Loss of direct and maintenance of indirect alloresponses in renal allograft recipients: Implications for the pathogenesis of chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is the principal cause of late renal al lograft failure. This complex process is multifactorial in origin, and ther e is good evidence for immune-mediated effects. The immune contribution to this process is directed by CD4(+) T cells, which can be activated by eithe r direct or indirect pathways of allorecognition. For the first time, these pathways have been simultaneously compared in a cohort of 22 longstanding renal allograft recipients (13 with good function and nine with CAN). CD4() T cells from all patients reveal donor-specific hyporesponsiveness by the direct pathway according to proliferation or the secretion of the cytokine s IL-2, IL-5, and IFN-gamma. Donor-specific cytotoxic T cell responses were also attenuated. In contrast, the frequencies of indirectly alloreactive c ells were maintained, patients with CAN having significantly higher frequen cies of CD4(+) T cells indirectly activated by allogeneic peptides when com pared with controls with good allograft function. An extensive search for a lloantibodies has revealed significant titers in only a minority of patient s, both with and without CAN. In summary, this study demonstrates widesprea d donor-specific hyporesponsiveness in directly activated CD4(+) T cells de rived from longstanding recipients of renal allografts, whether they have C AN or not. However, patients with CAN have significantly higher frequencies of CD4(+) T cells activated by donor Ags in an indirect manner, a phenomen on resembling split tolerance. These findings provide an insight into the p athogenesis of CAN and also have implications for the development of a clin ical tolerance assay.