10 results on '"Kevin Goudy"'
Search Results
2. Liver gene therapy by lentiviral vectors reverses anti-factor IX pre-existing immunity in haemophilic mice
- Author
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Maria Grazia Roncarolo, Fabio Russo, Mahzad Akbarpour, Andrea Annoni, Alessio Cantore, Patrizia Della Valle, Armando D'Angelo, Sara Bartolaccini, Luigi Naldini, Kevin Goudy, Annoni, A, Cantore, A, Della Valle, P, Goudy, K, Akbarpour, M, Russo, F, Bartolaccini, S, D'Angelo, A, Roncarolo, MARIA GRAZIA, and Naldini, Luigi
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immune tolerance ,Genetic enhancement ,Genetic Vectors ,haemophilia ,Haemophilia ,Hemophilia B ,Antibodies ,Immune tolerance ,Cell Line ,Factor IX ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Immunity ,medicine ,Animals ,Humans ,Haemophilia B ,Research Articles ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,B-Lymphocytes ,biology ,business.industry ,Lentivirus ,Genetic Therapy ,biology.organism_classification ,medicine.disease ,gene therapy ,3. Good health ,Mice, Inbred C57BL ,Liver ,030220 oncology & carcinogenesis ,Immunology ,biology.protein ,Molecular Medicine ,Antibody ,business ,medicine.drug - Abstract
"A major complication of factor replacement therapy for haemophilia is the development of anti-factor neutralizing antibodies (inhibitors). Here we show that liver gene therapy by lentiviral vectors (LVs) expressing factor IX (FIX) strongly reduces pre-existing anti-FIX antibodies and eradicates FIX inhibitors in haemophilia B mice. Concomitantly, plasma FIX levels and clotting activity rose to 50-100% of normal. The treatment was effective in 75% of treated mice. FIX-specific plasma cells (PCs) and memory B cells were reduced, likely because of memory B-cell depletion in response to constant exposure to high doses of FIX. Regulatory T cells displaying FIX-specific suppressive capacity were induced in gene therapy treated mice and controlled FIX-specific T helper cells. Gene therapy proved safer than a regimen mimicking immune tolerance induction (ITI) by repeated high-dose FIX protein administration, which induced severe anaphylactoid reactions in inhibitors-positive haemophilia B mice. Liver gene therapy can thus reverse pre-existing immunity, induce active tolerance to FIX and establish sustained FIX activity at therapeutic levels. These data position gene therapy as an attractive treatment option for inhibitors-positive haemophilic patients."
- Published
- 2013
3. Immune responses in liver-directed lentiviral gene therapy
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Andrea Annoni, Luigi Naldini, Maria Grazia Roncarolo, Mahzad Akbarpour, Kevin Goudy, Annoni, A, Goudy, K, Akbarpour, M, Naldini, Luigi, and Roncarolo, MARIA GRAZIA
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Genetic enhancement ,Transgene ,Biology ,Viral vector ,03 medical and health sciences ,Transduction (genetics) ,0302 clinical medicine ,Immune system ,Physiology (medical) ,Immune Tolerance ,Animals ,Humans ,Transgenes ,Antigen-presenting cell ,030304 developmental biology ,0303 health sciences ,Toll-like receptor ,Lentivirus ,Biochemistry (medical) ,Immunity ,Public Health, Environmental and Occupational Health ,FOXP3 ,Genetic Therapy ,General Medicine ,3. Good health ,Liver ,030220 oncology & carcinogenesis ,Immunology ,Cancer research - Abstract
The use of lentiviral vectors (LV)s for in vivo gene therapy is an ideal platform for treating many types of disease. Since LVs can transduce a wide array of cells, support long-term gene expression, and be modified to enhance cell targeting, LVs are a powerful modality to deliver life-long therapeutic proteins. A major limitation facing the use of LVs for in vivo gene therapy is the induction of immune responses, which can reduce the transduction efficiency of LV, eliminate the transduced cells, and inhibit the effect of the therapeutic protein. LV strategies designed to restrict transgene expression to the liver to exploit its naturally tolerogenic properties have proven to significantly reduce the induction of pathogenic immune responses and increase therapeutic efficacy. In this review, we outline the immunological hurdles facing in vivo LV gene therapy and highlight the advantages and limitations of using liver-directed LV gene therapy.
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- 2013
4. Human IL2RA null mutation mediates immunodeficiency with lymphoproliferation and autoimmunity
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Claudio Doglioni, Didem Aydin, Immacolata Brigida, Maurilio Ponzoni, Fabio Ciceri, Alberto Tommasini, Silvana Martino, Maria Grazia Roncarolo, Andrea Assanelli, Sara Ciullini Mannurita, Eleonora Gambineri, Kevin Goudy, Marina Vignoli, Alessandro Aiuti, Federica Barzaghi, Sven Olek, Rosa Maria Dellepiane, Rosa Bacchetta, Maria Pia Cicalese, Goudy, K, Aydin, D, Barzaghi, F, Gambineri, E, Vignoli, M, Mannurita, Sc, Doglioni, Claudio, Ponzoni, Maurilio, Cicalese, Mp, Assanelli, A, Tommasini, A, Brigida, I, Dellepiane, Rm, Martino, S, Olek, S, Aiuti, Alessandro, Ciceri, Fabio, Roncarolo, MARIA GRAZIA, Bacchetta, R., Ciullini Mannurita, S, Doglioni, C, Ponzoni, M, Aiuti, A, Ciceri, F, and Roncarolo, Mg
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T-Lymphocytes ,T cell ,Immunology ,IPEX-like ,Tregs ,Autoimmunity ,chemical and pharmacologic phenomena ,Biology ,medicine.disease_cause ,CD25 deficiency ,Article ,Cell Line ,CD25 ,Immunodeficiency ,IL-2 ,Immune system ,T-Lymphocyte Subsets ,medicine ,Humans ,Immunology and Allergy ,IL-2 receptor ,Child ,Cell Proliferation ,Skin ,Immunologic Deficiency Syndromes ,Interleukin-2 Receptor alpha Subunit ,FOXP3 ,hemic and immune systems ,medicine.disease ,medicine.anatomical_structure ,Mutation ,Leukocytes, Mononuclear ,Cytokines ,Female ,CD8 - Abstract
Cell-surface CD25 expression is critical for maintaining immune function and homeostasis. As in few reported cases, CD25 deficiency manifests with severe autoimmune enteritis and viral infections. To dissect the underlying immunological mechanisms driving these symptoms, we analyzed the regulatory and effector T cell functions in a CD25 deficient patient harboring a novel IL2RA mutation. Pronounced lymphoproliferation, mainly of the CD8+ T cells, was detected together with an increase in T cell activation markers and elevated serum cytokines. However, Ag-specific responses were impaired in vivo and in vitro. Activated CD8+STAT5+ T cells with lytic potential infiltrated the skin, even though FOXP3+ Tregs were present and maintained a higher capacity to respond to IL-2 compared to other T-cell subsets. Thus, the complex pathogenesis of CD25 deficiency provides invaluable insight into the role of IL2/IL-2RA-dependent regulation in autoimmunity and inflammatory diseases., Highlights ► CD25 deficiency leads to profound immune dysregulation. ► Preferential CD8+ T cell expansion and high cytokine serum levels were present. ► Proliferating CD8+ T cells infiltrated the skin but failed to respond to pathogens. ► CD4+FOXP3+CD127lowCD25null Tregs could be detected. ► Altered IL2 signaling events and failure of IL2 consumption contribute to autoimmunity.
- Published
- 2013
5. Hepatocyte-Targeted Expression by Integrase-Defective Lentiviral Vectors Induces Antigen-Specific Tolerance in Mice with Low Genotoxic Risk
- Author
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Alessio Cantore, Andrea Annoni, Anne Arens, Timothy C. Nichols, Marinee Chuah, Christof von Kalle, Pietro Genovese, Liesbeth De Waele, Thierry VandenDriessche, Ermira Samara-Kuko, Maria Grazia Roncarolo, Manfred G. Schmidt, Luigi Naldini, Cynthia C. Bartholomae, Ling Ma, Wei Wang, Janka Matrai, Martina Damo, Abel Acosta-Sanchez, Kevin Goudy, Cell Biology and Histology, Division of Gene Therapy & Regenerative Medicine, Mátrai, J, Cantore, A, Bartholomae, Cc, Annoni, A, Wang, W, Acosta Sanchez, A, Samara Kuko, E, De Waele, L, Ma, L, Genovese, P, Damo, M, Arens, A, Goudy, K, Nichols, Tc, von Kalle, C, L., Chuah MK, Roncarolo, MARIA GRAZIA, Schmidt, M, Vandendriessche, T, and Naldini, Luigi
- Subjects
Risk ,Transgene ,Genetic enhancement ,Genetic Vectors ,medicine.disease_cause ,liver ,in-vivo ,adenoassociated virus ,Immune tolerance ,Insertional mutagenesis ,03 medical and health sciences ,Epitopes ,Mice ,0302 clinical medicine ,Antigen ,Liver Biology/Pathobiology ,medicine ,Immune Tolerance ,Animals ,Humans ,Vector (molecular biology) ,Hemophilia ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Mutation ,therapy ,Mice, Inbred BALB C ,Hepatology ,biology ,Integrases ,Lentivirus ,FACTOR-IX ,Virology ,nondividing cells ,Integrase ,Cell biology ,030220 oncology & carcinogenesis ,biology.protein ,Hepatocytes ,Hepatic gene-transfer ,Female ,delivery ,transgene expression ,DNA Damage - Abstract
"Lentiviral vectors are attractive tools for liver-directed gene therapy because of their capacity for stable gene expression and the lack of preexisting immunity in most human subjects. However, the use of integrating vectors may raise some concerns about the potential risk of insertional mutagenesis. Here we investigated liver gene transfer by integrase-defective lentiviral vectors (IDLVs) containing an inactivating mutation in the integrase (D64V). Hepatocyte-targeted expression using IDLVs resulted in the sustained and robust induction of immune tolerance to both intracellular and secreted proteins, despite the reduced transgene expression levels in comparison with their integrase-competent vector counterparts. IDLV-mediated and hepatocyte-targeted coagulation factor IX (FIX) expression prevented the induction of neutralizing antibodies to FIX even after antigen rechallenge in hemophilia B mice and accounted for relatively prolonged therapeutic FIX expression levels. Upon the delivery of intracellular model antigens, hepatocyte-targeted IDLVs induced transgene-specific regulatory T cells that contributed to the observed immune tolerance. Deep sequencing of IDLV-transduced livers showed only rare genomic integrations that had no preference for gene coding regions and occurred mostly by a mechanism inconsistent with residual integrase activity. Conclusion: IDLVs provide an attractive platform for the tolerogenic expression of intracellular or secreted proteins in the liver with a substantially reduced risk of insertional mutagenesis. (HEPATOLOGY 2011;53:1696-1707)"
- Published
- 2011
6. Adeno-Associated Virus-Mediated IL-10 Gene Therapy Inhibits Diabetes Recurrence in Syngeneic Islet Cell Transplantation of NOD Mice
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Mark A. Atkinson, Martha Campbell-Thompson, Matthew Powers, Harry S. Nick, Antonello Pileggi, Todd M. Brusko, E. Zahr, Terence R. Flotte, Raffaella Poggioli, Clive Wasserfall, Camillo Ricordi, James M. Crawford, Marda Scott-Jorgensen, Tamir M. Ellis, Kevin Goudy, R. Damaris Molano, Luca Inverardi, Anupam Agarwal, and Y. Clare Zhang
- Subjects
viruses ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Genetic enhancement ,Genetic Vectors ,Green Fluorescent Proteins ,Islets of Langerhans Transplantation ,Gene Expression ,Autoimmunity ,Biology ,medicine.disease_cause ,Islets of Langerhans ,Mice ,Mice, Inbred NOD ,Secondary Prevention ,Internal Medicine ,medicine ,Animals ,Lymphocytes ,Muscle, Skeletal ,NOD mice ,Inflammation ,Autoimmune disease ,geography ,Type 1 diabetes ,Islet cell transplantation ,geography.geographical_feature_category ,Superoxide Dismutase ,Graft Survival ,Membrane Proteins ,Genetic Therapy ,Dependovirus ,Islet ,medicine.disease ,Interleukin-10 ,Transplantation ,Luminescent Proteins ,Diabetes Mellitus, Type 1 ,Heme Oxygenase (Decyclizing) ,Immunology ,Heme Oxygenase-1 - Abstract
Islet transplantation represents a potential cure for type 1 diabetes, yet persistent autoimmune and allogeneic immunities currently limit its clinical efficacy. For alleviating the autoimmune destruction of transplanted islets, newly diagnosed NOD mice were provided a single intramuscular injection of recombinant adeno-associated viral vector encoding murine IL-10 (rAAV-IL-10) 4 weeks before renal capsule delivery of 650 syngeneic islets. A dose-dependent protection of islet grafts was observed. Sixty percent (3 of 5) of NOD mice that received a transduction of a high-dose (4 × 109 infectious units) rAAV-IL-10 remained normoglycemic for at least 117 days, whereas diabetes recurred within 17 days in mice that received a low-dose rAAV-IL-10 (4 × 108 infectious units; 5 of 5) as well as in all of the control mice (5 of 5 untreated and 4 of 4 rAAV-green fluorescent protein-transduced). Serum IL-10 levels positively correlated with prolonged graft survival and were negatively associated with the intensity of autoimmunity. The mechanism of rAAV-IL-10 protection involved a reduction of lymphocytic infiltration as well as induction of antioxidant enzymes manganese superoxide dismutase and heme oxygenase 1 in islet grafts. These studies support the utility of immunoregulatory cytokine gene therapy delivered by rAAV for preventing autoimmune disease recurrence in transplant-based therapies for type 1 diabetes.
- Published
- 2003
7. Endogenous IL‐2 production governs the in vitro induction of FoxP3‐expressing adaptive Treg in the NOD mouse
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Kevin Goudy, Roland Tisch, and Bo Wang
- Subjects
Genetics ,FOXP3 ,Endogeny ,Biology ,Nod mouse ,Molecular Biology ,Biochemistry ,In vitro ,Il 2 production ,Biotechnology ,Cell biology - Published
- 2008
8. Recombinant adeno-associated virus-mediated alpha-1 antitrypsin gene therapy prevents type I diabetes in NOD mice
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Tamir M. Ellis, Kevin Goudy, Sihong Song, Marda Scott-Jorgensen, James M. Crawford, Qiushi Tang, Martha Campbell-Thompson, Terence R. Flotte, Clive Wasserfall, Jianming Wang, and Mark A. Atkinson
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viruses ,Genetic enhancement ,Genetic Vectors ,Biology ,Recombinant virus ,medicine.disease_cause ,Injections, Intramuscular ,Virus ,Antibodies ,law.invention ,Autoimmunity ,Mice ,law ,Mice, Inbred NOD ,Transduction, Genetic ,Genetics ,medicine ,Animals ,Humans ,Insulin ,Molecular Biology ,Adeno-associated virus ,NOD mice ,Autoantibodies ,Type 1 diabetes ,Genetic Therapy ,Dependovirus ,medicine.disease ,Virology ,Diabetes Mellitus, Type 1 ,alpha 1-Antitrypsin ,Immunology ,Recombinant DNA ,Molecular Medicine ,Female - Abstract
Type I diabetes results from an autoimmune destruction of the insulin-producing pancreatic beta cells. Although the exact immunologic processes underlying this disease are unclear, increasing evidence suggests that immunosuppressive, immunoregulatory and anti-inflammatory agents can interrupt the progression of the disease. Alpha 1 antitrypsin (AAT) is a multifunctional serine proteinase inhibitor (serpin) that also displays a wide range of anti-inflammatory properties. To test the ability of AAT to modulate the development of type I diabetes, we performed a series of investigations involving recombinant adeno-associated virus vector (rAAV)-mediated gene delivery of human alpha-1 antitrypsin (hAAT) to nonobese diabetic (NOD) mice. Recombinant AAV-expressing hAAT (rAAV2-CB-AT) was administered intramuscularly to 4-week-old female NOD mice (1 x 10(10) i.u./mouse). A single injection of this vector reduced the intensity of insulitis, the levels of insulin autoantibodies, and the frequency of overt type I diabetes (30% (3/10) at 32 weeks of age versus 70% (7/10) in controls). Transgene expression at the injection sites was confirmed by immunostaining. Interestingly, antibodies against hAAT were present in a majority of the vector-injected mice and circulating hAAT was undetectable when assessed 10 weeks postinjection. This study suggests a potential therapeutic role for AAT in preventing type I diabetes as well as the ability of AAV gene therapy-based approaches to ameliorate disease effectively.
- Published
- 2004
9. Adeno-associated virus vector-mediated IL-10 gene delivery prevents type 1 diabetes in NOD mice
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Terence R. Flotte, Martha Campbell-Thompson, Clive Wasserfall, Matthew J. Powers, Sihong Song, Kevin Goudy, Matthias H. Kapturczak, Andrew J. Muir, Mark A. Atkinson, Marda Scott-Jorgensen, James M. Crawford, Y. Clare Zhang, and Tamir M. Ellis
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Adoptive cell transfer ,viruses ,Genetic Vectors ,Nod ,Gene delivery ,Biology ,medicine.disease_cause ,Mice ,Immune system ,Adjuvants, Immunologic ,Mice, Inbred NOD ,medicine ,Animals ,Humans ,Muscle, Skeletal ,Adeno-associated virus ,NOD mice ,Type 1 diabetes ,Multidisciplinary ,Gene Transfer Techniques ,Biological Sciences ,Dependovirus ,medicine.disease ,Interleukin-10 ,Diabetes Mellitus, Type 1 ,Immunology ,Female ,Interleukin-4 ,Insulitis - Abstract
The development of spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice provides for their use as a model of human type 1 diabetes. To test the feasibility of muscle-directed gene therapy to prevent type 1 diabetes, we developed recombinant adeno-associated virus (rAAV) vectors containing murine cDNAs for immunomodulatory cytokines IL-4 or IL-10. Skeletal muscle transduction of female NOD mice with IL-10, but not IL-4, completely abrogated diabetes. rAAV-IL-10 transduction attenuated the production of insulin autoantibodies, quantitatively reduced pancreatic insulitis, maintained islet insulin content, and altered splenocyte cytokine responses to mitogenic stimulation. The beneficial effects were host specific, as adoptive transfer of splenocytes from rAAV IL-10-treated animals rapidly imparted diabetes in naive hosts, and the cells contained no protective immunomodulatory capacity, as defined through adoptive cotransfer analyses. These results indicate the utility for rAAV, a vector with advantages for therapeutic gene delivery, to transfer immunoregulatory cytokines capable of preventing type 1 diabetes. In addition, these studies provide foundational support for the concept of using immunoregulatory agents delivered by rAAV to modulate a variety of disorders associated with deleterious immune responses, including allergic reactions, transplantation rejection, immunodeficiencies, and autoimmune disorders.
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- 2001
10. Systemic overexpression of IL-10 induces CD4(+)CD25(+) cell populations in vivo and ameliorates type 1 diabetes in nonobese diabetic mice in a dose-dependent fashion
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Sihong Song, Brant R. Burkhardt, Matthew Powers, Mark A. Atkinson, Eric S. Sobel, Tamir M. Ellis, Michael J. Clare-Salzler, Terence R. Flotte, Clive Wasserfall, Kevin Goudy, Todd M. Brusko, and Martha Campbell-Thompson
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CD4-Positive T-Lymphocytes ,medicine.medical_specialty ,Adoptive cell transfer ,Time Factors ,viruses ,Insulin Antibodies ,Immunology ,Population ,Genetic Vectors ,Dose-Response Relationship, Immunologic ,Injections, Intramuscular ,Adenoviridae ,Islets of Langerhans ,Mice ,In vivo ,Mice, Inbred NOD ,T-Lymphocyte Subsets ,Diabetes mellitus ,Internal medicine ,Immunology and Allergy ,Medicine ,Animals ,IL-2 receptor ,education ,Autoantibodies ,Recombination, Genetic ,Type 1 diabetes ,education.field_of_study ,Immunity, Cellular ,business.industry ,Receptors, Interleukin-2 ,Genetic Therapy ,Dependovirus ,medicine.disease ,Interleukin-10 ,Mice, Inbred C57BL ,Interleukin 10 ,Endocrinology ,Diabetes Mellitus, Type 1 ,Antibody Formation ,Female ,business ,Insulitis - Abstract
Early systemic treatment of nonobese diabetic mice with high doses of recombinant adeno-associated virus (rAAV) vector expressing murine IL-10 prevents type 1 diabetes. To determine the therapeutic parameters and immunological mechanisms underlying this observation, female nonobese diabetic mice at 4, 8, and 12 wk of age were given a single i.m. injection of rAAV-murine IL-10 (104, 106, 108, and 109 infectious units (IU)), rAAV-vector expressing truncated murine IL-10 fragment (109 IU), or saline. Transduction with rAAV-IL-10 at 109 IU completely prevented diabetes in all animals injected at all time points, including, surprisingly, 12-wk-old animals. Treatment with 108 IU provided no protection in the 12-wk-old injected mice, partial prevention in 8-wk-old mice, and full protection in all animals injected at 4 wk of age. All other treatment groups developed diabetes at a similar rate. The rAAV-IL-10 therapy attenuated pancreatic insulitis, decreased MHC II expression on CD11b+ cells, increased the population of CD11b+ cells, and modulated insulin autoantibody production. Interestingly, rAAV-IL-10 therapy dramatically increased the percentage of CD4+CD25+ regulatory T cells. Adoptive transfer studies suggest that rAAV-IL-10 treatment alters the capacity of splenocytes to impart type 1 diabetes in recipient animals. This study indicates the potential for immunomodulatory gene therapy to prevent autoimmune diseases, including type 1 diabetes, and implicates IL-10 as a molecule capable of increasing the percentages of regulatory cells in vivo.
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