Despite recent advances in immunosuppresive drug therapy, rejection remains the principal cause of the organ transplant failure. In addition, serious side effects such as life-threatening infection or malignancy are often associated with chronic immunosuppression. The ability to induce functional, donor antigen-specific T cell tolerance with the reduction or (preferably) the elimination of systemic immunosuppressive drug treatment is a primary goal for more effective and safer organ transplantation. Recently, we and others have demonstrated the induciton of anergy in T cells, following """"""""incomplete"""""""" or """"""""inappropriate"""""""" activation by antigen presenting cells (APC). Our data show that dendritic cells (DC) lacking sufficient cell surface expression of costimulatory molecules for naive T cell activation, e.g. B7-1 (CD86), induce alloantigen=specific anergy. Moreover, we have reported that in mice, costimulatory molecule-deficient DC can promote the survival both of cell and organ allografts in otherwise non-immunosuppressed hosts. We also present evidence that the cytokine microenvironment to which DC are pre-exposed or that is present during T cell priming dictates the nature and magnitude of the resultant immune response. Thus, the """"""""immunosuppressive"""""""" cytokines viral (v) interleukin-10 (vIL-10) and transforming growth factor-beta (TGFbeta) can markedly inhibit the capacity of DC to activate naive T cells. In addition, we have shown for the first time that DC induced to produce nitric oxide (NO) or that express Fas (CD95) ligand can induce programmed cell death (apoptosis) in alloactivated T cells. In this study, we propose to AIM I: genetically modify DC to express """"""""immunosuppressive"""""""" molecules (subsequently identified in parentheses) that I) reduce the expression level of APC-associated costimulatory molecules (vIL-10, TGF-beta,CTLA44-Ig), 2) skew the balance of the alloantigen-specific T cell response towards a T helper 2 response (IFN-gammadR, EBI-3, CTLA4-Ig), or 3) promote the deletion (apoptosis) of alloantigen-specific T cell clones (Fas-L, iNOS, TRAIL);
AIM II; determine the impact of gene-engineered DC on in vitro models of anti-allograft immunity;
AIM III : by providing experimental organ (heart) transplant recipient with allogeneic DC modified to express one or more of these transgenes, we hope to enhance graft survival. Accrual of positive results from these animal studies will provide a basis for a trial of gene- engineered DC therapy in patients receiving organ transplants.
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