Local delivery of cytokines by retrovirally transduced antigen-specific TCR+ hybridoma cells in experimental autoimmune encephalomyelitis.
Autoimmune diseases in humans represent an immune attack on self tissue. Current therapies for almost all autoimmune diseases utilize potent and nonspecific immunosuppressive regimens. These therapies are complicated by their side effects and also place the patient at increased risk for opportunistic infections and malignancies. Our current understanding of immune mechanisms underlying autoimmune diseases remains limited. Ongoing studies include identifying genes that predispose an individual to developing autoimmunity, identification of autoantigens that trigger or perpetuate autoimmunity, and studies of immune cell interactions that lead to immune response. Although it may be many years before a full understanding of autoimmunity is obtained, treatment in animal models of autoimmune disease and some human clinical trials have begun to study alternative treatment approaches to therapy of autoimmune disease. Future therapies for autoimmune diseases should target the inappropriate autoimmune response. This article will describe the use of gene therapy in the treatment of autoimmune disease. We believe that autoimmunity can be ameliorated by delivering trans-acting immunoregulatory molecules by retrovirally transduced autoantigen specific T cells that home to lesions of autoimmunity. Until recently, there has not been a practical alternative to systemic delivery of immunoregulatory molecules, however systemic delivery suffers from toxic side effects and dangerous global immunosuppression. In order to study immune regulation using retroviral transduction for local delivery of immunoregulatory products, we used myelin basic protein (MBP) reactive T cell hybridomas in the murine model of multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE). In this report, we show that MBP reactive T cell hybridomas transduced to express IL-4 or TNF, ameliorated or exacerbated disease, respectively. Additionally, the effects of these cells were dependent on T cell receptor (TCR) expression, indicating that the effects were due to homing of the T cells and the local delivery of cytokines. We believe that gene therapy, allowing local delivery of immunoregulatory proteins by autoantigen specific T cells, represents an interesting potential therapy for autoimmune disease.
Dal Canto
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Costa
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Shaw
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Seroogy
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Nolan
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Fathman
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D019264:Adoptive Transfer; D000818:Animals; D002472:Cell Transformation, Viral / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000008:administration & dosage* / Q000097:blood / Q000235:genetics; D016503:Drug Delivery Systems; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics*; D006825:Hybridomas / Q000378:metabolism / Q000637:transplantation*; D015847:Interleukin-4 / Q000008:administration & dosage / Q000097:blood / Q000235:genetics; D051379:Mice; D004676:Myelin Basic Protein / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis*; D012190:Retroviridae / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000235:genetics
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D004676:Myelin Basic Protein; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4