Anti–Intercellular Adhesion Molecule-1 Antibodies in Sera of Heart Transplant Recipients: A Role in Endothelial Cell Activation

Abstract

Antiendothelial antibodies to non-human leukocyte antigens are made by a subset of heart transplant recipients, but the specificity of such antibodies is undefined. Intercellular adhesion molecule (ICAM)-1 is an abundantly expressed adhesion molecule with polymorphic residues, expressed on the surface of endothelial cells. The hypothesis that ICAM-1 acts as a minor histocompatibility antigen and that anti-ICAM-1 antibodies, directed against polymorphic residues, could be one component of the antiendothelial antibodies found after heart transplantation has been tested. Chinese hamster ovary cells were transfected with full-length polymorphic variants of human ICAM-1. The binding of antibodies (immunoglobulin [Ig] G or IgM) to these cells was measured using sera from 50 heart transplant recipients (pretransplant and 1 and 2 years posttransplant) and sera from 20 normal volunteers by flow cytometry. The recipients and donors were genotyped for ICAM-1 polymorphisms. Sixty-eight percent (n=34) of patients made IgM antibodies that bound to ICAM-1. However, it seems unlikely that ICAM-1 is a minor transplantation antigen, because there were no differences in antibody production from recipients matched or mismatched for ICAM-1 alleles. The antibodies bound to mouse endothelial cells that were engineered to overexpress human ICAM-1, and induced a robust activation of the Erk-2 mitogen-activated protein kinase pathway. Anti-ICAM-1 antibodies are produced after cardiac transplantation, but not to polymorphic residues. Such antibodies may contribute to the endothelial activation by binding to the endothelium, causing activation of proinflammatory signaling pathways.