β3 integrins regulate lymphocyte migration and cytokine responses in heart transplant rejection

Integrin αvβ3 is important for cell survival, signaling and migration, particularly during angiogenesis and tumorigenesis, where it has been proposed as a therapeutic target. αvβ3 is up-regulated following transplantation and β3 polymorphisms are associated with increased acute kidney rejection, suggesting that αvβ3 may also play a role in transplant rejection. Here, using a model of allogeneic heart transplantation, we show that allograft survival is prolonged in β3 integrin-deficient (β3-/-) mice. This is associated with Th2-type immune responses and reduced T-cell infiltration into grafts and T cells from β3-/- mice show impaired adhesion and migration, consistent with a role for αvβ3 in transmigration. These studies provide evidence that targeting β3 integrins impairs recruitment of effector cells and alters cytokine production, so prolonging graft survival. We also show that low doses of blocking antibodies against leukocyte function associated antigen-1 (LFA-1)/αLβ2 and very late antigen-4 (VLA-4)/α4β1, when combined with deletion of β3, lead to long-term survival of allografts with no evidence of chronic rejection. Hence we provide strong mechanistic evidence supporting previous genetic studies, demonstrate the involvement of β3 integrins in both acute and chronic rejection and identify β3 as a new target for immunosuppressive therapy.