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％的肺同种异体移植接受者在移植后的五年内屈服于 紧急未满足这些患者中慢性免疫抑制（IS）不足的需求。实现 肺接受者的耐受性耐受状态将减少或消除主要的肺特异性和药物相关因素 这有助于这种令人沮丧的统计数据。在非人类灵长类动物（NHP）中已经实现了肾脏同种异体的耐受性 和人类通过使用非甲状腺不可公因的调节和供体骨髓移植的组合 导致瞬时混合造血嵌合体。但是，相同的协议未能引起公差 肺同种异体移植物的接受者。尽管肺同种异体对耐受性诱导有抵抗力，但我们现在已显示 首次达到NHP接收者中持久状态（对于器官的生命）混合嵌合体导致 长期，无肺同种异体移植物生存。通过修改混合嵌合体来实现这一显着的结果 调节以增强宿主调节机制。虽然这是一个重大进展，但这种修改的混合嵌合体 方案仅在MHC Haplo匹配的肺同种异体的接受者中成功，并且与显着相关 移植后淋巴增生性疾病（PTLD），巨细胞病毒（CMV）感染的毒性和 辐射引起的骨髓抑制。我们现在的目标是通过产生一个临床上适用这一突破 能够诱导无关，完全MHC不匹配的长期耐受性的更安全，更有效的协议 使用FDA批准或即将批准的药物的肺同种异体移植物。该计划统一的假设是 严格的肺同种异体移植物接受者的持久嵌合和长期耐受性将需要下一代混合 嵌合式协议，增强了系统性和移植物内适应性和先天调节机制。在项目1中 我们将1）使用αIL-6R特异性纳米颗粒的管道内输送来降低急性排斥的风险并与 肺移植后立即并发症，2）使用MTORI特异性纳米疗法实现耐用 通过降低训练有素的免疫力和 促进调节机制，3）纳入Bcl-2抑制作用以促进耐用的混合嵌合作用，而 减少与αCD8mAb治疗和全身辐照（TBI）有关的毒性。这些研究将是 由项目2完成，该项目将使用基于抗体的新策略来检验我们的统一假设 调节，调节T细胞（TREG） - 支持性免疫调节和基因修饰的Tregs，全部毒害 立即进行临床翻译。由核心A协调的最先进的机械测定法（分子免疫学 核心，“麦克风”将能够快速跨越每个项目中获得的见解。我们期待这些，这些 高度互动的项目将产生一个或多个安全有效的耐用混合嵌合耐受性协议 准备在资金期结束之前进行临床试验。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性的见解 疾病。