Synergy between cyclosporin A and a monoclonal antibody to B7 in blocking alloantigen-induced T-cell activation.
Costimulatory signals are absolutely required for T-cell activation after T-cell receptor/major histocompatibility complex-peptide interaction. So far, the best-known candidate essential costimulatory signal is mediated by interaction of CD28 on T cells with B7 on antigen-presenting cells. Using an allogeneic B7+ Epstein-Barr virus-transformed B-cell line as stimulator, we found that addition of a monoclonal antibody (MoAb) to B7 that efficiently blocks B7-CD28 interaction only partially inhibited proliferation and interleukin-2 (IL-2) production in primary and secondary mixed lymphocyte reactions (MLR), whereas the generation of cytotoxic T lymphocytes (CTL) was not affected. Inhibition of primary or secondary MLR-induced T-cell activation with cyclosporin A (CsA) at nontoxic concentrations also was never complete. However, the combination of CsA and anti-B7 MoAb B7-24 synergistically blocked allogeneic B cell-induced T-cell proliferation, IL-2 production, and CTL generation. These data suggest that the mere blockage of B7-CD28 interaction during allotransplantation will be insufficient to prevent rejection or graft-versus-host disease. However, low CsA concentrations, when combined with an agent blocking B7-CD28 interaction, can potentially achieve complete immunosuppression.
Van Gool
S W
SW
Department of Pathophysiology, Catholic University of Leuven, Belgium.
Ceuppens
J L
JL
Walter
H
H
de Boer
M
M
D000069594:Abatacept; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D018122:B7-1 Antigen / Q000502:physiology*; D018106:CD28 Antigens / Q000502:physiology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D006801:Humans; D018796:Immunoconjugates; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D007519:Isoantigens; D000069594:Abatacept; D016572:Cyclosporine