title: Inhibition of transplant rejection by pretreatment of xenogeneic pancreatic islet cells with anti-ICAM-1 antibodies.
abstract: Cognate recognition of antigen-presenting cells by antigen-specific T cells is critically dependent on non-cognate adhesive interactions. For instance, several studies have shown that in vivo anti-LFA-1 plus anti-ICAM-1 mAb treatment results in prolongation of allograft survival. We have developed a xenogeneic islet transplant model to investigate the role of various adhesion interactions in the xenogeneic response and 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-term xenograft acceptance. The survival of human islets pretreated with anti-human ICAM-1 was significantly prolonged (MST = 53 days, with 40% of grafts surviving > 100 days). In contrast, the survival of human islets pretreated with the control antibody was similar to those of nontreated islets (MST = 7 days). A massive lymphocyte infiltrate into control xenografts was observed at 5 days post-transplant. In contrast, a lymphocyte 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 vitro and block graft rejection in vivo. However, graft prolongation is not accompanied by systemic tolerance. Mice transplanted simultaneously with human islet cells treated with control Ig (left kidney) or anti-ICAM-1 (right kidney) rejected the control islets but not anti-ICAM-1-treated 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 antibodies can profoundly alter graft recognition and rejection in the absence of any systemic drug therapy. However, graft prolongation is not accompanied by systemic tolerance induction.
authors.affiliation: Ben May Institute, Department of Pathology, University of Chicago, Illinois.
authors.forename: Y
authors.initials: Y
authors.lastname: Zeng
authors.forename: A
authors.initials: A
authors.lastname: Gage
authors.forename: A
authors.initials: A
authors.lastname: Montag
authors.forename: R
authors.initials: R
authors.lastname: Rothlein
authors.forename: J R
authors.initials: JR
authors.lastname: Thistlethwaite
authors.forename: J A
authors.initials: JA
authors.lastname: Bluestone
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000601:surgery; D006082:Graft Enhancement, Immunologic; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D011292:Premedication; D013601:T-Lymphocytes / Q000276:immunology; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D018799:Intercellular Adhesion Molecule-1