UPIT: Unleash the Potential of Intestinal Transplantation

UPIT：释放肠移植的潜力

基本信息

批准号：
9363192
负责人：
Alexander Helmut Kurt Kroemer
金额：
$ 49.38万
依托单位：
GEORGETOWN UNIVERSITY
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：
2017-05-05 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9363192
关键词：
Adaptive Immune System Address Adoptive Transfer Adverse effects Allografting Alpha Cell American Antigens B-Lymphocytes Biological Preservation Cells Child Complex Country Data Epithelial Failure Foundations Future Goals Grant Home environment Human Immune Immune response Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy Inflammatory Innate Immune System Interleukin-17 Intestines Knowledge Lead Life Light Lymphoid Lymphoid Cell Mediating Morbidity - disease rate Organ Organ Transplantation Outcome Patients Play Prevention Prevention approach Procedures Public Health Quality of life Regimen Regulatory T-Lymphocyte Research Risk Risk Factors Role Signal Transduction Solid System T-Cell Receptor T-Lymphocyte Therapeutic Total Parenteral Nutrition Transplantation Treatment Cost United States Work adaptive immune response allograft rejection antimicrobial base cell type cost high risk improved outcome in vivo innovation insight microbial mortality novel novel therapeutics prevent response sensor

项目摘要

Abstract Intestinal transplantation (ITx) has emerged as a key, but under-utilized and under-studied, therapeutic option for patients suffering from intestinal failure. Specifically, while an estimated 40,000 patients could benefit from ITx, a mere 141 ITx transplants were performed in the United States in 2015; the country's lowest volume solid organ transplant. This low volume is due to poor patient and allograft survival after ITx when compared to other fields of solid organ transplantation as this transplant is associated with the transplantation of the largest immune cell and microbial load of any solid organ. Because there is a high risk of allograft enteropathy/ immunological graft loss, strong regimens of generalized immunosuppression are typically applied, which lead to high morbidity and mortality. The result is a catch-22: if ITx is performed, the risk of rejection is high, which leads to over-immunosuppression, which results in complications and high treatment costs, which dissuades ITx from being offered in the first place. To untangle this catch-22 and unleash the potential of ITx, this project will leverage the fact that we are the leading ITx center in the country and lay the groundwork for a targeted immunotherapy approach to prevent/ control allograft enteropathy with minimization of generalized immunosuppression. Preliminary data has revealed that both the adaptive and innate immune systems are key players in stable allograft function and allograft enteropathy and as such, this project's three specific aims will focus on both systems: 1. To determine the roles and mechanisms of proinflammatory Th17 and protective regulatory T cell (Treg) responses in human ITx recipients with stable allograft function versus enteropathy 2. To determine the roles and mechanisms of proinflammatory type 1 innate lymphoid cell (ILC1) and protective type 3 innate lymphoid cell (ILC3) responses in human ITx recipients with stable allograft function versus enteropathy 3. To elucidate the crosstalk between the master regulators NOD2 (antimicrobial sensor) and CD39 (purinergic signaling) and innate and adaptive immune responses in human ITx recipients with stable allograft function versus enteropathy These three aims will lay the foundation for improving outcomes and quality of life for several patient groups: (A) patients who are on home-based TPN regimens could be considered for ITx, ideally before complications worsen that jeopardize the outcomes of ITx; (B) new and past recipients of ITx could avoid the life threatening complications from generalized immunosuppression, which will be especially beneficial for children who receive ITx in their earliest years of life; and (C) patients suffering from IBD could benefit from new therapeutic insights as we hypothesize that IBD is influenced by similar factors that modulate ITx enteropathy.

抽象的肠移植 (ITx) 已成为一种关键的治疗选择，但尚未得到充分利用和研究对于患有肠道衰竭的患者。具体来说，虽然估计有 40,000 名患者可以受益 ITx，2015年美国仅进行了141例ITx移植；全国最低量固体器官移植。如此低的体积是由于与其他方法相比，ITx 后患者和同种异体移植物的存活率较差实体器官移植领域，因为这种移植与最大的移植相关任何实体器官的免疫细胞和微生物负荷。因为同种异体移植肠病的风险很高/ 免疫性移植物丢失，通常采用强效的全身免疫抑制方案，这导致导致高发病率和死亡率。结果是第 22 条军规：如果进行 ITx，被拒绝的风险很高，这导致过度免疫抑制，从而导致并发症和高昂的治疗费用，这令人望而却步 ITx 从一开始就被提供。为了解决这个第 22 条军规并释放 ITx 的潜力，该项目将利用我们是国内领先的 ITx 中心，为有针对性的免疫治疗方法奠定基础，以预防/ 通过最小化全身免疫抑制来控制同种异体移植肠病。初步数据有研究表明，适应性免疫系统和先天免疫系统都是稳定同种异体移植功能的关键因素，同种异体移植肠病，因此，该项目的三个具体目标将集中于这两个系统： 1. 确定促炎性Th17和保护性调节T细胞的作用和机制具有稳定同种异体移植功能的人类 ITx 受体与肠病的 (Treg) 反应 2. 确定促炎1型先天淋巴细胞（ILC1）的作用和机制和保护性 3 型先天淋巴细胞 (ILC3) 反应在人类 ITx 接受者中稳定同种异体移植物功能与肠病 3. 阐明主调节器NOD2（抗菌传感器）和CD39之间的串扰（嘌呤能信号传导）以及人类 ITx 接受者的先天性和适应性免疫反应稳定的同种异体移植功能与肠病这三个目标将为改善多个患者群体的治疗结果和生活质量奠定基础： (A) 采用家庭 TPN 方案的患者可以考虑接受 ITx，最好是在出现并发症之前恶化，危及 ITx 的结果； (B) 新的和过去的 ITx 接受者可以避免生命全身免疫抑制带来的威胁性并发症，这对儿童特别有益在生命的最初几年接受 ITx 的人； (C) 患有 IBD 的患者可以从新的治疗中受益治疗见解，因为我们假设 IBD 受到调节 ITx 肠病的类似因素的影响。