Contribution of early acute rejection episodes to chronic rejection in a rat kidney retransplantation model

Abstract

Chronic graft rejection represents the single most important risk factor for unsatisfactory long-term results after organ transplantation. In addition to various alloantigen dependent and independent factors, acute rejection episodes have been cited as a major immunological risk factor. However, the effects of acute rejection episodes on long-term graft outcome remains unknown. To examine the influence of a single early rejection event on ultimate graft outcome, acutely rejecting rat kidney grafts were retransplanted sequentially into syngeneic rats and their functional and structural behavior assessed over time. LEWxBNF1 kidney allografts and LEW isografts were removed from their LEW recipients after three, four, five and seven days (N = 12/group/time period) and retransplanted into donor strain hosts. The grafts were followed functionally and harvested four, eight, and 32 weeks later. Urinary protein excretion was measured weekly. Kidneys were examined morphologically and immunohistologically using monoclonal antibodies (mAbs) against macrophages (ED-1), T cells and their subsets (CD5, CD4, CD8), MHC class II expression (OX3) and adhesion molecules (ICAM-1 and LFA-1α). The mean standard time ± so of nonretransplanted allografts was 14.5 ± two days; isografts functioned indefinitely. At five and seven days, acutely rejecting allografts showed massive cellular infiltrates associated with extensive necrosis. These changes could not be reversed by retransplantation and the syngeneic recipients later died of renal failure. In contrast, most allografts retransplanted earlier in the process recovered completely when retransplanted after three (12 of 12 allografts) and four (7 of 12 allografts) days. During the subsequent follow-up period, urinary protein excretion was comparable in retransplanted allografts and isografts. The increased mononuclear cell infiltration in non-retransplanted allografts seen at three and four days was only occasionally observed during the follow-up period after retransplantation. Only a few sclerosed glomeruli (~15%), mild arterial changes and minimal cellular infiltrates were observed by 32 weeks, which were similar to that seen in retransplanted isografts. A single acute rejection episode was completely reversible and did not progress to chronic rejection if retransplanted into syngeneic donors when the inflammatory changes are still early. Those results demonstrate the critical effect of alloantigen-dependent events on chronic graft deterioration, and indicate that prompt and aggressive treatment of initial acute rejection episodes are beneficial to protect against late deleterious changes in the graft.