The mechanisms of the induction and maintenance of the transplantation tolerance and usage of the Treg cells as a cellular therapy for treatment allograft rejection and GvHD

诱导和维持移植耐受的机制以及使用 Treg 细胞作为治疗同种异体移植排斥和 GvHD 的细胞疗法

基本信息

批准号：
17390355
负责人：
RII Ko
金额：
$ 9.53万
依托单位：
National Research Institute for Child Health and Development
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

Induction and maintenance of peripheral tolerance are important mechanisms for the balance of the immune system. Growing evidence indicates that the CD4+CD25+ regulatory T (Treg) cells play a central role in the suppression of autoimmunity, inflammation and allograft rejection. However, the underlying mechanism of their functions remains mostly elusive and many studies suggest that the Treg cells have proven difficult to grow, expand and clone in vitro and in vivo. Therefore, the investigations of the novel molecular and/or pathway for understanding their regulatory functions and therapeutic agents that are capable of enhancement the number and activity of this T cell subset are highly desirable. The use of the multiple animal transplantation models has not only improved our understanding of tolerance induction, but also contributed to new concepts of treatment strategies involving the use of regulatory T cells. The present research project summarizes : 1) our results suggest that lymp … More hocytes with regulatory cell activity can be generated in vitro by simultaneous blockade of CD28 and ICOS co-stimulatory signals and that they inhibit alloreactive T-cell proliferation. Moreover, these generated anergic lymphocytes may potentially prolong cardiac allograft survival by adoptive transfer. The key mechanism in these generated lymphocytes may be associated with the induction of regulatory T cells ; 2) our results provides a working model for understanding the crucial roles of Treg cell-mediated immunomodulation by the PD-1/PD-L1 pathway in regulating the alloimmune responses in vivo. Understanding the functions of the inhibitory T cell co-stimulatory pathways in alloimmunity and transplantation tolerance may allow us to utilize the physiologic mechanisms that regulate alloimmune responses, and, in combination with blockades of positive co-stimulatory pathways, may provide a novel approach to achieving long-lasting and reproducible tolerance and reduction of transplantation complications such as rejection and GvHD ; 3) our results confirm that sup CD28 mAb expands rat Foxp3 expressing CD4+CD25+ nTreg cells in vivo, which maintain their unique cell surface marker profile and inhibit alloreactive T-cell proliferation. Moreover, these expanded CD4+CD25+ Treg cells potently inhibit the GvH activity and prolong cardiac allograft survival. Regardless of the feasibility of direct in vivo expansion, the ability to isolate and expand human CD25+CD4+ nTreg cells in vitro for re-infusion will allow the further biological and biochemical characterization of this unique T cell subset and expedite progress towards clinical use of Treg cells as a cellular therapy for treatment allograft rejection and GvHD. Less

外周耐受的诱导和维持是免疫系统平衡的重要机制，越来越多的证据表明 CD4+CD25+ 调节性 T (Treg) 细胞在抑制自身免疫、炎症和同种异体移植排斥方面发挥着核心作用。其功能机制仍然大多难以捉摸，许多研究表明 Treg 细胞已被证明难以在体外和体内生长、扩增和克隆，因此，需要研究新的分子和/或途径来了解其调节功能和治疗剂。有能力的多种动物移植模型的使用不仅提高了我们对耐受诱导的理解，而且还促进了使用调节性 T 细胞的治疗策略的新概念。目前的研究项目总结：1）我们的结果表明，通过同时阻断 CD28 和 ICOS 共刺激信号，可以在体外产生具有调节细胞活性的淋巴细胞，并且它们会抑制同种异体反应性 T 细胞增殖。淋巴细胞可能通过过继转移延长同种异体心脏移植物的存活，这些产生的淋巴细胞的关键机制可能与调节性 T 细胞的诱导有关；2) 我们的结果为理解 PD 介导的 Treg 细胞免疫调节的关键作用提供了一个工作模型。 -1/PD-L1 通路在体内调节同种免疫反应中的作用了解抑制性 T 细胞共刺激通路在同种免疫和移植耐受中的功能可能使我们能够利用调节同种免疫的生理机制。反应，并与积极共刺激途径的阻断相结合，可能提供一种新的方法来实现持久和可重复的耐受性并减少移植并发症，如排斥和 GvHD；3) 我们的结果证实，sup CD28 mAb 可以扩增大鼠。 Foxp3 在体内表达 CD4+CD25+ nTreg 细胞，保持其独特的细胞表面标记特征并抑制同种反应性 T 细胞增殖。此外，这些扩增的 CD4+CD25+ Treg 细胞有效抑制无论直接体内扩增的可行性如何，在体外分离和扩增人类 CD25+CD4+ nTreg 细胞以进行再输注的能力将允许对这种独特的 T 细胞亚群进行进一步的生物学和生化表征。并加快 Treg 细胞作为治疗同种异体移植排斥和 GvHD 的细胞疗法的临床应用进展。