Project 1: Next Generation Mixed Chimerism Strategies to Induce Lung Allograft Tolerance in NHPs

项目总结/摘要 超过40%的肺移植受者在移植后5年内死亡，这表明， 迫切需要解决慢性免疫抑制（IS）在这些患者中的不足。实现 肺移植受者的耐受状态将减少或消除主要的肺特异性和药物相关因素 导致了这一令人沮丧的统计数据。非人灵长类动物（NHPs）已实现肾移植耐受 和人的骨髓移植， 导致短暂的混合造血嵌合体。然而，相同的方案未能诱导耐受性。 肺移植的接受者。尽管同种异体肺移植物对诱导耐受有抵抗性，我们现在已经证明， 第一次，在NHP接受者中实现持久的混合嵌合体状态（对于器官的寿命）导致 肺移植物的长期无IS存活。这一显著的结果是通过改变混合嵌合体 调节以增强宿主调节机制。虽然这是一个重大进展，但这种改良的混合嵌合体 方案仅在MHC半相合的肺同种异体移植受者中成功， 移植后淋巴增生性疾病（PTLD）、巨细胞病毒（CMV）感染形式的毒性，以及 辐射引起的骨髓抑制我们现在的目标是通过产生一种 一种更安全、更有效的方案，能够诱导对无关的、完全MHC错配的 使用FDA批准或即将批准的药物进行肺移植。该计划的统一假设是，诱导 严格肺同种异体移植受者的持久嵌合体和长期耐受性将需要下一代混合 嵌合方案，增强系统和移植物内的适应性和先天调节机制。在项目1中， 我们将1）使用αIL-6 R特异性纳米颗粒的器官内递送，以降低急性排斥反应和IS相关的风险。 2）使用mTORi特异性纳米疗法来实现持久的治疗， 通过降低训练的免疫力， 促进调节机制，以及3）结合Bcl-2抑制以促进持久的混合嵌合体， 减少与α CD 8 mAb治疗和全身照射（TBI）相关的毒性。这些研究报告将 补充项目2，这将测试我们的统一假设，使用新的策略，抗体为基础的 调节性T细胞（Treg）支持性免疫调节，以及基因修饰的TcR，所有这些都为 立即临床翻译由核心A（分子免疫学）协调的最先进的机制分析 核心，“MIC”）将使在每个项目中获得的见解快速交叉施肥。我们预计，这些 高度互动的项目将产生一个或多个安全和有效的持久的混合嵌合体耐受方案 在资助期结束前准备好进行临床试验。如果成功，这些研究可能会影响整个领域， 移植，并提供见解，也可能是改变领域的骨髓移植和自身免疫性 疾病

PROJECT SUMMARY / ABSTRACT Over 40% of lung allograft recipients succumb within five years of being transplanted, making it clear that there is an urgent unmet need to address the inadequacies of chronic immunosuppression (IS) in these patients. Achieving a robust state of tolerance in lung recipients would reduce or eliminate the major lung-specific and drug-related factors that contribute to this dismal statistic. Tolerance of kidney allografts has been achieved in nonhuman primates (NHPs) and humans by using a combination of nonmyeloablative conditioning and donor bone marrow transplantation that results in transient mixed hematopoietic chimerism. However, identical protocols have failed to induce tolerance in recipients of lung allografts. Despite the resistance of lung allografts to tolerance induction, we have now shown for the first time, that achieving a state of durable (for the life of the organ) mixed chimerism in NHP recipients results in long-term, IS-free survival of lung allografts. This remarkable result was achieved by modifying the mixed chimerism conditioning to augment host regulatory mechanisms. While a significant advance, this modified mixed chimerism protocol was only successful in recipients of MHC haplo-matched lung allografts and was associated with significant toxicity in the form of posttransplant lymphoproliferative disease (PTLD), cytomegalovirus (CMV) infection, and radiation-induced myelosuppression. Our goal now is to render this breakthrough clinically applicable by generating a safer and more effective protocol that is capable of inducing long-term tolerance of unrelated, fully MHC mismatched lung allografts using FDA-approved or soon-to-be-approved drugs. This Program’s unifying hypothesis is that inducing durable chimerism and long-term tolerance in recipients of stringent lung allografts will require next-generation mixed chimerism protocols that augment systemic and intra-graft adaptive and innate regulatory mechanisms. In Project 1, we will 1) use intra-organ delivery of αIL-6R-specific nanoparticles to reduce the risk of acute rejection and IS-related complications immediately following lung transplantation, 2) use mTORi-specific nanotherapies to achieve durable chimerism and tolerance of lung allografts transplanted across a full MHC barrier by reducing trained immunity and promoting regulatory mechanisms, and 3) incorporate Bcl-2 inhibition to promote durable mixed chimerism while diminishing the toxicities related to αCD8 mAb treatment and total body irradiation (TBI). These studies will be complemented by Project 2, which will test our unifying hypothesis using novel strategies for antibody-based conditioning, regulatory T cells (Treg)-supportive immunomodulation, and gene-modified Tregs, all poised for immediate clinical translation. State-of-the-art mechanistic assays coordinated by Core A (The Molecular Immunology Core, ‘MIC’) will enable rapid cross-fertilization of insights gained in each project. We anticipate that together, these highly interactive projects will generate one or more safe and effective durable mixed chimerism tolerance protocols ready for clinical trials by the end of the funding period. If successful, these studies could impact the entire field of transplantation and provide insights that could also be field-changing for bone marrow transplantation and autoimmune disease.