In this review, we have suggested that chronic vascular rejection, defined as alloimmune-mediated graft vascular stenosis, is the primary cause of late cardiac and hepatic graft failure. It may also commonly contribute to late renal and pulmonary allograft loss. In contrast, parenchymal changes in these failing grafts likely reflect ischemia rather than chronic parenchymal cell rejection. Vascular stenosis results from a combination of intimal hyperplasia and constrictive remodeling. In chronic vascular rejection, as in other chronic vascular diseases (e.g., atherosclerosis), constrictive remodeling caused by adventitial cicatrix formation may be the more important contributor to lumen loss. Functional vascular dysregulation due to endothelial injury may exacerbate the degree of stenosis by promoting vasoconstriction. The precise immunological mechanisms that cause chronic vascular rejection are unknown. Chronic DTH, mediated by host CD4+ T cells activated by graft alloantigens that are presented directly by graft endothelial and dendritic cells or indirectly by host dendritic cells, is a likely candidate. Evidence that IFN-γ, the prototypic cytokine of DTH, is necessary and sufficient to cause vascular remodeling in experimental transplantation supports this concept. (Animal models have limitations in recreating the human disease, although they do provide insights into possible mechanisms.) Alternatively, low-level, smoldering acute vascular rejection mediated by CD8+ CTL or alloantibodies could contribute to graft vascular disease. Nonimmunological factors, such as ischemia/reperfusion, hypertension, hyperlipidemia, and infection, all of which contribute to atherosclerotic vascular disease, all increase the incidence of chronic vascular rejection. These factors may act by enhancing the total burden of injury in the blood vessels or by activating the innate immune system, which favors the development of DTH. Human studies have not as yet resolved these issues. We currently lack effective preventive or therapeutic strategies for chronic vascular rejection. Current immunosuppressive regimens, which effectively prevent or abrogate acute rejection episodes, may target the wrong mechanisms; newer agents, such as rapamycin, may be more effective. Control of hypertension and restoration of normal lipid profiles, e.g., with HMG-CoA reductase inhibitors, may also be of benefit. In the future, as the pathogenesis is better understood, somatic gene therapy may provide a new avenue for therapy.
