Plasmacytoid Dendritic Cells and Their Role in Transplant Tolerance

浆细胞样树突状细胞及其在移植耐受中的作用

• 批准号: 8585057
• 负责人: AUDREY H LAU
• 金额: $ 6.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-02 至 2015-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8585057
• 关键词: Adoptive Transfer; Affect; Allografting; Antigens; Apoptosis; Biological Assay; Cells; Characteristics; Data; Dendritic Cells; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Frequencies; Generations; Graft Rejection; Graft Survival; Hepatic; Immune; Immune response; Immunosuppressive Agents; In Vitro; Intestines; Kidney Transplantation; Laboratories; Liver; Lymphoid Tissue; Mixed Lymphocyte Culture Test; Modeling; Mus; Myelogenous; Organ Transplantation; Outcome; Paper; Patients; Pattern; Play; Population; Property; Quality of life; Regulatory T-Lymphocyte; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Role; Small Intestines; Solid; T-Lymphocyte; Techniques; Therapeutic; Transplant Recipients; Transplantation; Work; gastrointestinal transplantation; improved; in vivo; liver allograft; liver transplantation; novel; toll-like receptor 4

DESCRIPTION (provided by applicant): Liver allografts are well tolerated, and other solid organ allografts, such as the small intestine and kidney, transplanted concurrently with livers show improved graft outcomes. However, the mechanisms underlying "hepatic tolerance" have yet to be elucidated. Previous data show that liver dendritic cells (DC) can regulate immune responses and have diminished antigen (Ag) presenting and immune stimulatory function compared with those in lymphoid tissue. Recent focus to explain this has been that functional differences between DC subsets including plasmacytoid (p)DC and myeloid (m)DC exist. It has been hypothesized that immature pDC are inherently tolerogenic. Indeed, data from multiple studies show that pDC play a unique and important role in the generation of tolerance. The tolerogenicity of pDC may be further enhanced when exposed to the unique immunosuppressive microenvironment of the liver, generating immunoregulatory hepatic DC (HDC) that impair induction of (alloreactive) T cells (3). Indeed, a recent paper examining patients who are rejecting small intestine transplant have a higher ratio of mDC to pDC, supporting a tolerogenic role for pDC (4). Little is currently known about the role of DC in small intestine transplant. This work proposes to investigate properties of hepatic and small intestine pDC to elucidate a mechanism by which pDC induce tolerance. Utilizing flow cytometry, reverse transcriptase polymerase chain reaction, enzyme-linked immunosorbent assay, mixed leukocyte reaction and T cell suppression assays, we propose in our Aims to elucidate a mechanism by which hepatic pDC induce tolerance, whether by T cell apoptosis and/or the generation of T regulatory cells. We will further examine how small intestinal transplantation alone alters immune regulatory properties. In our final Aim, we will utilize hepatic pDC as cellular therapy in a novel murine model of small intestine transplant to induce Ag specific tolerance. The models and techniques to perform the proposed studies are currently in place in the sponsor's laboratory, making the proposed Aims immediately feasible. Hepatic pDC have the potential to induce Ag specific tolerance in transplant models. By utilizing antigen specific cellular therapy, we have the potential to transform the outcome and management of organ transplantation.

描述（由申请人提供）：同种异体移植物的耐受性良好，其他同种异体移植物（例如小肠和肾脏）与肝脏同时移植显示出改善的移植结果。但是，尚未阐明“肝耐受性”的机制。先前的数据表明，与淋巴组织中的肝脏树突状细胞（DC）可以调节免疫反应，并减少抗原（Ag）的抗原（AG）和免疫刺激功能。最近解释这一点的重点是，存在包括浆细胞类动物（P）DC和髓样（M）DC在内的DC子集之间的功能差异。已经假设未成熟的PDC固有地是耐受性的。实际上，来自多个研究的数据表明，PDC在耐受性的产生中起着独特而重要的作用。当暴露于肝脏独特的免疫抑制微环境时，PDC的耐受性可能会进一步增强，从而产生免疫调节性肝直流（HDC），从而损害了（同种反应性）T细胞的诱导（3）。实际上，最近检查拒绝小肠移植的患者的一篇论文具有更高的MDC与PDC的比例，支持PDC的耐受性作用（4）。目前，DC在小肠移植中的作用知之甚少。这项工作建议研究肝和小肠PDC的性质，以阐明PDC诱导耐受性的机制。利用流式细胞术，逆转录酶聚合酶链反应，酶连接的免疫吸附测定，混合白细胞反应和T细胞抑制测定，我们的目的是阐明肝PDC的机制，无论是通过T细胞细胞和/或t rendecultory Condemultory Condemultory诱导耐受性的机制。我们将进一步研究单独的小肠移植如何改变免疫调节特性。在我们的最终目标中，我们将在小肠移植的新型鼠模型中利用肝PDC作为细胞疗法，以诱导Ag特异性耐受性。进行拟议的研究的模型和技术目前已在赞助商的实验室中进行，这使得拟议的目标立即可行。肝PDC有可能在移植模型中诱导Ag特异性耐受性。通过利用抗原特异性细胞疗法，我们有可能改变器官移植的结果和管理。