The precise role of donor dendritic cells in the inherent tolerogenicity of hepatic allografts remains unresolved. We have shown, however, that poorly stimulatory, immature liver dendritic cells, or dendritic cells whose co-stimulatory function is blocked, can strikingly enhance activation-induced death in allogeneic T cells. Moreover, infusion of such immature donor dendritic cells plus co-stimulatory blockade augments apoptotic death of host immunoreactive T cells and markedly enhances graft survival. These data support our hypothesis that liver dendritic cells have potential to promote the development of tolerance in allogeneic recipients by mediating the apoptotic death of allospecific T cells.
Aim 1 is to elucidate the role of apoptosis in the outcome of liver dendritic cell-allogeneic T cells interactions and the factors that influence this activity. These studies will test whether myeloid and lymphoid dendritic cells exhibit functional differences in their interaction with T cells and whether they have equal potential to mediate apoptosis in activated T cells and whether Th1 and Th2 cells are equally susceptible. The role of critical co-stimulatory pathways and of IL-2 in the regulation of T cell death will be examined.
Aim 2 will ascertain the death regulatory pathways that may determine T cell apoptosis by liver dendritic cells. Contribution of the Fas pathway and the role of TNF families, in particular TRAIL, will be examined. Cell survival factors and death resistance molecules will also be examined for the possible differential resistance of Th1/Th2 subsets to dendritic cell induced death.
Aim 3 studies will examine the ability of liver dendritic cells to delete alloreactive cells in vivo and will examine factors that modulate this activity. These studies will involve quantitative assessment of proliferation and apoptosis of CD4 and CD8 T cells in vivo. The impact of blockade of specific co-stimulaory pathways and whether antigen specific T cells are deleted selectively will be ascertained. Finally, Aim 4 studies will assess and maximize the therapeutic potential of liver dendritic cell induced alloantigen-specific T cell apoptosis in organ transplant recipients. In these clinically-relevant studies, emphasis will be placed on targeting specific costimulatory pathways, including use of novel blocking agents. The results will provide new insight into how liver dendritic cells can modulate survival of alloreactive T cells, and determine the potential of donor dendritic cells to delete allospecific T cells to facilitate transplant tolerance.
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