The overall goals of this Transplantation Program Project are to dissect the mechanisms which lead to allograft rejection and to facilitate the implementation of scientific insights gained in the laboratory as treatment modalities in the clinic. To attain these general goals, four complementary projects have been proposed: 1. A hamster mAb anti-murine CD3 mAb will be used to evaluate systematically the use of anti-CD3 to suppress transplantation responses in vivo in a well-defined, small animal model. The anti-CD3 and combined mAbs therapies will be exploited to more efficiently suppress transplantation responses in vivo. Other T cell subset-specific mAbs and antigens including staphylococcal toxins will be examined for their ability to selectively suppress T cell subsets which may play a predominant role in graft rejection. These studies will hopefully lead to the development of more sophisticated immunosuppressive regimens that selectively alters immunity towards the organ transplant. 2. The kinds of T cells involved in rejection of allografts which differ from the host in specific, defined regions of the MHC complex as well as the mechanisms by which these T cells cause graft rejection will be defined. Alloreactive T cells from unprimed spleen and lymph nodes, from the lymph nodes draining the site of a rejecting skin allograft, and from rejecting skin allografts will be characterized in terms of the array of lymphokines produced, the cell surface molecules expressed, and the specific epitopes with which these clones react. 3. The human/SCID mouse model will be developed to study the human cell interaction involved in graft rejection. This model will aid in the analyses of novel therapeutic approaches to overcome rejection of human allografts. 4. New modalities in man based on the basic research performed in the small animal and human/SCID mouse model systems will be directly analyzed at the humoral, cellular and molecular levels. Together, the four projects should provide information as to the mechanism of graft rejection and should help to develop new therapeutic modalities that will be directly implemented in the clinic.
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