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- 在北美开展了大量以研究为导向的成人和儿童肺移植项目。长期生存 肺移植术后的慢性肺移植物功能障碍（CLAD）是肺移植术后慢性肺移植物功能障碍的最终表现， 肺移植排斥反应肺移植免疫抑制剂不能有效预防CLAD，因为超过50%的CLAD患者的肺移植免疫抑制剂不能有效预防CLAD。 的移植患者在五年内发展为CLAD。越来越多的证据表明， 肺同种异体移植物中的细胞因子通过先天免疫和同种异体识别促进CLAD的发展， 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）， 淋巴细胞性细支气管炎（LB）、机化性肺炎（OP）或急性肺损伤（ALI）增加CLAD风险， 与肺液中I型和II型细胞因子的升高相关。因为I/II型细胞因子共享信号传导 通过Janus激酶（JAK）家族，阻断相关JAK可能是限制 炎症细胞因子反应和预防CLAD。我们的数据表明，选择性JAK 1和 部分JAK 2抑制剂在骨髓移植患者中进行测试，在完全缓解的情况下有效预防AR。 错配的小鼠原位肺移植模型，并且JAK 1在人肺中高度过表达 移植CLAD。因此，我们假设在标准的移植后免疫抑制中加入伊他替尼， 将减少由于细胞因子信号传导引起的炎症，进一步减少先天性和适应性免疫应答， 防止CLAD。为了测试这一点，我们建议完成INhIBIT-CLAD（ItacitiNIB随机，多中心， 一项双盲、安慰剂对照试验，旨在减少肺部炎症和预防CLAD）研究，招募了450名患者 两年内接受双侧肺移植的患者，随机选择280名CLAD风险较高的患者（证据 AR、LB、OP或ALI）接受伊他替尼或安慰剂治疗，并随访3 - 5年，以检测 CLAD的主要结局。我们还将从所有入组的参与者中收集生物标本， 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 有助于CLAD发展的适应性免疫应答通过选择性JAK抑制来减轻， itacitinib。最后，由于巨细胞病毒（CMV）是另一个关键的CLAD风险因素-并且是可以预防的-我们提出了一个 一项多中心感染性疾病研究，旨在预防肺移植后CMV感染， CMV特异性免疫的措施，以个性化的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以及儿童CTOTC-03、-05、-08和-11研究。已顺利完成，目前研究 建议有可能改变临床实践，改善肺移植结果，并扩大治疗 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.