Treg suppression of islet allograft rejection

Treg 抑制胰岛同种异体移植排斥

• 批准号: 8477114
• 负责人: Ramakrishna Vankayalapati
• 金额: $ 26.24万
• 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 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8477114
• 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(申请人提供)：调节性T(Treg)细胞抑制同种异体移植排斥反应，对外周耐受至关重要。尽管在动物模型中对Treg细胞和同种异体移植物的存活进行了广泛的研究，但在正常野生型(WT)动物中，仅过继转移Treg细胞仍然不能有效地诱导同种异体移植物的长期存活或耐受，因为系统注射的Treg细胞中只有一小部分可以达到同种异体移植物。此外，转移的Treg细胞的有限寿命也可能抑制它们的抑制。这些问题可能严重阻碍了使用Treg细胞疗法抑制同种异体移植排斥反应或自身免疫性疾病的临床试验的进展。这项建议将重点放在使用新的方法优化胰岛同种异体排斥反应的Treg抑制，并了解它们的作用机制。我们已经开发了一种系统，在该系统中，供体胰岛被激活并与CD4+CD25+Treg细胞孵育，导致在移植前胰岛内招募Treg细胞。我们发现，“全神贯注”的同种异体胰岛移植物比“空”胰岛移植物存活时间长得多。此外，系统内肝内胰岛移植的存活时间甚至比肾包膜下或经门静脉移植的存活时间更长。我们首次选择了肝实质作为移植部位，因为肝脏是免疫特许部位，但通过门静脉输注的胰岛会受到即时血液介导性炎症反应(IBMIR)的影响。因此，在肝实质内移植Treg占优势的胰岛是通过优化Treg抑制来延长同种异体胰岛移植物存活的一种新颖而实用的方法。然后，我们建议研究专注于抗凋亡的Treg细胞的同种异体胰岛移植物或过度表达IDO的Treg专注的同种异体胰岛移植物是否在肝脏中长期存活，是否修改Treg细胞中的MAPK和STAT信号通路增强其抑制，以及专注于Treg的同种异体胰岛移植物是否也在存在轻度免疫抑制的糖尿病NOD小鼠中长期存活。我们还建议进一步研究在肝实质中增强Treg抑制的机制。在这项研究中，将在化学诱导的糖尿病WT和NOD小鼠中实施一种独特的肝内胰岛移植模型。抗凋亡的Treg细胞和过度表达IDO的胰岛也将被用来最大限度地抑制Treg。此外，MAPK和STAT信号通路将被修改以增强Treg功能。综上所述，本研究旨在将转移的Treg细胞定位于同种异体胰岛移植物，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。这项建议揭示了一种诱导同种异体胰岛移植物长期存活的新方法，并可能有助于设计一种临床方案来促进1型糖尿病患者对同种异体胰岛移植的接受。