INHIBITION OF TRANSPLANT REJECTION BY PRETREATMENT OF XENOGENEIC PANCREATIC-ISLET CELLS WITH ANTI-ICAM-1 ANTIBODIES

Cognate recognition of antigen-presenting cells by antigen-specific T cells is critically dependent on noncognate adhesive interactions. For instance, several studies have shown that in vivo anti-LFA-1 plus ant i-ICAM-1 mAb treatment results in prolongation of allograft survival. We have developed a xenogeneic islet transplant model to investigate t he role of various adhesion interactions in the xenogeneic response an d study the effect of pretreating donor tissue with immunosuppressive drugs. Pancreatic islet cells were pretreated in vitro with anti-human ICAM-1 mAb, transplanted under the renal capsule of diabetic B6 mice in the absence of systemic immunosuppression and examined for long-ter m xenograft acceptance. The survival of human islets pretreated with a nti-human ICAM-1 was significantly prolonged (MST=53 days, with 40% of grafts surviving >100 days). In contrast, the survival of human islet s pretreated with the control antibody was similar to those of nontrea ted islets (MST=7 days). A massive lymphocyte infiltrate into control xenografts was observed at 5 days posttransplant. In contrast, a lymph ocyte infiltrate did not appear in the anti-ICAM-1-treated islets for at least 11 days. Only mAbs specific for the LFA-1 binding epitope of ICAM-1 were found to inhibit a mixed islet/lymphocyte reaction in vitr o and block graft rejection in vivo. However, graft prolongation is no t accompanied by systemic tolerance. Mice transplanted simultaneously with human islet cells treated with control Ig (left kidney) or anti-I CAM-1 (right kidney) rejected the control islets but not anti-ICAM-1-t reated islets. These results suggest that the LFA-1/ICAM-1 interaction is a critical component for xenograft rejection and, more important, that pretreatment of islet tissue with anti-adhesion molecule antibodi es can profoundly alter graft recognition and rejection in the absence of any systemic drug therapy. However, graft prolongation is not acco mpanied by systemic tolerance induction.