Contribution of TFH and of TREG cells to DSA generation in sensitized KTx recipients

 描述（由申请人提供）：器官移植是终末期器官衰竭相关疾病的治疗选择。尽管医学的进步和新的和更有效的免疫抑制方案的可用性，器官移植后的长期同种异体移植结果仍然很差，10年平均只有60%的同种异体移植物存活。移植排斥反应是导致移植物功能障碍和损失的重要原因之一，由多层次的细胞和体液免疫触发的损伤组成。大约30%的HLA致敏的肾移植受者在Tx后出现DSA，这显著增加了细胞和抗体介导的排斥反应（ACR，AMR）的风险。尽管DSA代表了同种异体移植物存活率降低的重要生物标志物，但迄今为止，DSA生成中涉及的确切免疫机制尚未完全了解。虽然DSA是亲和力成熟的IgG Ab，表明它们是在T细胞帮助下产生的，但是在DSA发育和维持期间T滤泡辅助（TFH）细胞的直接作用以及它们与TREG和B细胞的关系在移植领域中尚未研究，并且仍有待阐明。我们最近的初步数据显示，在一组胸腺球蛋白诱导的KTx接受者中，DSA患者中循环TFH细胞的总体%与年龄和性别匹配的健康对照（HC）或静止的DSA阴性KTx接受者的那些没有显著差异。然而，DSA阳性KTx患者显示出TFH细胞亚群向Th 1-TFH表型的显著偏斜，伴随着TREG的伴随降低，这导致与来自两个对照组的比率相比显著升高的Th 1-TFH：TREG比率。基于这些结果，我们的中心假设是，Th 1-TFH，为记忆B细胞分化为浆母细胞和产生回忆DSA提供关键帮助，并且保护T辅助细胞免疫稳态的Th 1-TFH和TREG之间的失衡与KTx后致病性DSA的发展相关。我们的具体目标是：1）确定KTx受体中CXCR 5 + Th 1 TFH对DSA产生的直接贡献; 2）研究TREG在调节CXCR 5 + Th 1 TFH细胞功能或调节B细胞DSA产生中的作用。该提议将提供对TFH和TREG在KTx后产生DSA的回忆同种免疫应答中的作用的有价值的机制理解。它还将为设计临床研究提供一个强大的科学平台，旨在加强早期发现和治疗有移植结果不良风险的患者。在肾移植受者中获得的知识可能适用于其他类型器官移植的受者，例如心脏和肺，这些器官移植的临床结果明显落后。

 DESCRIPTION (provided by applicant): Organ transplantation represents the treatment of choice for end-stage organ failure associated diseases. Despite the advancements in medicine and the availability of novel and more potent immunosuppressive regimens, the long-term allograft outcomes after organ transplantation remain poor, with an average of only 60% allograft survival by 10 years. Transplant rejection, is one of the most important causes of allograft dysfunction and loss, and consists of multi-layered cellular and humoral immunologic-triggered injuries. Approximately 30% of HLA-sensitized kidney transplant recipients present with DSA post-Tx, which significantly increase the risk for cellular- and antibody-mediated rejection (ACR, AMR). Although DSA represents an important biomarker for decreased allograft survival, till date the exact immune mechanisms implicated in DSA generation are not entirely understood. While DSA are affinity matured IgG Abs, indicating that they are generated with T cell help, the direct role of T follicular helper (TFH) cells during DSA development and maintenance, as well as their relationship with TREG and B cells has not been investigated in the field of transplantation, and remains to be elucidated. Our recent preliminary data show that in a cohort of Thymoglobulin-induced KTx recipients the overall % of circulating TFH cells in patients with DSA were not significantly different from those of age- and gender- matched healthy controls (HC) or of quiescent, DSA negative KTx recipients. However, DSA positive KTx patients display a significant skewing of TFH cell subsets toward a Th1-TFH phenotype, accompanied by a concomitant decrease in TREG that results in significantly elevated Th1-TFH:TREG ratio as compared to ratios from both control groups. Based on these results, our central hypothesis is that Th1-TFH, provide key help for memory B cells to differentiate into plasmablasts and produce recall DSA, and an imbalance between Th1-TFH and TREG which protect T helper cell immune homeostasis, correlates with the development of pathogenic DSA after KTx. Our specific aims are: 1) To determine the direct contribution of CXCR5+Th1 TFH to DSA generation in KTx recipients; 2) To study the role of TREG in tempering CXCR5+Th1 TFH cell function or in regulating B cell DSA production. This proposal will provide valuable mechanistic understanding of the roles of TFH and TREG in recall allo- immune responses that generate DSA after KTx. It will also provide a robust scientific platform for designing clinical studies aimed at enhancing the early detection and treatment of patients at risk of poor graft outcomes. Knowledge gained in kidney transplant recipients is likely to apply to recipients of other types of organ transplants, such as the heart and lung, where clinical outcomes lag significantly behind.