Allogeneic marrow transplantation can be curative for a variety of hematological disorders, but clinical results largely depend upon histocompatibility between donor and recipient. With the use of appropriate immunosuppression before and after marrow transplantation, differences for histocompatibility determinants encoded outside the major histocompatibility complex on human chromosome 6 (HLA) have become minimally relevant to the clinical outcome. On the other hand, incompatibility for antigens encoded within the HLA complex, even if limited to a single locus, carries a significant risk of graft rejection and severe graft-versus-host disease. The goal of this project is to provide new information on the biology of immune response, which could lead to the development of new methods to allow marrow transplantation in spite of donor histoincompatibility. In particular, this project will address the mechanisms for cellular regulation of alloimmune response. We and others have observed that the addition of either cyclosporine or an antibody specific for the IL-2 binding site of the 55 kDa alpha chain of the IL-2 receptor (CD25) during the course of an in vitro mixed leukocyte reaction allows preferential expansion of antigen-specific suppressor- inducer and suppressor-effector T lymphocytes. These two types of lymphocytes can suppress both the proliferation of autologous cells exposed to specific alloantigen and the generation of cytotoxic T lymphocytes. Using culture conditions defined in our preliminary studies, we propose to generate T cell clones with antigen-specific suppressor function. By studying a panel of T cell clones, we expect to be able to determine function, specificity, MHC restriction and surface receptor phenotype of each cellular subset operating in the circuit suppressing T lymphocyte proliferation and CTL generation in response to specific alloantigen. Definition of requirements for generation and expansion of antigen specific suppressor T cell in vitro, may allow the development of strategies for inducing a similar process in vivo, with the goal of achieving specific immunosuppression. Furthermore, these studies may provide the methodology for in vitro expansion of antigen-specific suppressor T cells to be infused directly into patients. The murine model available in our laboratory for the experiments described in project IV would be used for in vivo studies as a prelude to the clinical application in human marrow transplantation.
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