Inhibition of ICAM-1/LFA-1 interaction prevents allograft tolerance induced by anti-CD45RB

Abstract Introduction: Long-term allograft tolerance may be established by elimination of peripheral graft-reactive cell, by the induction of regulatory cells, or by induced ignorance through alteration of lymphocyte trafficking. We have investigated the contribution of the intracellular adhesion molecules ICAM-1/LFA-1 to tolerance induced by anti-CD45RB. Methods: Cardiac allografts from C3H mice were transplanted to either wild-type or ICAM-deficient C57BL/6 mice. Recipients were untreated, treated with anti-CD45RB mAb (100ug ip days 0, 1, 3, 5, and 7), or treated with a combination of anti-CD45RB and anti ICAM-1 or anti-LFA1 (50ug ip x5). Immunophenotyping of B cells by flow cytometry was performed after exposure of mice to alloantigen and anti-CD45RB. Results: Exposure of lymphocytes in vivo to anti-CD45RB and alloantigen induces upregulation of ICAM-1 on B cells. Although treatment with anti-CD45RB uniformly establishes permanent acceptance of C3H allografts (MST > 100days, n=14), coadministration of either anti-ICAM-1 or anti-LFA-1 prevents tolerance induction (MST = 28.25 ± 2.96 and 14 ± 3.11 days, respectively). Neither anti-ICAM-1 or anti-LFA-1 therapy alone induced permanent allograft survival despite modest prolongation of survival. Treatment of genetically ICAM deficient B6 animals with anti-CD45RB also failed to induce tolerance (MST = 23.66 ± 3.57 days). Conclusions: These data suggest the involvement of ICAM-1/LFA-1 interactions during tolerance induction mediated by anti-CD45RB. Whether this effect is mediated by inter- or intracellular signaling through these molecules or by alterations of lymphocyte trafficking patterns is under investigation.