Experimental pancreas allograft rejection: correlation between histologic and functional rejection and the efficacy...

In this study the sequence of histologic changes in rejecting pancreatic allografts was correlated with the recurrence of hyperglycemia to evaluate the usefulness of serum glucose monitoring in pancreas transplantation. In addition, various immunosuppressive agents were evaluated for their efficacy in reversing rejection. Diabetic (streptozocin) Lewis rats were recipients of histoincompatible Lewis X Brown Norway F1 pancreatic grafts, which uniformly resulted in a fall in serum glucose levels from greater than 400 mg/dl to less than 150 mg/dl. Specimens were examined daily from the time of transplantation to determine the time of earliest histologic rejection. Functional rejection was defined as a rise in serum glucose levels to greater than 200 mg/dl and occurred at 8.5 +/- 0.8 days in the control group. Histologic evidence for rejection was present by day 3 as a perivascular lymphoid infiltrate while islets remained normal. Extensive cellular rejection of the exocrine tissue occurred by day 6 when most recipients were still normoglycemic. Complete pancreatic destruction was present by day 9. Antirejection therapy with methylprednisolone (MP), antithymocyte serum (ATS), or cyclosporine (CS) started at the time of recurrent hyperglycemia (days 8 or 9) and was uniformly unsuccessful in prolonging graft survival, with mean survival times of 8.3 +/- 0.8 (MP), 9.0 +/- 0.7 (ATS), and 9.3 +/- 0.4 (CS). In contrast, either ATS or CS but not MP begun on day 3, when histologic rejection was first observed, significantly prolonged graft survival to greater than 11 days in most recipients. We conclude that islet destruction is irreversible by the time that marked elevation in serum glucose levels occurs and therefore a more sensitive measure of pancreas rejection is needed. Furthermore, ATS and CS are more effective than are corticosteroids in reversing early rejection.