CTLA4 engagement is required for induction of murine liver transplant spontaneous tolerance

Liver transplantation in mice is accepted spontaneously in all strain combinations. The mechanisms remain largely undefined. We hypothesize that signaling via the B7-CTLA4 receptor pathway is required for induction of liver transplant tolerance. Liver transplantation was performed from B10 (H2 ^b) to C3H (H2^k) mice. The recipients received anti-mouse CTLA4 mAb 0.25 mg i.p. every other day post-operatively. Liver grafts in anti-CTLA4 mAb treated recipients were acutely rejected. The allo-specific proliferative responses, anti-donor CTL and NK cell activities of GIC and SC and the serum levels of IFN-γ and IL-2 from anti-CTLA4 mAb treated recipients were elevated significantly in comparison to the control mice. The frequency of IFN-γ and IL-2 producing cells were markedly increased also in the anti-CTLA4 treated recipients. The immunohistology of liver grafts from anti-CTLA4 mAb treated mice showed extensively increased lymphocyte infiltration in the portal and general parenchymal areas, and expanded T-cell area in the spleen, with a reduction in the frequency of apoptotic cells observed by TUNEL staining compared with control mice. Thus CTLA4 signaling is critical for murine liver transplant tolerance induction. CTLA4 blockade promotes donor specific T-cell activation, cytotoxicity and Th1 polarization; protects alloreactive T cells from apoptotic death and induces liver allograft acute rejection.