Expansion of alloantigen reactive Tregs for transplantation tolerance

描述（由申请人提供）：一小部分T淋巴细胞表达FoxP3，被称为调节性T细胞或T淋巴细胞。各种器官的移植通常需要治疗许多人类疾病或与疾病相关的并发症。然而，移植的组织需要在宿主T淋巴细胞的排斥反应中存活。宿主来源的供体特异性TdR提供了一种抑制移植器官排斥反应的天然方法，而没有与免疫抑制药物相关的副作用或脱靶。发现Tlymphocyte的频率非常低，动物模型表明，需要大量的Tlymphocyte才能达到临床疗效;因此，阐明Tlymphocyte扩增的机制将有助于该特定T淋巴细胞亚群诱导移植耐受的治疗应用。我们已经发现，持续的和聚集的CD3和CD28信号传导诱导效应T细胞的凋亡，并允许在不到2周内扩增T细胞。在该条件下培养12天的未分选的人CD4 T细胞（最初6%FoxP3+细胞）高度富集TcB（在培养结束时> 75%细胞Foxp3+细胞）。因此，这种方法具有很大的前景和潜力的临床应用TdR。该研究将详细研究小鼠和人的供体反应性Treg扩增以诱导移植耐受，并阐明该系统中选择性Treg扩增的机制。目的1将测试Treg特异性转录因子FoxP3在该系统中主动抑制凋亡，允许选择性增殖和扩增TcB的假设。目的2将使用MHC-肽四聚体诱导TCR连接，以测试通过固定化MHC-肽四聚体和抗-CD28选择性扩增来自小鼠和人的同种异体抗原特异性功能性TCR的持续和聚集信号传导的假设。这些研究结果将极大地促进Tclase在临床上的应用，以提高移植耐受性。 公共卫生相关性：调节性T细胞提供了一种诱导移植器官长寿的自然方式，而没有副作用。使用一种新的系统，拟议的研究旨在扩大同种异体反应性TdR，以促进移植组织对不匹配受体的长期接受。

DESCRIPTION (provided by applicant): A small subset of T lymphocytes expresses FoxP3 and is called as regulatory T cells or Tregs. Transplantation of various organs is often required to treat many human diseases or disease-related complications. However, transplanted tissues need to survive rejection by host T lymphocytes. Host-derived donor-specific Tregs offer a natural way of suppressing rejection of transplanted organs without side effects or off targets associated with immunosuppressive drugs. Tregs are found at very low frequency and animal models have shown that large numbers of Tregs are required to achieve clinical efficacy; therefore elucidation of the mechanisms underlying the expansion of Tregs will facilitate the therapeutic application of this specific subset of T lymphocytes for induction of transplantation tolerance. We have found that sustained and clustered CD3 and CD28 signaling induces apoptosis of effector T cells and allows expansion of Tregs in less than 2 weeks. Unsorted human CD4 T cells (initially 6% FoxP3+ cells) cultured for 12 days under this condition were highly enriched for Tregs (>75% cells Foxp3+ cells at end of culture). Therefore, this procedure has great promise and potential for clinical application of Tregs. The proposed study will investigate in detail the expansion of donor reactive Tregs from mice and humans for induction of transplantation tolerance and elucidate the mechanism of selective Treg expansion in this system. Aim 1 will test the hypothesis that Treg specific transcription factor FoxP3 actively suppresses apoptosis in this system, allowing selective proliferation and expansion of Tregs. Aim 2 will employ MHC-peptide tetramers for induction of TCR ligation to test the hypothesis that sustained and clustered signaling by immobilized MHC-peptide tetramers and anti-CD28 selectively expand alloantigen specific functional Tregs from mice and humans. The outcome of these studies will greatly facilitate clinical application of Tregs to improve transplantation tolerance. PUBLIC HEALTH RELEVANCE: Regulatory T cells offer a natural way of inducing longevity of transplanted organs to recipients without side effects. Using a novel system, proposed study aims to expand alloreactive Tregs to facilitate the long term acceptance of transplanted tissue to mismatch recipients.