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

项目 1：诱导 NHP 肺同种异体移植耐受的下一代混合嵌合策略

• 批准号: 10622127
• 负责人: Joren C Madsen
• 金额: $ 135.29万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-23 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622127
• 关键词: Acute; Address; Allograft Tolerance; Antibodies; Antigens; Apoptosis; Autoimmune Diseases; B-Lymphocytes; BCL2 gene; Biological Assay; Bone Marrow Diseases; Bone Marrow Transplantation; Chimerism; Chronic; Complement; Cytomegalovirus Infections; Data; Dose; Epigenetic Process; Eragrostis; Exposure to; FDA approved; Fertilization; Funding; Gene Modified; Generations; Goals; Hematopoietic; High Density Lipoprotein therapy; High Density Lipoproteins; Human; Immune; Immunity; Immunologic Memory; Immunology; Immunosuppression; Immunosuppressive Agents; Inflammatory; Kidney; Life; Lipoproteins; Lung; Lung Transplantation; Lymphoproliferative Disorders; Macrophage; Metabolic; Molecular Immunology; Monoclonal Antibodies; Myeloid Cells; Myelosuppression; Organ; Organ Survival; Organ Transplantation; Patients; Pharmaceutical Preparations; Play; Protocols documentation; Radiation; Regulatory T-Lymphocyte; Resistance; Risk Reduction; Role; Sirolimus; Stress; System; T memory cell; T-Lymphocyte; Testing; Time; Toxic effect; Training; Transplant Recipients; Transplant-Related Disorder; Transplantation; Whole-Body Irradiation; allograft rejection; clinical application; clinical translation; clinical trial readiness; conditioning; design; experience; immunoregulation; infection risk; insight; kidney allograft; lung allograft; mTOR Inhibitor; mTOR inhibition; nanobiologic; nanoparticle; nanoparticle delivery; nanotherapy; next generation; nonhuman primate; novel strategies; post-transplant; preimplantation; prevent; programs; statistics

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.

项目概要/摘要 超过 40% 的同种异体肺移植受者在移植后五年内死亡，这表明存在 解决这些患者慢性免疫抑制（IS）不足的迫切需求。实现一个 肺受体的强大耐受状态将减少或消除主要的肺特异性和药物相关因素 这导致了这一惨淡的统计数据。非人灵长类动物 (NHP) 已实现同种异体肾移植的耐受性 和人类通过结合使用非清髓性调理和供体骨髓移植 导致短暂的混合造血嵌合。然而，相同的方案未能诱导耐受 同种异体肺移植受者。尽管同种异体肺移植物对耐受诱导有抵抗力，但我们现在已经证明 第一次，在 NHP 接受者中实现持久（对于器官的生命）混合嵌合状态会导致 同种异体肺移植物的长期、无 IS 存活。这一显着的结果是通过修改混合嵌合体实现的 调节以增强宿主调节机制。虽然这是一个重大进步，但这种改良的混合嵌合现象 该方案仅在 MHC 单倍体匹配肺同种异体移植受者中成功，并且与显着相关 移植后淋巴细胞增殖性疾病（PTLD）、巨细胞病毒（CMV）感染等形式的毒性 辐射引起的骨髓抑制。我们现在的目标是通过生成一个 更安全、更有效的方案，能够诱导不相关、完全 MHC 不匹配的长期耐受 使用FDA批准或即将批准的药物进行同种异体肺移植。该程序的统一假设是诱导 严格肺同种异体移植受者的持久嵌合和长期耐受将需要下一代混合 增强系统性和移植物内适应性和先天调节机制的嵌合协议。在项目1中， 我们将 1) 使用 αIL-6R 特异性纳米颗粒的器官内递送来降低急性排斥反应和 IS 相关的风险 肺移植后立即出现并发症，2) 使用 mTORi 特异性纳米疗法实现持久 通过降低受过训练的免疫力和跨完整 MHC 屏障移植的肺同种异体移植物的嵌合和耐受性 促进调节机制，3) 结合 Bcl-2 抑制以促进持久的混合嵌合状态，同时 减少与 αCD8 mAb 治疗和全身照射 (TBI) 相关的毒性。这些研究将 项目 2 对此进行了补充，该项目将使用基于抗体的新策略来测试我们的统一假设 调理、调节性 T 细胞 (Treg) 支持性免疫调节和基因修饰的 Treg，所有这些都已准备就绪 立即临床转化。由 Core A（分子免疫学）协调的最先进的机械检测 核心（“MIC”）将使每个项目中获得的见解能够快速交叉融合。我们预计，这些 高度互动的项目将产生一个或多个安全有效的持久混合嵌合耐受方案 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 移植并提供可能改变骨髓移植和自身免疫领域的见解 疾病。