Novel Approaches to Inducing Lung Allograft Tolerance in NHPs

诱导 NHP 肺同种异体移植耐受的新方法

• 批准号: 10622123
• 负责人: Joren C Madsen
• 金额: $ 348.59万
• 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/10622123
• 关键词: Acute; Address; Allograft Tolerance; Allografting; Antibodies; Autoimmune Diseases; BCL2 gene; Biological; Biological Assay; Bone Marrow Diseases; Bone Marrow Transplantation; Cell Therapy; Chimerism; Chronic; Clinical; Collaborations; Complement; Computer Analysis; Cytomegalovirus Infections; Dedications; Engineering; Environment; FDA approved; Fertilization; Flow Cytometry; Funding; Gene Modified; Goals; Hematopoietic; Human; Immune system; Immunity; Immunogenetics; Immunosuppression; Immunosuppressive Agents; Life; Lung; Lung Transplantation; Lymphoproliferative Disorders; Molecular Immunology; Monoclonal Antibodies; Myelosuppression; Organ; Organ Survival; Organ Transplantation; Patients; Pharmaceutical Preparations; Physicians; Play; Preparation; Procedures; Protocols documentation; Radiation; Regulation; Regulatory T-Lymphocyte; Research Personnel; Resistance; Risk Reduction; Sampling; Solid; Stress; Sum; Testing; Time; Toxic effect; Training; Transplant Recipients; Transplant Surgeon; Transplant-Related Disorder; Transplantation; Transplantation Tolerance; Whole-Body Irradiation; career; clinical application; clinical translation; clinical trial readiness; conditioning; experimental study; immunoregulation; improved; innovation; insight; kidney allograft; lung allograft; lung basal segment; nanoparticle; nanotherapy; next generation; nonhuman primate; novel strategies; post-transplant; programs; statistics; synergism; transcriptomics; virology

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 test this hypothesis using intra-organ delivery of αIL-6R-specific and mTORi-specific nanotherapies to reduce IS-related complications, block trained immunity, and promote intra-graft regulation. Bcl-2 inhibition will be used to promote durable mixed chimerism while diminishing the toxicities related to total body irradiation (TBI)-driven myelosuppression. 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.

项目总结/文摘