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Targeting LFA‐1 Synergizes with CD40/CD40L Blockade for Suppression of Both CD4‐Dependent and CD8‐Dependent Rejection

Allogeneic hepatocytes elicit CD4‐dependent and (CD4‐independent) CD8+ T‐cell‐initiated graft rejection. The (CD4‐independent) CD8+ T‐cell pathway is resistant to immunosuppressive strategies that readily and indefinitely suppress CD4+ T‐cell‐dependent rejection responses. Consequently, successful immunoregulation of hepatocyte‐initiated immune responses requires a strategy which regulates both CD4‐dependent and CD8‐dependent rejection responses. Interference with CD40/CD40 ligand (CD40L) costimulation only transiently suppresses CD4‐ and CD8‐dependent hepatocyte rejection. Interference with CD28/B7 costimulation transiently suppresses CD4‐dependent hepatocyte rejection, but is ineffective for suppression of CD8‐dependent hepatocyte rejection. To date, hepatocyte survival > 60 days post‐transplant has not been achieved by any immunotherapeutic strategy. In the current study, we evaluated a novel immunosuppressive strategy which targets both LFA‐1 and CD40L‐mediated signals. Targeting LFA‐1 suppressed (CD4‐independent) CD8+ T‐cell‐initiated hepatocyte rejection such that allogeneic hepatocyte survival > 60 days was achieved in 70% of CD4 KO mice. Targeting both LFA‐1‐mediated signals and CD40/CD40L costimulation resulted in synergistic effects, such that hepatocellular survival > 60 days was achieved in 100% of C57BL/6 mice (which have both CD4‐ and CD8‐dependent T‐cell pathways available).