INCREASED EXPRESSION OF INTERFERON-GAMMA IN A RAT MODEL OF CHRONIC INTESTINAL ALLOGRAFT-REJECTION

Chronic rejection remains a major cause of late graft dysfunction. Alt hough much research has focused on acute rejection, little is known ab out the mechanisms of chronic rejection, Our group has recently report ed evidence of significant intestinal smooth muscle hypertrophy and hy perplasia associated with abnormal contractile and electrical activiti es in a rat model of chronic intestinal rejection. The changes in the smooth muscle layer are associated with a significant inflammatory inf iltrate. In order to further delineate the immune mechanisms of chroni c rejection, we sought to clarify the nature of this infiltrate. Ortho topic small bowel transplantation was performed using an allogeneic (A CI-Lewis) rat combination, The rats only received immunosuppression fo r the first 28 days posttransplantation (cyclosporine 15 mg/kg daily f rom postoperative day 0 to 6 and every other day from postoperative da y 7 to 28). This led to chronic rejection of the graft by day 90, at w hich time the rats were sacrificed, Analysis by immunohistochemistry r evealed NK and CD5+ leukocytes infiltrating the muscular layer. Examin ation of cytokine production by radiolabeled polymerase chain reaction showed high levels of steady state interferon-gamma mRNA in full thic kness intestinal segments and within the isolated muscularis of chroni cally rejecting intestinal allografts as compared to syngeneic and con trol grafts. Interferon-gamma mRNA was localized to both the musculari s and mucosa. Interestingly, positively hybridized cells within the mu scularis tended to preferentially localize to the myenteric and submuc osal plexuses suggesting a potential role for this cytokine in chronic intestinal rejection.