Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease
Selective targeting of the LIGHT-HVEM costimulatory system for the treatment of graft-versus-host disease
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DOI：
10.1182/blood-2006-09-047332
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发表时间：
2007-05-01
期刊：
影响因子：
20.3
通讯作者：
Tamada, Koji
中科院分区：
文献类型：
--
作者：
Xu, Yanhui;Flies, Andrew S.;Tamada, Koji
诱骗淋巴毒素V受体(LTβR)具有很强的免疫抑制活性，是治疗炎症、自身免疫性疾病和移植物抗宿主病(GVHD)的良好生物材料。由于该试剂可阻断多个分子间的相互作用，包括LTβ-LTβR和Light-HVEM/LTβR，其潜在的分子机制尚不完全清楚。在这项研究中，我们证明阻断LIGH-HVEM通路足以在小鼠模型中诱导GVHD的改善。当供体细胞为光缺陷(KO)T细胞时，体内转移同种异体淋巴细胞后的抗宿主细胞毒性T淋巴细胞(CTL)活性被完全消除。因此，移植异基因骨髓细胞加Light-KO或hvem-KO T细胞后，受体小鼠的存活时间显著延长。在没有LIGH-HVEM共刺激的情况下，同种异体反应性供者T细胞经历强烈的凋亡，同时它们的增殖能力保持不变。此外，我们还制备了一种针对HVEM的中和性单抗，结果表明，抗HVEM单抗能显著改善GVHD，并导致供者细胞与供者细胞完全嵌合。总之，我们的结果证明了LIGH-HVEM共刺激在移植物抗宿主病发病机制中不可或缺的作用，并为异基因骨髓移植的选择性免疫治疗提供了一个新的靶点。
Decoy lymphotoxin V receptor (LT beta R) has potent immune inhibitory activities and thus represents a promising biologic for the treatment of inflammation, autoimmune diseases, and graft-versus-host disease (GVHD). As this reagent interrupts multiple molecular interactions, including LT beta-LT beta R and LIGHT-HVEM/LT beta R, underlying molecular mechanisms have yet to be fully understood. In this study, we demonstrate that blockade of the LIGHT-HVEM pathway is sufficient to induce amelioration of GVHD in mouse models. Anti-host cytotoxic T lymphocyte (CTL) activity following in vivo transfer of allogeneic lymphocytes was completely abrogated when LIGHT- or HVEM-deficient (KO) T cells were used as donor cells. Accordingly, survival of the recipient mice following the transfer of allogeneic bone marrow cells plus LIGHT-KO or HVEM-KO T cells was significantly prolonged. In the absence of LIGHT-HVEM costimulation, alloreactive donor T cells undergo vigorous apoptosis while their proliferative potential remains intact. Furthermore, we prepared a neutralizing monoclonal antibody (mAb) specific to HVEM and showed that administration of anti-HVEM mAb profoundly ameliorated GVHD and led to complete hematopoietic chimerism with donor cells. Collectively, our results demonstrate an indispensable role of LIGHT-HVEM costimulation in the pathogenesis of GVHD and illustrate a novel target for selective immunotherapy in allogeneic bone marrow transplantation.