TIGIT活化CD155信号促进调节性APC产生诱导异体复合组织移植免疫耐受的机制及应用研究

Composite tissue allotransplantation (CTA) is a crucial or even the only effective therapeutic method for large-area tissue and organ defect and dysfunction. However, its clinical application is limited by allograft rejection. Regulatory APC can induce immune tolerance, and its mechanism and application research shows good clinical application prospect in the therapeutic fields of allograft rejection and autoimmune disease. The co-inhibitory molecule CD155 plays an important role in promoting the generation of regulatory APC. Our recent study found that the activation of CD155 signal by TIGIT-Fc recombinant protein promoted the secretion of anti-inflammatory cytokine IL-10, and inhibited the secretion of pro-inflammatory cytokines IL-12, TNF-α, IL-6 by APC, which further induced Treg cells proliferation and differentiation and inhibited recipient T cells activation, proliferation and cytotoxicity against allograft antigens. Regulatory APC induced by TIGIT-Fc/CD155 signaling could protect against allograft rejection, but the potential molecule mechanism is still unclear. Thus, this study is intends to further explore the relationship between the TIGIT-CD155 signaling and transplant immune tolerance, to elucidate the cellular biological effects and related molecular mechanisms during the promotion of regulatory APC generation and Treg cells induction by this co-inhibitory signaling, and eventually to provide new ideas and molecular targets for the basic research and immunotherapy of allograft rejection.

同种异体复合组织移植（CTA）是体表大面积组织器官缺损及功能障碍重要的、甚至唯一有效的治疗手段，移植排斥反应限制了其在临床的推广应用。调节性APC可诱导免疫耐受，其机制及应用研究在移植排斥、自身免疫等领域显示了良好的临床应用前景。共抑制分子CD155对于调节性APC的产生发挥重要的调控效应。课题组研究发现，TIGIT-Fc重组蛋白活化CD155信号可促进APC分泌抑炎因子IL-10，抑制IL-12、TNF-α、IL-6等促炎因子的分泌，进而诱导Treg细胞分化增殖，抑制受体T细胞对于移植物抗原的活化、增殖和杀伤作用，显示了良好的抗移植排斥治疗效果，但相关分子机制尚不清楚。据此，本课题拟深入探讨共抑制信号TIGIT-CD155与移植免疫耐受的关系，阐明该信号促进调节性APC产生，进而诱导Treg细胞分化增殖的细胞生物学效应及相关分子机制，为移植排斥的基础研究和免疫治疗提供新思路和新靶点。

同种异体复合组织移植（CTA）是体表大面积组织器官缺损及功能障碍重要的、甚至唯一有效的治疗手段，移植排斥反应限制了其在临床的推广应用。调节性APC可诱导免疫耐受，其机制及应用研究在移植排斥、自身免疫等领域显示了良好的临床应用前景。共抑制分子CD155对于调节性APC的产生发挥重要的调控效应。本课题按既定研究方案进行，基于体外模拟移植排斥反应的混合淋巴细胞反应模型和小鼠同种异体皮瓣移植模型，研究了共抑制信号TIGIT-CD155与移植免疫耐受的关系，阐明了该信号促进调节性APC产生，进而诱导Treg细胞分化增殖，抑制同种异体移植排斥反应的细胞生物学效应及相关分子机制。研究结果表明，TIGIT/CD226-CD155信号参与移植排斥反应的发生发展，应用TIGIT-Fc重组蛋白活化CD155信号可抑制SHP1磷酸化，通过ERK-MSK1通路促进IL10转录因子CREB的入核，最终促进巨噬细胞向M2型极化。进而受体Treg细胞分化增值，显著抑制皮瓣移植排斥反应。本研究为移植排斥反应的基础研究和免疫治疗提供了新思路和新靶点，开发TIGIT-Fc重组蛋白作为一种生物制剂用于移植排斥反应的治疗具有巨大的临床需求和市场潜力。

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