Lung Transplant Clinical Trial Network (LT-CTN)

摘要 这个肺移植临床试验网络(LT-CTN)CTOT-CA联盟包括八个领先的高 北美的成人型和儿科肺移植项目的数量和数量。长期生存 肺移植后受限于慢性移植肺功能障碍(CLAD)，最终表现为慢性 肺移植排斥反应。肺移植免疫抑制不能有效预防包裹性肺炎，因为超过50% 的移植患者在五年内会变得衣冠楚楚。越来越多的证据表明炎症性疾病的上调 同种异体肺移植中的细胞因子通过先天免疫和同种异体识别促进包膜发育- 驱动适应性免疫反应。我们的初步数据表明，移植后急性排斥反应(AR)， 淋巴细胞性毛细支气管炎(LB)、机化性肺炎(OP)或急性肺损伤(ALI)增加风险， 与肺液中I型和II型细胞因子升高有关。因为I型/II型细胞因子共享信号 通过Janus Kinase(JAK)家族，阻止相关JAK可能是限制 炎性细胞因子反应和防止包衣。我们的数据表明，伊塔西替尼是一种选择性JAK1和 部分JAK2抑制剂在骨髓移植患者中试验，在完全预防AR方面是有效的 失配的小鼠原位肺移植模型及JAK1在人肺中的高表达 移植时穿着衣服。因此，我们假设在标准移植后免疫抑制的基础上加用伊他西尼。 将减少因细胞因子信号而引起的炎症，进一步减弱先天和获得性免疫反应，以及 防止衣着不整。为了测试这一点，我们建议完成Inhibit-clad(ItacitiNIB随机化，多中心， 减少肺部炎症和预防包膜的双盲安慰剂对照试验)研究，共招募450人 超过两年的双侧肺移植受者，并随机选择280名风险较高的患者(证据 AR、LB、OP或ALI)、伊卡西替尼或安慰剂治疗以及超过三到五年的随访，以检测 CLAD的主要结果。我们还将从所有登记的参与者那里收集生物检疫试剂，并进行 使用随机患者的肺液和组织进行的机制研究，以确定先天免疫和 选择性JAK抑制可减轻有助于包膜发育的获得性免疫反应 依塔西替尼。最后，由于巨细胞病毒(CMV)是另一个关键的危险因素，而且是可以预防的，我们建议 新型抗病毒药物预防肺移植术后巨细胞病毒感染的多中心传染病研究 测量CMV特异性免疫以个性化抗病毒预防持续时间。我们高素质的团队 调查人员带来了长期的、协作的、高度相关的经验，包括领导成人CTOT-20 和-22以及儿科CTOTC-03、-05、-08和-11研究。顺利完成，研究现在 建议有可能改变临床实践，改善肺移植结果，并扩大治疗范围 实体器官移植后免疫抑制和抗病毒预防的范例。

ABSTRACT This Lung Transplant Clinical Trials Network (LT-CTN) CTOT-CA consortium includes eight of the leading high- volume, research-oriented adult and pediatric lung transplant programs in North America. Long-term survival after lung transplantation is limited by chronic lung allograft dysfunction (CLAD), the final manifestation of chronic lung transplant rejection. CLAD is not effectively prevented by lung transplant immunosuppression, as over 50% of transplant patients develop CLAD within five years. Growing evidence suggests upregulation of inflammatory cytokines in the lung allograft contributes to CLAD development through innate immunity and allorecognition- driven adaptive immune responses. Our preliminary data demonstrate that post-transplant acute rejection (AR), lymphocytic bronchiolitis (LB), organizing pneumonia (OP), or acute lung injury (ALI) increase CLAD risk and are associated with elevations of Types I & II cytokines in the lung fluid. Because Type I/II cytokines share signaling through the Janus Kinase (JAK) family, blocking the relevant JAKs could be an effective strategy to limit inflammatory cytokine responses and prevent CLAD. Our data demonstrate that itacitinib, a selective JAK1 and partial JAK2 inhibitor being tested in patients with bone marrow transplant, is effective in preventing AR in a fully mismatched murine orthotopic lung transplant model, and that JAK1 is highly overexpressed in human lung transplant CLAD. Thus, we hypothesize that addition of itacitinib to standard post-transplant immunosuppression will reduce inflammation due to cytokine signaling, diminish further innate and adaptive immune responses, and prevent CLAD. To test this, we propose to complete the INhIBIT-CLAD (ItacitiNIB randomized, multi-center, double-blind, placebo-controlled trial to reduce lung Inflammation and prevenT CLAD) study, enrolling 450 bilateral lung transplant recipients over two years and randomizing 280 of those at higher CLAD risk (evidence of AR, LB, OP, or ALI) to treatment with itacitinib or placebo and follow-up over three to five years, to detect the primary outcome of CLAD. We also will collect biospecimens from all enrolled participants and conduct mechanistic studies using lung fluid and tissue from randomized patients to determine how innate immunity and adaptive immune responses that contribute to CLAD development are mitigated by selective JAK inhibition with itacitinib. Finally, as Cytomegalovirus (CMV) is another key CLAD risk factor – and preventable – we propose a multi-center infectious disease study targeting prevention of CMV infection after lung transplant using novel measures of CMV-specific immunity to personalize antiviral prophylaxis duration. Our highly qualified team of investigators bring longstanding, collaborative, highly relevant experience, including leading the adult CTOT-20 and-22 and the pediatric CTOTC-03, -05, -08, and -11 studies. Successfully completed, the studies now proposed have potential to transform clinical practice, improve lung transplant outcomes, and expand treatment paradigms for immune suppression and anti-viral prophylaxis after solid organ transplantation.