Previous studies in this program project have demonstrated that immune mechanisms play a critical role in the success of allogeneic stem cell transplantation. The previous projects outline a series of clinical and laboratory studies designed to apply new concepts and methods of graft engineering to allogeneic stem cell transplantation. These projects will develop and test novel methods to selective modulate T cell reconstitution in the allogeneic stem cell recipient. In this context, the project will focus on developing a better understanding of the specific targets of allo- immunity in vivo. In previous clinical trials we have demonstrated that infusion of CD4+ donor T cells results in a dramatic and sustained response against relapsed leukemia. This response appears to be directed against antigens expressed on normal as cell as malignant hematopoietic cells, but is not frequently associated with a clinical syndrome of graft-vs. host disease (GVHD). Recent studies in our laboratory have shown that donor lymphocyte infusion (DLI) initiates a complex immune response, resulting in both B cell and T cell immunity against recipient hematopoietic stem cells., but is not frequently associated with a clinical syndrome of graft-vs-host disease (GVHD). Recent studies in our laboratory have shown that donor lymphocyte infusion (DLI) initiates a complex immune response, resulting in both B cell and T cell immunity against recipient hematopoietic sem cells. We have recently identified a series of both B cell and T cell immunity against recipient hematopoietic stem cells. We have recently identified a series of target antigens based on their recognition by specific antibodies after DLI. Thirteen antigens have been cloned using a SEREX approach and further studies in this project will focus on this novel antigens as targets of the immune response against recipient stem cells. As we continue to characterize the role of B cell and T cell responses in selected individual, we hope to develop a better understanding of the relevant target antigens for both GVHD and graft-vs-leukemia (GVL). Working with other investigators in this Program Project, these experiments will lead to the development of new methods for selectively enhancing appropriate responses or selectively abrogating inappropriate responses. These experiments will be carried out in 4 Specific Aims: 1. Characterization of B cell responses specific for defined antigens expressed on recipient hematopoietic stem cells and leukemic stem cells. 2. Identify T cell defined antigens that represent clinically relevant targets for selective elimination of recipient hematopoietic stem cells and residual leukemia cells. 3. Molecular characterization of B and T cell defined antigens in DLI responders. 4. Develop new methods for identifying target antigens associated with GVHD.
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