Acceptance reaction: Intragraft events associated with tolerance to renal allografts in miniature swine

Inbred miniature swine that are treated for 12 d with a high dose of cyclos porin A develop tolerance to MHC class II matched, class I-mismatched renal allografts. The aim of this study was to clarify the intrarenal allograft events associated with the development of tolerance in this protocol. Morph ologic and immunologic studies were performed in serial biopsies from accep ting grafts after 12 d of cyclosporin A treatment (n = 4) and were compared with those from untreated control rejecting grafts (n = 4). In accepting g rafts with stable function, a transient interstitial infiltrate developed. The cellular infiltrate had many similarities to that in rejecting grafts; both had T cells and macrophages, similar proportions of T-cell subsets, an d a similar frequency of in situ nick end labeling (TUNEL) + apoptotic infi ltrating cells. However, the cellular infiltrate in the acceptance reaction was distinguished by less T-cell activation (interleukin-2 receptor+), les s proliferation (proliferating cell nuclear antigen+) of infiltrating cells , and less graft cell apoptosis in arteries, tubules, glomeruli, and peritu bular capillaries. Thereafter, the infiltrate in the accepting grafts progr essively resolved with decreased cell proliferation, activation, and apopto tic graft parenchymal cell injury, but the high frequency of apoptosis pers isted in graft-infiltrating cells. In parallel to the intragraft events, do nor-specific unresponsiveness developed as assessed by cell-mediated cytoto xicity by blood mononuclear cells in vitro. In conclusion, the acceptance r eaction in transplanted grafts is characterized by progressive resolution o f T-cell proliferation and activation and of cell-mediated graft injury, as well as prolonged T-cell apoptosis. These intragraft events suggest that b oth T-cell anergy and T-cell deletion occur in the graft during the develop ment of tolerance. Some of the described immunopathologic findings (activat ion, proliferation, apoptosis) may be useful in distinguishing acceptance f rom rejection, as well as in predicting later graft acceptance in tolerance induction protocols.