OKT3 is a murine monoclonal antibody directed against the CD3epsilon chain of the T cell receptor complex on human T-cells. OKT3 has been widely used over the past decade in transplantation to treat corticosteroid- resistant organ graft rejections, and more recently, as prophylaxis of rejection. This mAb induces an efficient and rapid immunosuppression, at least in part due to, the prevention of allorecognition as a result of modulation of the T cell receptor (TCR) from the surface of T lymphocytes and clearance of T cells from the circulation. However, there are several clinical and scientific issues that remain unresolved regarding anti-CD3 therapy. First, a variety of side effects are associated with OKT3 that limits its usefulness in other diseases such as autoimmunity and bone marrow transplantation. These limitations are, in large part, a result of the first dose toxicity as a consequence of T cell activation and the subsequent massive cytokine release. In addition, the therapy has been limited by the generation of a potent humoral antibody response against the murine mAb limiting the potential for retreatment. During the past 4 years, Dr. Bluestone's laboratory has systematically evaluated the use of anti-CD3 to suppress transplantation responses in vivo first in a well- defined, small animal model and then in the hu-SPL-SCID model in collaboration with Dr. Thistlethwaite. The toxic effects of the mAb were defined and largely eliminated, immunosuppressive agents such as deoxyspergualin and CTLA4Ig were used in conjunction with anti-CD3 to potentiate immunosuppression and block the humoral response, and genetically-engineered monoclonal anti-CD3 antibodies were developed to examine the role of T cell activation and Co-stimulation in immune suppression. However, many questions remain including: the relative efficacy of """"""""activating"""""""" and """"""""non-activating"""""""" anti-CD3 mAbs; the signal transducing ability of """"""""non-activating"""""""" anti-CD3 mAbs and how it regulates T cell activation; the role of co-stimulatory in the activating and toleragenic effects of anti-CD3; and the role of other inhibitors of T cell signalling, such as cyclosporin A in the efficacy of anti-CD3 therapy. In order to answer these questions the following specific aims are proposed: 1. To study the in vivo effects of non-mitogenic anti-CD3 mAbs alone and in conjunction with donor antigen; 2. To determine the role of CD28/B7 interactions in anti-CD3-mediated immunosuppression; 3. To determine the molecular mechanism(s) controlling apoptosis and anergy in mice treated with mitogenic anti-CD3. The results of these studies will provide important insights into the effects of anti-CD3 and the CD28/B7 family of cell surface molecules in the regulation of transplant rejection that may translate into clinical application.
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