REVERSIBILITY OF CHRONIC RENAL-ALLOGRAFT REJECTION - CRITICAL EFFECT OF TIME AFTER TRANSPLANTATION SUGGESTS BOTH HOST IMMUNE DEPENDENT AND INDEPENDENT PHASES OF PROGRESSIVE INJURY

The characteristic and progressive morphological changes of glomerulos clerosis, interstitial fibrosis, and vascular obliteration that occur in renal allografts experiencing chronic rejection correlate directly with declining function and eventual graft loss. Using an established rat transplant model of chronic rejection where such changes occur in predictable sequence, allografts were retransplanted back into the don or strain at serial intervals after the initial engraftment to determi ne at what stage of development the lesions could still be reversed by removing the continuing immunological drive of the host. Morphologica l changes were compared with those in retransplanted isografts and non retransplanted allografts at comparable time intervals. Histological a nd immunohistological characteristics of chronic rejection were revers ible by retransplantation of the kidneys into the donor strain within 12 weeks after their original placement. Retransplantation at or later than week 12 could not reverse the intense humoral and cellular immun e responses, or the structural changes (particularly fibrosis) that de veloped after that period. However, the sparse but inevitably progress ing cellular infiltration and cytokine expression in retransplanted an d nonretransplanted isograft controls suggest the persistent influence of alloantigen-independent factors in addition to those of host immun ity. Thus, the early stages of chronic rejection are alloantigen depen dent and reversible, whereas the later changes were irreversible and a lloantigen-independent factors appeared increasingly important.