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.

项目摘要/摘要 超过40%的同种异体肺移植接受者在移植后五年内死亡，这表明有一种 迫切需要解决这些患者慢性免疫抑制(IS)的不足。实现 肺部受体的强健耐受状态将减少或消除主要的肺部特异性和药物相关因素。 这导致了这一令人沮丧的统计数据。异体肾移植在非人灵长类动物(NHP)中已获得耐受性 和人类通过使用非清髓性调节和供体骨髓移植的组合 导致一过性混合造血嵌合体。然而，相同的方案未能诱导对 同种异体肺移植受者。尽管同种异体肺移植对耐受诱导有抵抗力，但我们现在已经证明 第一次，在NHP接受者中达到持久的状态(在器官的寿命内)混合嵌合体导致 同种异体肺移植的长期、无IS存活。这一显著的结果是通过修改混合嵌合体而实现的 条件反射以增强宿主调节机制。虽然这是一个重大的进步，但这种修改后的混合嵌合体 该方案仅在MHC半相合的同种异体肺移植受者中成功，并与显著的 移植后淋巴增生性疾病(PTLD)、巨细胞病毒(CMV)感染的毒性； 辐射引起的骨髓抑制。我们现在的目标是通过产生一种 更安全、更有效的方案，能够诱导对无关的、完全不匹配的MHC的长期耐受 使用FDA批准或即将批准的药物的同种异体肺移植。这个节目的统一假设是，诱导 严格的同种异体肺移植受者的持久嵌合和长期耐受性将需要下一代混合细胞 嵌合体协议，增强系统和移植物内的适应性和固有调节机制。在项目1中， 我们将1)使用器官内传递αIL-6R特异性纳米粒来降低急性排斥和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 同种异体肺移植的嵌合体和耐受性通过降低训练性免疫和免疫耐受 促进调节机制，以及3)整合抑制Bcl-2以促进持久的混合嵌合体 减少与αCD8mAb治疗和全身照射相关的毒性。这些研究将是 由项目2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 调节，调节性T细胞(Treg)支持的免疫调节，以及基因修饰的Treg，所有这些都准备好 立即进行临床翻译。由核心A(分子免疫学)协调的最先进的机械分析 CORE，“MIC”)将使在每个项目中获得的见解能够快速相互促进。我们期待着一起，这些 高度互动的项目将产生一个或多个安全有效、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 并提供了也可能改变骨髓移植和自身免疫领域的见解 疾病。