Th1 Adaptive Immune Responses in Cardiac Graft Arteriosclerosis

Heart transplants are not rejected in the absence of adaptive immune responses, eg, in transplantations between genetically identical donors and hosts or to recipients with severe combined immunodeficiencies. Activation of adaptive immunity to an allograft causes destructive responses against donor parenchymal or vascular cells, called acute rejection. In the presence of adequate immunosuppression, acute rejection is suppressed; however, chronic rejection may occur, manifesting as conduit arterial lumen loss resulting from expansion of the tunica intima and remodeling of vessel size, called graft arteriosclerosis.1 The differences in pathological findings and in sensitivity to immunosuppressive agents suggest that chronic graft failure arises from different mechanisms operative in separate allograft compartments than in acute graft rejection. The precise pathogenesis of graft arteriosclerosis is unknown, although there is broad consensus that it is, at least in part, an alloimmune process in that the arteriosclerotic changes are limited to the vascular bed of the allograft and spare the host vasculature. Adaptive immunity may activate a variety of effector mechanisms that cause chronic graft rejection in murine transplantation models.1 Although it is not the only factor that can cause graft arteriosclerosis, the evidence for the signature Th1 cytokine, interferon (IFN), is particularly compelling. In mouse transplantation models, serological neutralization or the genetic absence of IFNreduces intimal expansion of graft arteries.2,3 Moreover, in a chimeric human-mouse model, antibody neutralization of IFNprevents allogeneic T cell– mediated endothelial dysfunction, intimal thickening, and outward vascular remodeling; administration of IFNaccelerates these effects; and exogenous IFNin the absence of leukocytes is sufficient to cause the arteriosclerotic changes.4–6 However, definitive evidence for a pathogenetic role of IFNin clinical cardiac transplantation is lacking.