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

诱导和维持外围耐受性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t（Treg）细胞在抑制自身免疫，注射和同种异体排斥反应中起着核心作用。但是，其功能的潜在机制主要是弹性，许多研究表明，Treg细胞被证明很难在体外和体内生长，扩展和克隆。因此，对能够增强该T细胞子集的数量和活性的新分子和/或途径进行了新的分子和/或途径的研究是非常需要的。多种动物移植模型的使用不仅提高了我们对耐受性诱导的理解，而且还提高了涉及使用调节性T细胞的新的治疗策略概念。本研究项目总结：1）我们的结果表明，淋巴……可以通过简单的CD28和ICOS共同刺激信号在体外产生具有调节细胞活性的hocytes，并且它们抑制了同种反应性的T细胞增殖。此外，这些产生的厌食症淋巴细胞可能通过自适应转移可能延长心脏同种异体移植的存活。这些产生的淋巴细胞中的关键机制可能与调节T细胞的诱导有关。 2）我们的结果提供了一个工作模型，以理解PD-1/PD-L1途径在体内调节同种免疫反应中Treg细胞介导的免疫调节的关键作用。了解抑制性T细胞在同种免疫性和移植耐受性中的抑制性T细胞共刺激途径的功能可能会使我们能够利用调节同种免疫反应的生理机制，并结合积极的共同刺激途径的阻塞，可以为实现长期延长和重复的耐受性和再生能力延伸的新颖方法提供新颖的方法。 3）我们的结果证实，SUP CD28 mAb在体内扩展了表达CD4+ CD25+ NTREG细胞的大鼠Foxp3，它们维持其独特的细胞表面标记谱并抑制同种反应性T细胞增殖。此外，这些扩展的CD4+ CD25+ Treg细胞可能会抑制GVH活性并延长心脏同种异体移植的存活率。不管直接体内扩张的可行性如何，在体外分离和扩展人CD25+ CD4+ NTREG细胞进行重新灌注的能力将允许对这种独特的T细胞子群的进一步生物学和生物化学表征，并加快将TREG细胞临床使用作为治疗Allograft Allograft Adlograft抑制和GVHD的临床使用。较少的