Tamada Koji, Tamura Hideto, Flies Dallas, Fu Yang-Xin, Celis Esteban, Pease Larry R, Blazar Bruce R, Chen Lieping
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
J Clin Invest. 2002 Feb;109(4):549-57. doi: 10.1172/JCI13604.
Previous studies have shown that blockade of LIGHT, a T cell costimulatory molecule belonging to the TNF superfamily, by soluble lymphotoxin beta receptor-Ig (LTbetaR-Ig) inhibits the cytotoxic T lymphocyte (CTL) response to host antigenic disparities and ameliorates lethal graft-versus-host disease (GVHD) in a B6 to BDF1 mouse model. Here, we demonstrate that infusion of an mAb against CD40 ligand (CD40L) further increases the efficacy of LTbetaR-Ig, leading to complete prevention of GVHD. We further demonstrate that alloantigen-specific CTLs become anergic upon rapid expansion, and persist in the tolerized mice as a result of costimulatory blockade. Transfer of anergic CTLs to secondary F1 mice fails to induce GVHD despite the fact that anergic CTLs can be stimulated to proliferate in vitro by antigens and cytokines. Our study provides a potential new approach for the prevention of lethal GVHD.
先前的研究表明，可溶性淋巴毒素β受体-Ig（LTβR-Ig）阻断属于肿瘤坏死因子超家族的T细胞共刺激分子LIGHT，可抑制细胞毒性T淋巴细胞（CTL）对宿主抗原差异的反应，并改善B6至BDF1小鼠模型中的致死性移植物抗宿主病（GVHD）。在此，我们证明输注抗CD40配体（CD40L）单克隆抗体可进一步提高LTβR-Ig的疗效，从而完全预防GVHD。我们进一步证明，同种异体抗原特异性CTL在快速扩增后会变为无反应性，并由于共刺激阻断而在耐受小鼠中持续存在。尽管无反应性CTL可在体外被抗原和细胞因子刺激增殖，但将其转移至二级F1小鼠中却未能诱导GVHD。我们的研究为预防致死性GVHD提供了一种潜在的新方法。
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