Pathophysiology of chronic rejection.
Acute rejection and chronic rejection have entirely different characteristics as immune responses. Episodes of acute rejection are characterized by the strong stimulation of T cells by alloantigen presentation and the subsequent activation and proliferation of immunocompetent antiallograft T cells. In comparison, chronic rejection appears to result as a response to ongoing, low-grade injuries to the allograft vascular endothelium. We have proposed that the parenchymal and endothelial cells in the allograft secrete growth factors in response to this irritation, leading to proliferation of smooth muscle cells and influx of myocytes into the intima. The end product is the clinically observed allograft inflammation and arteriosclerosis. The different biologic mechanisms of acute and chronic rejection demand correspondingly different methods of treatment. Recent research exploring the causes and mechanisms of chronic rejection thus emphasize the importance of several interrelated inflammatory cascades within the vascular walls of the allograft. The complexity of this immune response probably precludes the development of a single therapy for the prophylaxis or treatment of chronic rejection. The best way to control chronic rejection may be to regulate the allograft's local production of cytokines, growth factors, and eicosanoids. No current drug or treatment protocol has been proven to do this effectively. Second-generation immunosuppressants, such as mycophenolate mofetil, may prove helpful by reducing the frequency and intensity of acute rejection episodes, a primary risk factor for chronic rejection. It may be possible in the next few years to develop new treatments that would double the current 7-to 8-year half-life expected for renal transplants. This would be a significant advance in the treatment of chronic rejection.
Häyry
P
P
Transplantation Laboratory, University of Helsinki, Finland.
D002908:Chronic Disease; D006084:Graft Rejection / Q000276:immunology* / Q000503:physiopathology*; D006801:Humans; D013997:Time Factors