Acute versus chronic graft rejection: Related manifestations of allosensitization in graft recipients

I n the earlier years of clinical transplantation, there was a tendency among clinicians and investigators to focus on the immediate problem of acute graft rejection, which occurred soon arter transplantation in a large number or transplant recipients and was a major cause ofgraft loss. In the current clinical era, acute rejection can be pharmacologically controlled in most patients, and clinical concerns have begun to focus on the less immediate problem of chronic graft rejection. This phenomenon occurs in about half of all transplant patients, and is a majot cause of late graft loss. Chronic rejection is generally unresponsive to therapies that are effective against acute rejection, and to date, there is no accepted clinical therapy for chronic graft rejection. As a result, chronic rejection now claims more grafts than acute rejection. Chronic rejection is not simply delayed acute rejection. Indeed, acute and chronic rejection are diKerent in many ways. Acute rejection is histologically characterized by a rapid, intense and destructive leukocytic inliltration of graft tissues, and generally represents a pathologic inflammatory response.‘” In contrast, chronic rejection is characterized by a slower development within the graft or interstitial librosis and neointimal formation within the large1 vessels, and seems to represent a pathologic tissue remodeling response .+a For some time, these disparate characteristics led clinicians and investigators to consider acute and chronic rejection as separate and unrelated entities. However, there is developing cvidence that the two pathologies are closely related manifestations of post-transplant cellular and humoral sensitization to graft alloantigens. provided by several investigators,‘* who indcpendently showed that long-term (5-10 year) graft survival decreases signilicantly in direct relation to the number of acute rejection episodes experienced by the patients. For esample, Matas et al” have calculated that the half-life of kidney allografts in patients with no clinical acute rejection episodes is 733 years, compared with 5 1 years in patients with one rejection episode, and 6 years in patients with more than one acute rejection episode. Conversely, these data indicate that late graft loss due to chronic rejection is relatively rare among patients who do not esperience an early acute rejection episode. This suggests that the two types of graft rejection are somehow related. It also suggests that control of chronic rejection in transplant patients might be achieved by developing immunosuppressive strategies that efTectively avoid, rather than reverse, acute rejection episodes. Indeed, the current clinical tendency to accept acute rejection, because it is treatable, may indirectly promote chronic rejection development. The purpose of this discussion is to review some current concepts regarding the related mechanisms of acute and chronic grart rejection in the light of some key observations in experimental transplant models. This is not meant to be a comprehensive review of the subject, and many interesting studies will not be cited for the sake of clarity and brevity. What should emerge from this discussion is a broadened view of transplant biology, and a working model of the continuum of pathologic events associated with acute and chronic graft rejection.