Graft Tolerance with Apoptotic Cells and Dendritic Cells

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DESCRIPTION (provided by applicant): The main cause of transplant rejection is the immune response against donor allogeneic (allo) antigens (Ags) elicited by the recipient. Following transplant surgery, Dendritic cells (DCs) are the Ag-presenting cells that, as passenger leukocytes, present donor alloAgs to recipient T cells and trigger graft rejection. However, DCs also participate in induction of T cell tolerance. This tolerogenic property of DCs may be exploited to induce donor-specific T cell tolerance for treatment of allograft rejection or autoimmune diseases. There is evidence that phagocytosis of cells in early stages of apoptosis delivers a potent inhibitory signal to DCs. DCs that have internalized apoptotic cells downregulate expression of MHC and costimulatory molecules, decrease their T cell stimulatory capacity and reduce the synthesis of pro-inflammatory cytokines while maintaining high levels of TGF-B1. We propose to use the same principle to induce donor-specific tolerance to prolong cardiac allograft survival. This proposal will study the mechanism(s) by which early apoptotic cells exerts immuno-suppressive effects on DCs. It will test the hypothesis that administration of donor (MHC+) cells in early stages of apoptosis prolongs cardiac allograft survival by inducing anergy/apoptosis of alloreactive T cells or generation of allospecific T cells with regulatory function (Treg cells). We hypothesize that donor-specific T cell tolerance will be achieved by the following mechanisms: i) processing of donor apoptotic cells by recipient immature/semi-mature) DCs in the tolerogenic environment of secondary lymphoid organs (indirect pathway), ii) direct interaction of donor apoptotic/dying cells with recipient T cells (direct pathway); iii) transference of donor "intact" MHC molecules from donor apoptotic/dying cells to recipient DCs and iv) reduced synthesis of alloAbs, due to lack of allospecific CD4+ T cell help. This proposal will define the optimal conditions for the use of donor apoptotic cells to achieve long-term cardiac allograft survival as follows: i) by optimizing the dose, kinetics, frequency and efficiency of delivery of donor apoptotic cells; ii) by simultaneous targeting of the direct and indirect pathways and iii) by combination of donor apoptotic cells with suboptimal levels of immunosuppression. We propose to employ this approach to induce donor-specific tolerance in heart allograft recipients as an alternative to pharmacological treatments that induce generalized immunosuppression and harmful side effects. The knowledge gained will clarify the therapeutic potential of administration of donor cells in early stages of apoptosis to target recipient DCs in vivo to promote donor-specific tolerance. We will address the following specific aims: Aim 1; To study the effect that early apoptotic cells exerts on the allostimulatory function of DCs. Aim 2: To monitor in vivo the effect of allogeneic apoptotic cells on allospecific T and B cell immune responses. Aim 3; To optimize the therapeutic effect of donor apoptotic cells on heart allograft survival. To investigate the mechanism(s) of action of donor apoptotic cells in graft recipients.