The proposed studies are directed towards resolving two inter-related current problems in pig-tononhuman primate (NHP) organ xenotransplantation using GTKO.CD46.CD55 pigs (designated GE pigs) (i) to identify a clinically-applicable regimen that prevents an adaptive immune response, and (ii) to identify a means of preventing coagulation dysfunction - in the form of thrombocytopenia and/or consumptive coagulopathy (CC) with associated thrombotic microangiopathy. The immune response may influence the development of coagulation disorders, and coagulation dysregulation may influence the immune response. The exact causative factors of CC remain uncertain, but (i) heightened innate immunity (antibody, complement, platelets, macrophages, NK cells), (ii) the adaptive immune response (T and B cells), and (iii) molecular incompatibilities between pig and NHP, may all play roles. Graft vascular heterogeneity may also be evident as CC and thrombocytopenia occur more rapidly in NHPs with pig kidney rather than heart grafts. We propose that genetic modifications in pigs and novel therapies may protect against these factors. We shall use CIITA mutant pigs (with knock-down of SLA Class II) and other pigs transgenic for human thromboregulatory factors on the GTKO background.
Aim 1 : To investigate the efficacy in baboons of a clinically-applicable immunosuppressive regimen in preventing the innate and adaptive immune responses after heterotopic heart Tx from (A) GE pigs (n=6) and (B) GE.CIITA pigs (n=6), and to determine whether prevention of elicited xenogeneic immunity correlates with delay in"""""""" the onset or prevention of coagulation dysfunction.
Aim 2 : To investigate the coagulation disorders that develop after (A) heterotopic heart Tx (n=6) or (B) lifesupporting kidney Tx (n=6) from GE.CIITA pigs additionally transgenic for human TBM in baboons immunosuppressed with a clinically-applicable regimen, and to determine the causes of graft failure and coagulation dysfunction.
Aim 3 : To investigate the coagulation disorders that develop after (A) heterotopic heart Tx (n=6) or (B) lifesupporting kidney Tx (n=6) from GE.CIITA.TBM pigs additionally transgenic for human EPCR in baboons immunosuppressed with a clinically-applicable regimen, and to determine the causes of graft failure and coagulation dysfunction.
The proposed studies should provide a clinically-applicable immunosuppressive regimen, and elucidate the efficacy of the expression of human TBM and/or EPCR on pig endothelial cells in preventing the coagulation dysfunction seen following pig heart and kidney Tx in NHPs. The studies should throw light on the remaining barriers that need to be overcome, and indicate what further genetic modifications of the organ-source pig might be advantageous.
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