Treg suppression of islet allograft rejection

Treg 抑制胰岛同种异体移植排斥

• 批准号: 8664335
• 负责人: Ramakrishna Vankayalapati
• 金额: $ 27.92万
• 依托单位: UNIVERSITY OF TEXAS HLTH CTR AT TYLER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8664335
• 关键词: Adoptive Transfer; Allograft Tolerance; Allografting; Animal Model; Animals; Apoptosis; Autoimmune Diseases; Biopsy; Blood; Cell Therapy; Cells; Chemicals; Clinical Protocols; Clinical Trials; Coculture Techniques; Fibrous capsule of kidney; Graft Rejection; Graft Survival; Hepatic; Human; IL2RA gene; Immune; Immunosuppression; In Vitro; Inbred NOD Mice; Incubated; Inflammatory; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans Transplantation; Kidney; Liver; Liver parenchyma; Longevity; MAP Kinase Gene; Mediating; Modeling; Mus; Patients; Portal vein structure; Reaction; Regulatory T-Lymphocyte; Resistance; Role; Signal Pathway; Signal Transduction; Site; System; Time; Transplantation; allograft rejection; base; capsule; cytokine; design; diabetic; intrahepatic; islet; islet allograft; novel; novel strategies; peripheral tolerance; public health relevance; response

DESCRIPTION (provided by applicant): Regulatory T (Treg) cells suppress allograft rejection and are critical for peripheral tolerance. Despite the extensive studies on Treg cells and allograft survival in animal models, adoptive transfer of Treg cells alone remains ineffective in inducing long-term allograft survival or tolerance in normal wild-type (WT) animals, because only a small fraction of systemically administered Treg cells can reach an allograft. Moreover, the limited life span of transferred Treg cells also likely restrains their suppression. These problems may have severely hampered the progress in clinical trial using Treg cell therapies for suppressing allograft rejection or autoimmune diseases. This proposal will focus on optimizing Treg suppression of islet allograft rejection using novel approaches, and understanding the mechanisms of their action. We have developed a system in which donor islets are activated and incubated with CD4+CD25+ Treg cells, resulting in intra-islet recruitment of Tregs before transplantation. We found that "Treg-preoccupied" islet allografts survived much longer than "empty" islets. In addition, intra-hepatic islet transplantation in the system resulted in even longer survival than that under kidney capsule or via the portal vein. We for the first time have selected the hepatic parenchyma as a grafting site based on the facts that the liver is an immune privileged site but that islets infused via the portal vein are subject to instant blood-mediated inflammatory reaction (IBMIR). Hence, transplanting Treg-preoccupied islets in the hepatic parenchyma is a novel and practical approach to prolonging islet allograft survival by optimizing Treg suppression. We then propose to investigate whether islet allografts that are preoccupied with apoptosis-resistant Treg cells or Treg- preoccupied islet allografts that over-express IDO survive long term in the liver, whether modifying MAPK and STAT signaling pathways in Treg cells enhances their suppression, and whether Treg-preoccupied islet allografts also survive long-term in diabetic NOD mice in the presence of mild immunosuppression. We also propose to further study the mechanisms underlying the enhanced Treg suppression in the hepatic parenchyma. In this study, a unique model of intra-hepatic islet transplantation in both chemical-induced diabetic WT and NOD mice will be implemented. Apoptosis-resistant Treg cells and islets over-expressing IDO will also be utilized to maximize Treg suppression. Moreover, MAPK and STAT signaling pathways will be modified to enhance Treg function. Taken together, this study is to localize transferred Treg cells to islet allografts and promote the survival, expansion, and/or function of Treg cells so that they can optimally exert suppression. This proposal reveals a novel approach to inducing long-term islet allograft survival and may help design a clinical protocol to promote islet allograft acceptance in patients with type 1 diabetes.

描述（由申请人提供）：调节性 T (Treg) 细胞抑制同种异体移植排斥，对于外周耐受至关重要。尽管对动物模型中的 Treg 细胞和同种异体移植物存活进行了广泛的研究，但单独 Treg 细胞的过继转移仍然无法有效诱导正常野生型 (WT) 动物的长期同种异体移植物存活或耐受，因为只有一小部分全身施用的 Treg 细胞可以到达同种异体移植物。此外，转移的Treg细胞的有限寿命也可能限制了它们的抑制。这些问题可能严重阻碍了利用Treg细胞疗法抑制同种异体移植排斥或自身免疫性疾病的临床试验的进展。该提案将重点关注使用新方法优化 Treg 对胰岛同种异体移植物排斥的抑制，并了解其作用机制。我们开发了一种系统，其中供体胰岛被激活并与 CD4+CD25+ Treg 细胞一起孵育，从而在移植前在胰岛内募集 Tregs。我们发现“Treg 占据的”胰岛同种异体移植物比“空”胰岛存活的时间长得多。此外，该系统中的肝内胰岛移植比肾被膜下或门静脉移植的生存期更长。我们首次选择肝实质作为移植部位，因为肝脏是免疫特权部位，但通过门静脉注入的胰岛会发生即时血液介导的炎症反应（IBMIR）。因此，将 Treg 占据的胰岛移植到肝实质中是一种通过优化 Treg 抑制来延长胰岛同种异体移植物存活的新颖且实用的方法。然后，我们建议研究抗凋亡 Treg 细胞占据的同种异体胰岛移植物或过度表达 IDO 的 Treg 占据的同种异体胰岛移植物是否能在肝脏中长期存活，修改 Treg 细胞中的 MAPK 和 STAT 信号通路是否会增强其抑制作用，以及在存在 轻度免疫抑制。我们还建议进一步研究肝实质中 Treg 抑制增强的机制。在这项研究中，将在化学诱导的糖尿病 WT 和 NOD 小鼠中实施独特的肝内胰岛移植模型。抗凋亡 Treg 细胞和过度表达 IDO 的胰岛也将用于最大限度地抑制 Treg。此外，MAPK和STAT信号通路将被修改以增强Treg功能。总而言之，本研究旨在将转移的 Treg 细胞定位到同种异体胰岛移植物中，并促进 Treg 细胞的存活、扩增和/或功能，以便它们能够最佳地发挥抑制作用。该提案揭示了一种诱导同种异体胰岛移植物长期存活的新方法，并可能有助于设计临床方案以促进 1 型糖尿病患者接受同种异体胰岛移植物。

项目成果

c-Jun N-terminal kinase 1 defective CD4+CD25+FoxP3+ cells prolong islet allograft survival in diabetic mice.

• DOI: 10.1038/s41598-018-21477-9
• 发表时间: 2018-02-19
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Tripathi D;Cheekatla SS;Paidipally P;Radhakrishnan RK;Welch E;Thandi RS;Tvinnereim AR;Vankayalapati R
• 通讯作者: Vankayalapati R

A TLR9 agonist promotes IL-22-dependent pancreatic islet allograft survival in type 1 diabetic mice.

• DOI: 10.1038/ncomms13896
• 发表时间: 2016-12-16
• 期刊: Nature communications
• 影响因子: 16.6