Increased expression of interferon-gamma in a rat model of chronic intestinal allograft rejection

Chronic rejection remains a major cause of late graft dysfunction. Although much research has focused on acute rejection, little is known about the mechanisms of chronic rejection. Our group has recently reported evidence of significant intestinal smooth muscle hypertrophy and hyperplasia associated with abnormal contractile and electrical activities in a rat model of chronic intestinal rejection. The changes in the smooth muscle layer are associated with a significant inflammatory infiltrate. In order to further delineate the immune mechanisms of chronic rejection, we sought to clarify the nature of this infiltrate. Orthotopic small bowel transplantation was performed using an allogeneic (ACI-Lewis) rat combination. The rats only received immunosuppression for the first 28 days posttransplantation (cyclosporine 15 mg/kg daily from postoperative day 0 to 6 and every other day from postoperative day 7 to 28). This led to chronic rejection of the graft by day 90, at which time the rats were sacrificed. Analysis by immunohistochemistry revealed NK and CD5+ leukocytes infiltrating the muscular layer. Examination of cytokine production by radiolabeled polymerase chain reaction showed high levels of steady state interferon-gamma mRNA in full thickness intestinal segments and within the isolated muscularis of chronically rejecting intestinal allografts as compared to syngeneic and control grafts. Interferon-gamma mRNA was localized to both the muscularis and mucosa. Interestingly, positively hybridized cells within the muscularis tended to preferentially localize to the myenteric and submucosal plexuses suggesting potential role for this cytokine in chronic intestinal ejection.