The liver is a unique organ in that it is accepted across complete MHC mismatch in allotransplantation in a number of species. The mechanisms behind its immunoprivileged state are unclear. We have previously identified the importance of IFN-γ signaling and downstream B7-H1 expression in spontaneous allograft acceptance. When WT or B7H1^-/- liver (H-2^b) were transplanted into C3H recipients (H-2^k) recipients, B7-H1^-/- grafts were rapidly rejected in 5 days with WT grafts surviving into the long term. This is in contrast to other models of acute rejection (e.g. IFN-γR1^-/- allografts) where grafts are rejected at day 10-15. Histological examination of the B7-H1^-/- grafts was notable for extensive hemorrhage, massive microvascular thrombosis and necrosis in addition to lymphocytic and granulocytic infiltration. There was no evidence of a humoral process since there was no complement deposition or detectable donor specific antibodies. Histochemical staining revealed an abundance of neutrophils (Gr-1⁺) in B7-H1^-/- in comparison to WT grafts. qPCR analysis of graft infiltrating cells was notable for a marked increase in granzyme B in the B7-H1^-/- allografts compared to the WT grafts. Depletion of neutrophils by anti-Gr-1 Ab (confirmed by flow analysis) did not prolong the survival of B7-H1^-/- allografts. However, CD8⁺ cell depletion with administration of anti CD-8 antibody led to an increase in graft survival to a mean of 9 days with reduction in hemorrhage, thrombosis and necrosis. Our findings demonstrate that the absence of B7-H1 expression in the allograft leads to a complete breakdown of tolerance leading to a picture of non-antibody mediated acute vascular rejection with widespread endothelial damage and resulting graft thrombosis and necrosis, which is mediated by cytotoxic CD8+ lymphocytes. The extent of coagulation and thrombosis suggests that B7-H1 is a key gatekeeper molecule in the maintenance of peripheral tolerance. Furthermore, the extensive accumulation of neutrophils in the B7-H1^-/- graft suggests that B7-H1 may regulate neutrophil recruitment in a CD8⁺ dependent fashion. In conclusion, our data shows that B7-H1 is a key regulator of the alloimmune response in the early post transplantation period with its absence leading to early graft rejection and thrombosis. These findings provide novel insights into potential therapeutic targets to attenuate the alloreactive CD8⁺ T cell response.

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