Inhibition of ICAM-1/LFA-1 interactions prevents B-cell-dependent anti-CD45RB-induced transplantation tolerance.

Huang X, Moore DJ, Mohiuddin M, Lian MM, Kim JI, Sonawane S, Wang J, Gu Y, Yeh H, Markmann JF, Deng S
Transplantation. 2008 85 (5): 675-80

PMID: 18337659 · PMCID: PMC2934773 · DOI:10.1097/TP.0b013e3181663422

BACKGROUND - Allogeneic tolerance can be reliably obtained with monoclonal antibody therapy targeting CD45RB. Although regulatory T cells play an important role in the mechanism, we have recently demonstrated the active participation of host B lymphocytes. After anti-CD45RB therapy, B lymphocytes demonstrate phenotypic alterations that include up-regulation of CD54 (intercellular adhesion molecule [ICAM]-1). We have investigated the hypothesis that alteration in ICAM-1 expression is required for tolerance induction.

MATERIALS AND METHODS - Recipients of heterotopic allogeneic cardiac grafts (C3H donors into B6 recipients) were treated with anti-CD45RB, anti-ICAM, anti-lymphocyte function-associated antigen-1 (LFA), or the combination of these agents. These data were extended by performing allogeneic cardiac transplants into ICAM or LFA recipients treated with a 5-day course of anti-CD45RB. Finally, B-cell-deficient animals were reconstituted with ICAM splenocytes to create a recipient with a selective deficiency of ICAM-1 restricted to the B-cell compartment.

RESULTS - Anti-CD45RB alone or the combination of anti-LFA/anti-ICAM reliably induced transplantation tolerance. However, the triple combination was routinely unsuccessful and induced long-term graft survival in no recipients. ICAM-deficient or LFA-deficient recipients were also resistant to tolerance induced by anti-CD45RB. Finally, transfer of control splenocytes to B-cell-deficient recipients permitted anti-CD45RB-induced tolerance, whereas transfer of ICAM cells was unable to support tolerance induction.

CONCLUSIONS - Expression of ICAM-1 by B lymphocytes and interaction with LFA-1 form a central aspect of transplantation tolerance induced by anti-CD45RB therapy. These data further elucidate the cellular mechanisms used by B lymphocytes in the induction of transplantation tolerance.

MeSH Terms (16)

Animals Antibodies B-Lymphocytes Flow Cytometry Heart Transplantation Intercellular Adhesion Molecule-1 Leukocyte Common Antigens Lymphocyte Function-Associated Antigen-1 Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Knockout Spleen T-Lymphocytes Transplantation, Homologous Transplantation Tolerance

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