Anti-CD8 Abrogates Effect of Anti-CD4–Mediated Islet Allograft Survival in Rat Model Free

We studied the effects of anti-CD4 treatment of diabetic ACI rats on the induction oftolerance to allogeneic (Lewis) islet allografts. When given as a 4-day treatment regimen, OX38, a mouse anti-rat CD4 antibody, caused depletion of >80% of CD4⁺ cells from the peripheral blood of treated rats. After induction of diabetes (a single high-dose bolus of streptozocin) and 3 days after the initiation of anti-CD4 immunotherapy, recipient ACI rats were transplanted with fully allogeneic (Lewis) islets of Langerhans via the portal circulation. These transplanted islets were capable of returning the anti-CD4–treated ACI recipients to normoglycemia, which was maintained indefinitely in the absence of further immunosuppression. In contrast, treatment of recipient rats with OX8, an anti-CD8 monoclonal antibody (MoAb), induced only a slight prolongation of graft survival (≤30 days). Further characterization of the cellular requirements for the induction of long-term transplantation survival revealed thatsuccessful pretransplantation anti-CD4 therapy could be ablated by the coincident treatment of recipient rats with depleting levels of anti-CD8 MoAb. These data point to the necessity of a regulator CD8⁺ cell in the induction of anti-CD4–mediated transplantation survival in this rat model of islet transplantation.