封闭CD25对调节性T细胞功能演变及下游信号通路影响的研究

Strategies of immune tolerance induction may interfer the characteristic of regulatory T cell (Treg) and further affect its immune-regulating-role, which greatly influences both the rejection and immune tolerance. Anti-CD25 monoclonal antibody is one of the most commonly used agents for inducing therapy during the clinical procedure. It is able to potently block the site of CD25 (also known as IL-2Rα), and therefore probably affect the intracellular signaling of Treg. In our previous studies, we have found that the anti-CD25 monoclonal antibody could significantly decrease the number of CD25+ T cells and maintain it in low for about two weeks. However, the expression of Foxp3 in peripheral T cells was not affected. Furthermore, the activated subpopulation of Treg showed an obvious dynamic down-up alteration. Therefore, we suppose that the charactristical marker of Treg should be maintained independent the IL-2Rα signaling pathway and the effect on its function is still not sure. Herein, we are going to do further exploration on how the immune inhibiting function changes and how the intracellular signaling activity and Foxp3 expression of Treg are regulated. This study will provide a meaningful demonstration to reveal the underlying immune mechanism of anti-CD25 clonal antibody.

器官移植的免疫诱导治疗可导致调节性T淋巴细胞(Treg)细胞表型的变化，Treg分子表型与其免疫调节作用密切相关，对移植排斥和耐受诱导两方面均有显著影响。作为器官移植临床诱导治疗的一线药物，抗CD25单抗在封闭Treg表面IL-2Rα的同时，也必然影响下游信号通路及蛋白表达。课题组前期研究证实抗CD25单抗诱导治疗虽然在早期显著降低患者外周血CD25+T淋巴细胞比例,但并未下调Foxp3的表达，而Treg的活化亚型亦呈现明显下降-恢复的动态变化,提示CD25封闭后的Treg可能通过独立于IL-2Rα的受体信号通路维持其特征分子表达，对其功能影响亦待明确。本课题拟在前期工作基础上，深入探索抗CD25单克隆抗体封闭后调节性T细胞免疫抑制功能演变，并探究下游各受体信号通路的作用，进一步阐明抗CD25单抗对调节性T细胞的生物学效应，研究结果对进一步明确抗CD25单抗的免疫学机制具有重要意义。

器官移植的免疫诱导治疗可导致调节性T细胞（Treg）细胞表型的变化，Treg分子表型与其免疫调节作用密切相关，对移植排斥和耐受诱导两方面均有显著影响。作为器官移植临床诱导治疗的一线药物，抗CD25单抗在封闭Treg表面IL-2Rα的同时，也必然影响下游信号通路及蛋白表达。课题组前期研究证实抗CD25单抗诱导治疗虽然在早期显著降低患者外周血CD25+ T细胞比例，但并未下调Foxp3的表达，而Treg的活化亚型亦呈现明显下降-恢复的动态变化，提示CD25封闭后的Treg可能通过独立于IL-2Rα的受体信号通路维持其特征分子表达，对其功能影响亦待明确。本课在前期工作基础上，深入探索了抗CD25单克隆抗体封闭后Treg免疫抑制功能演变，发现抗CD25单抗可能有助于诱导用药后短期患者体内的低反应时间窗，而不影响Treg的生存，并保留其细胞因子分泌谱及免疫抑制功能和表面受体的表达。同时，发现肾移植急性排斥发生时，Treg效应分子可溶性纤维介素sFGL2的水平与Treg的比例呈正相关，并可促进肾小管上皮细胞凋亡。这些发现对Treg诱导免疫耐受的机制及开发临床有效作用靶点具有重要意义。