ORTHOTOPIC LIVER TRANSPLANTATION

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This application is designed to study the mechanisms of transplantation tolerance with particular reference to the liver. The principal hypothesis driving these studies if the Principal Investigator's so- called "Two-Way Paradigm". This proposes that the ultimate outcome of allograft transplantation represents the composite of two immunologic forces: classic host vs. graft attack, i.e. allograft rejection, and graft vs. host. The latter is an occult immunologic force at work. Although the clinical entity of graft vs. host disease in liver transplantation is uncommon, it represents in essence a serious effort by leukocytes contained in the graft to reject the recipient after their migration. Thus, it is the investigator's proposal that the recipient becomes populated with small numbers of cells from the donor organ and that the effect of this "graft vs. host" reaction is the promotion of tolerance. As these cells leave the graft, they are replaced in the transplant by immune cells of the recipient in successful cases. In this hypothesis, host vs. graft disease if uncontrolled is bad because it leads to rejection of the allograft. The other way round, graft vs. host disease if unchecked can kill the patient, but if controlled it tempers rejection. The studies proposed will test this hypothesis. Moreover, the investigators will attempt to develop novel techniques to modify the number and character of the donor cells that ultimately reside in the recipient and promote tolerance to the allograft.