Regulation of Liver DC Function and Transplant Tolerance

肝脏 DC 功能和移植耐受的调节

基本信息

批准号：
9927591
负责人：
Angus W Thomson
金额：
$ 45.88万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9927591
关键词：
Acute Adaptor Signaling Protein Agonist Allogenic Allograft Tolerance Allografting Anti-Inflammatory Agents Antibiotic Therapy Antigen-Presenting Cells Attenuated Behavior Blood Blood Circulation Cell Maturation Cell Transplantation Cell physiology Cell surface Cells Clinical Data Dendritic Cells Disease Environment Exhibits FDA approved Hepatocyte Human Immune Immune Tolerance Immunity In Situ Inferior Inflammatory Interleukin-10 Interleukin-12 Kidney Lead Leukocytes Liver Liver diseases Lung Lymphoid Tissue MHC antigen Maintenance Mediating Microbe Molecular Mus Myelogenous Natural Immunity Nuclear Organ Organ Donor Organ Transplantation Outcome Phase Phosphotransferases Population Proteins Receptor Activation Receptor Signaling Refractory Regulation Reporting Resistance Role STAT3 gene Signal Pathway Signal Transduction Spleen Stimulus T cell response T-Cell Activation T-Lymphocyte TLR4 gene TREM2 gene Technology Testing Therapeutic Tissues Toll-like receptors Transforming Growth Factor beta Transplantation Transplantation Tolerance Work adaptive immunity allograft rejection conditioning cytokine image reconstruction improved in vivo innovation insight intravital imaging isoimmunity liver allograft liver transplantation macrophage migration mouse development novel novel marker novel strategies prevent receptor response restoration

项目摘要

Summary The liver displays inherent tolerogenicity and liver allografts promote tolerance more readily than other organs. Compared to circulating or secondary lymphoid tissue dendritic cells (DC), liver conventional myeloid (m) DC produce lower IL-12, secrete more IL-10, induce alloAg-specific T cell hyporesponsiveness and prolong allograft survival. Liver DC are refractory to Toll-like receptor (TLR) agonism and nuclear factor (NF)κβ activation,- a critical determinant of DC maturation. Underlying mechanisms may contribute to their regulatory function and the inherent tolerogenicity of hepatic allografts. Importantly, our new data show that selective deletion of donor mDC prevents ‘spontaneous’ liver transplant tolerance in mice. Mechanisms underlying unresponsiveness to TLR agonism in DC in general, and in liver DC, in particular, are poorly defined. We have identified the signaling adaptor DNAX-activating protein of 12KDa (DAP12), that can mediate inhibition of TLR activation and that is upregulated in liver mDC, as a critical novel regulator of liver DC function and liver transplant tolerance. Consequently, we hypothesize that negative regulators of TLR signaling, in particular IL-1R-associated kinase (IRAK)-M (that we show is upregulated with DAP12 in liver mDC) confer resistance to maturation and tolerogenic capacity. We further postulate that anti- inflammatory IL-10 and TGFβ, produced in the liver, potentiate liver DC tolerogenicity through molecular ‘crosstalk’ between their respective signaling pathways (Smad for TGFβ and STAT3 for IL-10) and the TLR signaling pathway. The tolerogenic function attributed to liver mDC may contribute to induction/maintenance of liver transplant tolerance in the face of continuous TLR agonism and other pro-inflammatory stimuli. Our studies will use innovative approaches and cutting edge technology, including intravital imaging and generation of novel, chimeric donor mouse livers, to provide new mechanistic insight into the molecular regulation of liver DC function and its impact on alloreactive T cell responses and liver transplant tolerance. We will also evaluate the therapeutic potential of negative regulators of TLR signaling/liver DC maturation for restoration/promotion of transplant tolerance. We propose the following aims: AIM 1: To elucidate the role of DAP12 and inducible regulation of TLR signaling in the development of mouse liver mDC tolerogenicity, and the influence of anti- and pro-inflammatory factors; AIM 2: To establish using innovative in vivo approaches, the roles of donor mDC, TLR4, and DAP12-IRAK-M expression by liver mDC in control of T cell responses and tolerance to liver allografts.

概括肝脏表现出固有的耐受性，同种异体肝脏移植物比其他器官更容易促进耐受性。与循环或次级淋巴组织树突状细胞 (DC) 相比，肝脏常规骨髓 (m) DC 产生较低的 IL-12，分泌更多的 IL-10，诱导同种抗原特异性 T 细胞反应低下并延长同种异体移植物存活对 Toll 样受体 (TLR) 激动和核因子 (NF)κβ 具有抵抗力。激活，- DC 成熟的关键决定因素，可能有助于其调节。重要的是，我们的新数据表明，同种异体肝的功能和固有的耐受性具有选择性。缺失供体 mDC 可阻止小鼠“自发”肝移植耐受。一般 DC，特别是肝脏 DC 对 TLR 激动无反应的机制，我们已经鉴定出 12KDa (DAP12) 的信号传导接头 DNAX 激活蛋白，它可以介导 TLR 激活的抑制，并且在肝脏 mDC 中上调，作为一种重要的新型肝 DC 功能调节剂和肝移植耐受性测试，我们追求阴性。 TLR 信号传导的调节因子，特别是 IL-1R 相关激酶 (IRAK)-M（我们证明其上调是通过肝脏 mDC 中的 DAP12 赋予成熟抗性和耐受能力。肝脏产生的炎症性 IL-10 和 TGFβ 通过分子增强肝脏 DC 的耐受性各自信号通路（TGFβ 的 Smad 和 IL-10 的 STAT3）与 TLR 之间的“串扰” 肝脏 mDC 的耐受性功能可能有助于诱导/维持面对持续的 TLR 激动和其他促炎刺激，肝移植耐受。我们的研究将使用创新方法和尖端技术，包括活体成像和生成新型嵌合供体小鼠肝脏，为分子机制提供新的见解肝脏 DC 功能的调节及其对同种异体反应性 T 细胞反应和肝移植耐受的影响。还将评估 TLR 信号/肝脏 DC 成熟的负调节因子的治疗潜力我们提出以下目标：目标 1：阐明 DAP12 和 TLR 信号传导的诱导调节在细胞发育中的作用小鼠肝脏 mDC 耐受性以及抗炎和促炎因子 AIM 2 的影响；使用创新的体内方法确定供体 mDC、TLR4 和 DAP12-IRAK-M 的作用肝脏 mDC 的表达控制 T 细胞反应和对肝脏同种异体移植物的耐受性。