications for therapeutic use.
- Published
- 2012
11. IL-10 within the CNS is necessary for CD4+ T cells to mediate neuroprotection
- Author
-
Virginia M. Sanders, Kathryn J. Jones, Derek A. Wainwright, Junping Xin, Nichole A. Mesnard, and Craig J. Serpe
- Subjects
CD4-Positive T-Lymphocytes ,Central Nervous System ,medicine.medical_treatment ,T cell ,Interleukin-10 Receptor alpha Subunit ,Immunology ,Central nervous system ,Enzyme-Linked Immunosorbent Assay ,Biology ,Neuroprotection ,Article ,Mice ,Behavioral Neuroscience ,medicine ,Animals ,Facial Nerve Injuries ,Inflammation ,Mice, Knockout ,Motor Neurons ,Neurons ,Immunity, Cellular ,Reverse Transcriptase Polymerase Chain Reaction ,Endocrine and Autonomic Systems ,FOXP3 ,Interleukin-10 Receptor beta Subunit ,Adoptive Transfer ,Facial nerve ,Interleukin-10 ,Mice, Inbred C57BL ,Interleukin 10 ,medicine.anatomical_structure ,Cytokine ,Female ,Axotomy ,Neuroscience - Abstract
We have previously shown that immunodeficient mice exhibit significant facial motoneuron (FMN) loss compared to wild-type (WT) mice after a facial nerve axotomy. Interleukin-10 (IL-10) is known as a regulatory cytokine that plays an important role in maintaining the anti-inflammatory environment within the central nervous system (CNS). IL-10 is produced by a number of different cells, including Th2 cells, and may exert an anti-apoptotic action on neurons directly. In the present study, the role of IL-10 in mediating neuroprotection following a facial nerve axotomy model in Rag2- and IL-10-deficient mice was investigated. Results indicate that IL-10 is neuroprotective, but only in the presence of CD4+ T cells that are not the requisite source of IL-10. In addition, using real-time PCR analysis of laser microdissected brainstem sections, results show that IL-10 mRNA is constitutively expressed in the facial nucleus and that a transient, significant reduction of IL-10 mRNA occurs following axotomy under immunodeficient conditions. Dual labeling immunofluorescence data show, unexpectedly, that the IL-10 receptor (IL-10R) is constitutively expressed by facial motoneurons, but is selectively induced in astrocytes within the facial nucleus after axotomy. Thus, a non-CD4+ T cell source of IL-10 is necessary for modulating both glial and neuronal events that mediate neuroprotection of injured motoneurons, but only with the cooperation of CD4+ T cells, providing an avenue of novel investigation into therapeutic approaches to prevent or reverse motoneuron diseases, such as amyotrophic lateral sclerosis (ALS).
- Published
- 2011
12. Short Hairpin RNA-Mediated Fibronectin Knockdown Delays Tumor Growth in a Mouse Glioma Model
- Author
-
Maciej S. Lesniak, Sadhak Sengupta, Derek A. Wainwright, Enal Hindi, Suvobroto Nandi, and Yu Han
- Subjects
Male ,Cancer Research ,Leupeptins ,Survivin ,Apoptosis ,T-Lymphocytes, Regulatory ,Inhibitor of Apoptosis Proteins ,Immunoenzyme Techniques ,Small hairpin RNA ,Mice ,0302 clinical medicine ,Tumor Cells, Cultured ,Phosphorylation ,RNA, Small Interfering ,0303 health sciences ,Gene knockdown ,biology ,Brain Neoplasms ,Reverse Transcriptase Polymerase Chain Reaction ,Integrin beta1 ,Glioma ,Cell cycle ,Flow Cytometry ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,src-Family Kinases ,030220 oncology & carcinogenesis ,Signal transduction ,Cell Division ,Signal Transduction ,Research Article ,G2 Phase ,STAT3 Transcription Factor ,Blotting, Western ,Cysteine Proteinase Inhibitors ,lcsh:RC254-282 ,03 medical and health sciences ,medicine ,Animals ,Humans ,RNA, Messenger ,Cell Proliferation ,030304 developmental biology ,Cell growth ,medicine.disease ,Fibronectins ,Mice, Inbred C57BL ,Repressor Proteins ,Fibronectin ,Disease Models, Animal ,Tumor progression ,Cancer research ,biology.protein - Abstract
Glioblastoma multiforme is the most common and lethal primary brain tumor. Glioma progression depends on the rapid proliferation of tumor cells accompanied by an acute immunosuppressive environment, facilitated mainly by tumor infiltration of regulatory T cells (Tregs). In this study, we characterize the role of fibronectin, a high-molecular weight extracellular matrix glycoprotein secreted by tumor cells, in controlling glioma progression and in mediating immunosuppression. Fibronectin binds to membrane-spanning integrin receptors and plays an important role in cell signaling, in defining cellular shape, in mobility, and in regulating the cell cycle. We found that inhibition of fibronectin expression in glioma cells, using short hairpin RNA-mediated silencing of gene expression, delayed cell proliferation in vitro. This delayed growth is explained, in part, by the observed reduced expression of integrin β1 fibronectin receptor, which was restored by the inhibition of proteosomal activity. In our analysis of the downstream signaling targets of integrin β1, we demonstrated reduced phosphorylation of Src kinase and STAT-3. We also observed reduced survivin expression that induced a three-fold increased accumulation of fibronectin-knockdown cells in the G2/M phase. In an experimental animal model, the fibronectin knockdown tumors had a mean survival advantage of 23 days over wild-type tumors. Moreover, brain samples of animals bearing fibronectin-knockdown tumors showed delayed Treg recruitment. Collectively, we propose that fibronectin is a key mediator of glioma progression because its inhibition delays both tumor progression and immunosuppression.
- Published
- 2010
13. Bone Marrow Mesenchymal Stem Cells Loaded With an Oncolytic Adenovirus Suppress the Anti-adenoviral Immune Response in the Cotton Rat Model
- Author
-
Cleo E. Rolle, Maciej S. Lesniak, Irina V. Balyasnikova, Ilya V. Ulasov, Atique U. Ahmed, Sadhak Sengupta, Derek A. Wainwright, Matthew A. Tyler, and Yu Han
- Subjects
Male ,Oncolytic adenovirus ,Bone Marrow Cells ,Enzyme-Linked Immunosorbent Assay ,Biology ,Lymphocyte Activation ,medicine.disease_cause ,Adenoviridae ,Interferon-gamma ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,In vivo ,Drug Discovery ,Genetics ,medicine ,Animals ,Humans ,Sigmodontinae ,Virotherapy ,Molecular Biology ,Cells, Cultured ,Cell Proliferation ,030304 developmental biology ,Oncolytic Virotherapy ,Pharmacology ,0303 health sciences ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Rats ,3. Good health ,Oncolytic virus ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Molecular Medicine ,Original Article ,Bone marrow - Abstract
Oncolytic adenoviral virotherapy is an attractive treatment modality for cancer. However, following intratumoral injections, oncolytic viruses fail to efficiently migrate away from the injection site and are rapidly cleared by the immune system. We have previously demonstrated enhanced viral delivery and replicative persistence in vivo using human bone marrow–derived mesenchymal stem cells (MSCs) as delivery vehicles. In this study, we evaluated the immune response to adenovirus (Ad)-loaded MSCs using the semipermissive cotton rat (CR) model. First, we isolated MSCs from CR bone marrow aspirates. Real-time quantitative PCR analysis revealed that CR MSCs supported the replication of Ads in vitro. Moreover, we observed similar levels of suppression of T-cell proliferation in response to mitogenic stimulation, by MSCs alone and virus-loaded MSCs. Additionally, we found that MSCs suppressed the production of interferon-γ (IFN-γ) by activated T cells. In our in vivo model, CR MSCs enhanced the dissemination and persistence of Ad, compared to virus injection alone. Collectively, our data suggest that the use of MSCs as a delivery strategy for oncolytic Ad potentially offers a myriad of benefits, including improved delivery, enhanced dissemination, and increased persistence of viruses via suppression of the antiviral immune response.
- Published
- 2010
14. Toll-like receptor 2 and facial motoneuron survival after facial nerve axotomy
- Author
-
Virginia M. Sanders, Derek A. Wainwright, Kathryn J. Jones, Nichole A. Mesnard, and Junping Xin
- Subjects
Stylomastoid foramen ,Cell Survival ,Facial motor nucleus ,medicine.medical_treatment ,Central nervous system ,Antigens, Differentiation, Myelomonocytic ,Fluorescent Antibody Technique ,Nerve Tissue Proteins ,Biology ,Article ,Mice ,Th2 Cells ,Antigens, CD ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,RNA, Messenger ,Oligonucleotide Array Sequence Analysis ,Mice, Knockout ,Motor Neurons ,Toll-like receptor ,Microglia ,General Neuroscience ,Axotomy ,Facial nerve ,Immunity, Innate ,Toll-Like Receptor 2 ,Up-Regulation ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,Facial Nerve ,TLR2 ,medicine.anatomical_structure ,Astrocytes ,Female ,Neuroscience - Abstract
We have previously demonstrated that CD4(+) Th2 lymphocytes are required to rescue facial motoneuron (FMN) survival after facial nerve axotomy through interaction with peripheral antigen presenting cells, as well as CNS resident microglia. Furthermore, the innate immune molecule, toll-like receptor 2 (TLR2), has been implicated in the development of Th2-type immune responses and can be activated by intracellular components released by dead or dying cells. The role of TLR2 in the FMN response to axotomy was explored in this study, using a model of facial nerve axotomy at the stylomastoid foramen in the mouse, in which blood-brain-barrier (BBB) permeability does not occur. After facial nerve axotomy, TLR2 mRNA was significantly upregulated in the facial motor nucleus and co-immunofluorescence localized TLR2 to CD68(+) microglia, but not GFAP(+) astrocytes. Using TLR2-deficient (TLR2(-/-)) mice, it was determined that TLR2 does not affect FMN survival levels after axotomy. These data contribute to understanding the role of innate immunity after FMN death and may be relevant to motoneuron diseases, such as amyotrophic lateral sclerosis (ALS).
- Published
- 2010
15. Effects of facial nerve axotomy on Th2- and Th1-associated chemokine expression in the facial motor nucleus of wild-type and presymptomatic mSOD1 mice
- Author
-
Virginia M. Sanders, Derek A. Wainwright, Junping Xin, Christine M Politis, Nichole A. Mesnard, and Kathryn J. Jones
- Subjects
Chemokine CCL11 ,Pathology ,medicine.medical_specialty ,Chemokine ,Cell Survival ,Facial motor nucleus ,medicine.medical_treatment ,Immunology ,Mice, Transgenic ,Neuroprotection ,Article ,Mice ,Superoxide Dismutase-1 ,Th2 Cells ,parasitic diseases ,medicine ,Animals ,Humans ,Immunology and Allergy ,CXCL11 ,CCL11 ,Facial Nerve Injuries ,Motor Neurons ,biology ,Microglia ,Superoxide Dismutase ,Amyotrophic Lateral Sclerosis ,Axotomy ,Th1 Cells ,respiratory system ,Facial nerve ,Chemokine CXCL11 ,Nerve Regeneration ,Mice, Inbred C57BL ,Disease Models, Animal ,Facial Nerve ,stomatognathic diseases ,medicine.anatomical_structure ,Neurology ,Astrocytes ,biology.protein ,Female ,Neurology (clinical) ,Chemokines ,Neuroscience - Abstract
We have previously demonstrated a neuroprotective mechanism of facial motoneuron (FMN) survival after facial nerve axotomy that is dependent on CD4(+) Th2 cell interaction with peripheral antigen-presenting cells, as well as CNS resident microglia. To investigate this mechanism, we chose to study the Th2-associated chemokine, CCL11, and Th1-associated chemokine, CXCL11, in wild-type and presymptomatic mSOD1 mice after facial nerve axotomy. In this report, the results indicate that CCL11 is constitutively expressed in the uninjured facial motor nucleus, but CXCL11 is not expressed at all. Facial nerve axotomy induced a shift in CCL11 expression from FMN to astrocytes, whereas CXCL11 was induced in FMN. Differences in the number of CCL11- and CXCL11-expressing cells were observed between WT and mSOD1 mice after facial nerve axotomy.
- Published
- 2009
16. 46. Upregulation of indoleamine 2,3-dioxygenase in brain tumors is associated with decreased survival through a T cell-dependent mechanism
- Author
-
Derek A. Wainwright, Yu Han, Maciej S. Lesniak, Brenda Auffinger, I.B. Balyasnikova, and Atique U. Ahmed
- Subjects
Gene knockdown ,Endocrine and Autonomic Systems ,business.industry ,T cell ,Immunology ,Brain tumor ,FOXP3 ,medicine.disease ,Behavioral Neuroscience ,medicine.anatomical_structure ,Downregulation and upregulation ,Tumor progression ,Glioma ,Cancer research ,medicine ,Indoleamine 2,3-dioxygenase ,business - Abstract
Glioblastoma multiforme (GBM) is a malignant and aggressive primary brain tumor with an average patient survival of 14.6 months following diagnosis. Our laboratory has previously demonstrated that immunosuppressive regulatory T cells (Tregs; CD4+FoxP3+) infiltrate and accumulate in brain tumors, by utilizing mouse models. Importantly, depleting those Tregs is associated with a significant increase in overall survival. To understand the underlying mechanisms that promote Treg recruitment to brain tumors, our laboratory has investigated the enzyme, indoleamine 2,3-dioxygenase 1 (IDO). We have found that the upregulation of IDO in glioma patients (n = 343) is associated with a significantly decreased probability of overall survival (p
- Published
- 2012
17. 156. Thymus-derived rather than tumor-induced regulatory T cells predominate in human and experimental mouse brain tumors
- Author
-
Derek A. Wainwright, Yu Han, Sadhak Sengupta, and Maciej S. Lesniak
- Subjects
Behavioral Neuroscience ,Endocrine and Autonomic Systems ,Immunology ,Cancer research ,Biology - Published
- 2011
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.