UPIT: Unleash the Potential of Intestinal Transplantation

摘要 肠移植（ITx）已成为一个关键的，但未充分利用和研究，治疗选择 治疗肠衰竭的病人具体来说，虽然估计有40，000名患者可以受益于 ITx，2015年在美国仅进行了141例ITx移植;该国的最低量 器官移植这种低容量是由于与其他方法相比，ITx后患者和同种异体移植物存活率较差。 实体器官移植领域，因为这种移植与最大的 免疫细胞和任何实体器官微生物负荷。因为移植物肠病的风险很高/ 免疫移植物丢失，通常应用强的全身免疫抑制方案，这导致 高发病率和死亡率。结果是一个两难的选择：如果进行ITx，拒绝的风险很高， 导致过度免疫抑制，从而导致并发症和高昂的治疗费用， ITx从一开始就被提供。 为了解开这个第22条军规并释放ITx的潜力，这个项目将利用我们是 全国领先的ITx中心，并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移植物肠病。初步数据显示， 揭示了适应性和先天性免疫系统都是稳定同种异体移植功能的关键因素， 同种异体移植物肠病，因此，该项目的三个具体目标将集中在两个系统： 1.探讨促炎性Th 17细胞和保护性调节性T细胞的作用及机制 具有稳定同种异体移植物功能的人ITx接受者中的Treg应答与肠病 2.目的：探讨促炎性1型先天淋巴样细胞（ILC 1）的作用和机制。 和保护性3型先天性淋巴细胞（ILC 3）的反应，在人类ITx受体，稳定 同种异体移植物功能与肠病 3.阐明主调节器NOD 2（抗菌传感器）和CD 39之间的串扰 （嘌呤能信号传导）和先天性和适应性免疫反应的人ITx受体， 稳定的同种异体移植物功能与肠病 这三个目标将为改善几个患者群体的结局和生活质量奠定基础： (A)接受家庭TPN方案的患者可考虑接受ITx，最好在出现并发症之前 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 广泛的免疫抑制引起的威胁性并发症，这对儿童特别有益 在生命的最初几年接受ITx的患者;和（C）患有IBD的患者可以受益于新的 我们假设IBD受到调节ITx肠病的类似因素的影响。

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.