This investigation postulates that chronic rejection of allografts is caused by the elimination of donor antigen presenting cells residing in the graft, and that through retention of these cells, promotes low grade stimulation of the recipient s immune system leading to prevention of CR. An animal model as been developed to test this hypothesis. Animals are pretreated with donor bone marrow or a hepatic allograft in concert with Tacrolimus. Donor microchimerism persists for at least 100 days, and then, the animals are challenged with a heterotopic cardiac allograft (CCA). The PI has found that animals previously receiving a liver allograft do not experience CR while those that receive bone marrow do. The hypothesis is advanced that the liver provides the stromal elements for survival of donor hematopoietic stem cells which protect cardiac allografts from CR. In contrast, with animals receiving donor bone marrow, there is induction of a strong Th-1 type cell response due to a loss of microchimerism, which leads to CR. In this project, the PI proposes to study the mechanisms responsible for lymphocyte trafficking and cellular activation, the influence of persistent donor antigen presenting cells on the incidence and intensity of CR and whether maneuvers for augmentation of donor chimerism in human liver transplant patients lowers the severity of CR.
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