Critical Role for Microvasculature in Airway Transplantation

项目摘要/摘要 淋巴循环在移植中的作用是复杂的。功能正常的淋巴管促进 通过清除炎症浸润物和水肿液促进移植物的健康，但也会导致加速排斥反应 促进同种异体免疫运输到引流的淋巴结节。在本R01的首两个授权期内，我们 已经证明了保护微血管可能是一种临床上相关的预防策略 慢性肺移植排斥反应。伴发淋巴管的健康可能会如何影响(积极或 消极的)移植的命运仍然未知。此R01竞争续订申请的目的是 应用从淋巴水肿和微血管研究中获得的知识来研究淋巴管 对同种异体移植物整体健康的贡献。 在肺移植手术中，淋巴管被切断，不能通过手术重新连接。初步研究 表明淋巴管生成，即从现有淋巴管生长出来的新淋巴管，驱动重新连接 并帮助淋巴管恢复其引流功能。 这一“早期淋巴管生成”事件通过强化免疫促进急性排斥反应，从而对移植器官造成伤害。 同种异体免疫运输，特别是在器官植入后免疫危险信号较高的情况下。 然而，在围手术期进行免疫刺激后，会出现“晚期淋巴管生成”反应。 炎症已经消退，可以通过有效地化解炎症，恢复液体平衡和 诱导免疫耐受。重要的是，试点结果表明，干扰“早期” “淋巴管生成”减弱同种免疫反应，同时抑制“晚期淋巴管生成”加速 拒绝。越来越多的证据表明，外源性促进“晚期淋巴管生成”(所谓的 ‘治疗性淋巴管生成’)通过减轻炎症和水肿减轻同种异体肺移植排斥反应。 缺氧、血管内皮生长因子C/血管内皮生长因子受体3、Notch和1-磷酸鞘氨醇是血管紧张素转换酶的关键调节因子 淋巴管生成。了解这些介质是如何调控淋巴循环功能的有助于 提出移植中治疗性淋巴管生成的概念。这笔赠款的全球假设是 移植淋巴循环对呼吸道疾病和健康的双相贡献是 由关键的淋巴管生成途径控制。特殊目标1利用药物疗法以及淋巴疗法- 特定的转基因小鼠研究移植淋巴管双相参与这两个过程的概念 疾病的发病机制和解决办法。本研究旨在探讨血管内皮生长因子-C/血管内皮生长因子受体3、Notch、S1P和 淋巴循环负性和正性特有的低氧相关信号通路 在呼吸道移植中。特定目标2使用一系列采用细胞转移或删除的实验 耐受免疫疗法以验证淋巴循环是排斥反应的唯一靶点的假设 可以保守地促进宽容。

PROJECT SUMMARY / ABSTRACT The role of the lymphatic circulation in transplantation is complex. Properly functioning lymphatics promote allograft health by clearing inflammatory infiltrates and edema fluid but also lead to accelerated rejection by facilitating alloimmune trafficking to the draining lymph nodes. In the first two grant periods of this R01, we have demonstrated how preserving blood microvessels may be a clinically-relevant strategy for preventing chronic lung transplant rejection. How the health of the accompanying lymphatics might influence (positively or negatively) the transplant's fate is still unknown. The purpose of this R01 competitive-renewal application is to apply knowledge gleaned from new lymphedema and microvascular research to study the lymphatic contribution to the overall allograft health. In lung transplantation surgery, the lymphatics are severed and not surgically-reconnected. Preliminary studies indicate that lymphangiogenesis, the growth of new lymphatics from the existing ones, drives the reconnection of the donor and recipient lymphatic vessels and help the lymphatic vessels to regain their drainage function. This “early lymphangiogenesis” event is harmful to transplants by promoting acute rejection through enhanced alloimmune trafficking, especially when immune danger signals are high following organ implantation. However, a “late lymphangiogenesis” response, occurring after immune priming when perioperative inflammation has subsided, can be beneficial by efficiently resolving inflammation, restoring fluid balance and inducing immune tolerance. Importantly, pilot results indicate that interfering with the “early lymphangiogenesis” attenuates alloimmune responses, while inhibiting “late lymphangiogenesis” accelerates rejection. Emerging evidence suggests that exogenously promoting “late lymphangiogenesis” (so-called `therapeutic lymphangiogenesis') alleviates lung allograft rejection by attenuating inflammation and edema. Hypoxia, VEGF-C/VEGFR3, Notch, and sphingosine-1-phosphate are the critical mediators of lymphangiogenesis. Understanding how these mediators govern the function of lymphatic circulation can help advance the concept of therapeutic lymphangiogenesis in transplantation. The global hypothesis of this grant is that the biphasic contribution of the transplant lymphatic circulation, to both airway disease and health, is governed by key lymphangiogenic pathways. Specific Aim 1 utilizes pharmacotherapy as well as lymphatic- specific transgenic mice to investigate the concept that transplant lymphatics biphasically participate in both disease pathogenesis and resolution. This aim investigates the roles of VEGF-C/VEGFR3, Notch, S1P and hypoxia-related signaling pathways unique to the negative and positive properties of the lymphatic circulation in airway transplants. Specific Aim 2 uses a series of adoptive cell transfer or deletion experiments and tolerizing immunotherapy to test the hypothesis that the lymphatic circulation is a unique target of rejection that can be conserved to promote tolerance.