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  • Title: Synergistic tolerance induced by LF15-0195 and anti-CD45RB monoclonal antibody through suppressive dendritic cells.
    Author: Min WP, Zhou D, Ichim TE, Xia X, Zhang X, Yang J, Huang X, Garcia B, Dutartre P, Jevnikar AM, Strejan GH, Zhong R.
    Journal: Transplantation; 2003 Apr 27; 75(8):1160-5. PubMed ID: 12717196.
    Abstract:
    BACKGROUND: LF 15-0195 (LF), a novel analogue of 15-deoxyspergualin (DSG), inhibits maturation of dendritic cells (DC). Anti-CD45RB is a monoclonal antibody (mAb) that blocks activation of T-helper (Th) 1 cells and generates T-regulatory cells. This study addressed whether these two reagents act synergistically to inducing tolerance, and investigated associated cellular mechanisms. METHODS: BALB/c recipients were treated by a short course of mAb alone, LF alone, or the combination of both agents. Mice that accepted a C57BL/6 cardiac allograft for more than 100 days were considered tolerant. Splenic DC were purified using positive selection for CD11c. Bone marrow DC were generated by culture with interleukin-4 and granulocyte-macrophage colony-stimulating factor. Surface marker expression was determined by fluorescence-activated cell sorter analysis. DC function was assessed by the ability to stimulate or inhibit T cells in vitro. RESULTS: Although monotherapy with LF or mAb failed to induce tolerance, combination therapy resulted in long-lasting acceptance of allogeneic hearts (>200 days) and secondary donor skin grafts (>100 days). DC from tolerant recipients possessed lower major histocompatibility complex class II and CD40 expression, and were poorer co-stimulators for T-cell proliferation than control DC. Furthermore, DC from tolerant mice induced Th2 differentiation, suppressed overall T-cell proliferation, and were poor presenters of T cells specific for antigen to pigeon cytochrome c 81-104. CONCLUSIONS: The combination of LF and anti-CD45RB mAb induced stable tolerance. The synergy of these two approaches appears to be mediated through formation of tolerogenic DC and T-regulatory cells.
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