GENOMICS OF CHRONIC RENAL ALLOGRAFT REJECTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The principal hypotheses are: 1. Chronic rejection is mediated by ongoing indolent specific immune reactivity against the mismatched MHC antigens of the graft; 2. The immune response underlying chronic rejection is driven by CD4+ T cell clones primed to donor allo-epitopes presented as peptides by recipient APCs (indirect allorecognition pathway), which give rise to cell and antibody mediated responses directed against the graft; 3. The development of chronic rejection can be predicted by quantitative analysis of pre-inflammatory gene activation in the graft during the course of transplantation; and 4. The susceptibility to chronic rejection is modified by inherited genetic polymorphisms that alter the level of response in genes that are known to modify the immune response. The term chronic allograft nephropathy (CAN), as defined by Banff classification, does not describe a specific pathological process but rather it comprises various types of chronic injury that may result from a variety of underlying pathogenic mechanisms. The pathogenesis of CAN is poorly understood, but involves both antigen dependent and independent mechanisms. The uncertainty about the pathogenic mechanisms involved in CAN is major obstacle to the development of specific therapeutic interventions. More recently it has been suggested that the pathologic findings of duplication of the glomerular basement membrane (chronic allograft glomerulopathy), intimal proliferation of arteries with a mononuclear infiltrate (chronic allograft arteriopathy), and lamination of the peritubular capillary basement membrane, arise due to a chronic immunologic process and therefore should be referred to as true chronic rejection. This has been further strengthened by the finding that C4d, which acts as a surrogate marker for antibody mediate rejection, may be found in up to 61% of cases of chronic rejection. Most studies to date examining causes of late graft loss have used graft survival or CAN as the endpoints. By using CAN as an endpoint individual pathological processes may be missed, or results may be ambiguous, due to the contribution of the multiple factors leading to fibrosis and the end stage kidney. By considering the distinct pathological picture of chronic rejection separately we may eliminate potential interference, allowing us to determine whether it truly is an immune mediated response.