Acute allograft rejection occurs mainly because recipient T lymphocytes mount a vigorous specific immune reaction against donor allogeneic (allo) antigens (Ag). DC are the professional Ag presenting cells (APC) that as """"""""passenger leukocytes"""""""" present the allo-Ag to recipient naive T cells and trigger graft rejection. However, DC are also involved in the induction/maintenance of Ag-specific self-tolerance. There is evidence that certain APC (macrophages and likely DC) increase production of the immunoregulatory cytokines interleukin (IL)-10 and transforming growth factor (TGF)beta1 after ingestion of apoptotic bodies. We propose to test the hypothesis that recipient DC, after interaction with donor major histocompatibility complex (MHC)+ apoptotic bodies in the appropriate extracellular environment, are able to generate T cells with regulatory function. We propose to employ this approach to induce Ag-specific tolerance in heart allograft recipients as an alternative to pharmacological treatments that induce generalized immunosuppression and severe side effects. To reach these goals we propose the following aims.
AIM 1 : To investigate the effect of apoptotic bodies on the phenotype, synthesis of cytokines, and T helper (Th)-driving capacity of DC in vitro. We will develop a phagocytosis assay of apoptotic bodies for mouse DC to analyze the phenomenon and molecules involved. We will analyze the phenotype and pattern of cytokines synthesized by DC under such conditions and the impact on the subset of Th lymphocytes induced.
AIM 2 : To characterize the T cell stimulator's function and the Th-driving capacity in vivo of DC exposed to apoptotic bodies. Our purpose is to learn how DC exposed to apoptotic bodies can regulate, in vivo, the outcome of a T cell response from Ag-specific immune reactivity to potential Ag-specific tolerance.
AIM 3 : To evaluate the effect of recipient DC exposed to donor MHC+ apoptotic bodies on heart allograft survival. After focusing on the influence of DC exposed to apoptotic bodies on alloimmune responses in normal hosts, we will investigate their role in allogeneic heart graft recipients. The results may provide new insight into how apoptotic bodies can modulate the Th-driving capacity of DC and determine the therapeutic potential of DC and apoptotic bodies in transplant tolerance.
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