Nuffield Department of Surgical Sciences, Transplantation Research Immunology Group, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Transplantation. 2010 Dec 27;90(12):1265-71. doi: 10.1097/TP.0b013e3181fe5396.
OX40 is a member of the tumor necrosis factor receptor superfamily and is a potent T-cell costimulatory molecule. Although the impact of blockade of the OX40-OX40L pathway has been documented in models of autoimmune disease, the effect on allograft rejection is less well defined.
The expression of OX40 and impact of OX40 blockade on BM3 T cells (H2Kb-reactive, T-cell receptor-transgenic) after stimulation with alloantigen were assessed in vitro by the incorporation of 3H-thymidine and flow cytometry. In vivo, naïve BM3 or polyclonal CD8+ T cells were transferred into syngeneic recombinase-activating gene(-/-) mice, which received an H2b+ skin allograft with and without anti-OX40. Skin allograft survival was monitored, and the proliferation, number, and phenotype of BM3 T cells were determined using flow cytometry.
In vitro allogeneic stimulation of CD8+ T cells resulted in OX40 expression, the blockade of which was found to partially inhibit 3H-thymidine incorporation as a result of increased cell death among activated T cells. Similarly, in vivo, anti-OX40 prevented skin allograft rejection mediated by CD8+ T cells. However, after cessation of anti-OX40 therapy, skin allografts were eventually rejected indicating that tolerance had not been induced. Correlating with the in vitro data, analysis of lymph nodes draining skin allografts revealed that OX40 blockade had no effect on the activation and proliferation of BM3 T cells but rather resulted in diminished effector T-cell accumulation.
Taken together, these data demonstrate that anti-OX40 attenuates CD8+ T-cell responses to alloantigen by reducing the pool of effector T cells, suggesting that this may be a worthwhile adjunct to preexisting costimulatory molecule-blocking regimens.
OX40 是肿瘤坏死因子受体超家族的一员，是一种有效的 T 细胞共刺激分子。尽管 OX40-OX40L 途径的阻断在自身免疫性疾病模型中已有报道，但对同种异体移植物排斥的影响还不太明确。
通过 3H-胸腺嘧啶掺入和流式细胞术评估 OX40 的表达以及 OX40 阻断对与同种抗原刺激后的 BM3 T 细胞（H2Kb 反应性，T 细胞受体转基因）的影响。在体内，将 naive BM3 或多克隆 CD8+T 细胞转移到同种基因重组激活基因（-/-）小鼠中，这些小鼠接受 H2b+皮肤同种异体移植物，并用或不用抗 OX40。监测皮肤同种异体移植物的存活，并通过流式细胞术确定 BM3 T 细胞的增殖、数量和表型。
体外同种异体刺激 CD8+T 细胞导致 OX40 的表达，阻断 OX40 发现可通过激活 T 细胞中的细胞死亡增加部分抑制 3H-胸腺嘧啶掺入。同样，在体内，抗 OX40 可防止由 CD8+T 细胞介导的皮肤同种异体移植物排斥。然而，在停止抗 OX40 治疗后，皮肤同种异体移植物最终被排斥，表明没有诱导耐受。与体外数据相关，对皮肤同种异体移植物引流淋巴结的分析表明，OX40 阻断对 BM3 T 细胞的激活和增殖没有影响，而是导致效应 T 细胞积聚减少。
总之，这些数据表明，抗 OX40 通过减少效应 T 细胞池来减弱 CD8+T 细胞对同种抗原的反应，这表明这可能是现有共刺激分子阻断方案的一个有价值的辅助手段。
