Project 2: Next-Generation Mixed Chimerism Induction for Heart Allograft Tolerance

项目 2：用于心脏同种异体移植耐受的下一代混合嵌合诱导

• 批准号: 10270361
• 负责人: Leslie S Kean
• 金额: $ 66.32万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10270361
• 关键词: Address; Allograft Tolerance; Allografting; Antibodies; Antibody-drug conjugates; Bone Marrow Stem Cell; Cells; Chest; Chimerism; Chronic; Clinic; Clinical; Data; Defect; Development; Engraftment; Goals; Half-Life; Heart Diseases; Heart Transplantation; Hematopoietic; Hematopoietic Stem Cell subsets; Homeostasis; Human; Immune Tolerance; Immunity; Immunosuppression; Kidney; Life; Lung; Lymphoproliferative Disorders; Marrow; Methods; Morbidity - disease rate; Mus; Mutation; Organ; PTPRC gene; Patient risk; Patients; Proto-Oncogene Protein c-kit; Protocols documentation; Regimen; Regulatory T-Lymphocyte; Risk; Rosaniline Dyes; Safety; Sirolimus; Stem cell transplant; TNFSF4 gene; Testing; Therapeutic; Toxic effect; Translating; Translations; Transplant Recipients; Transplantation Tolerance; allograft rejection; base; cancer risk; clinical translation; clinically translatable; conditioning; design; genotoxicity; graft vs host disease; heart allograft; heart-lung allograft; high risk; immunomodulatory strategy; immunoregulation; improved; innovation; irradiation; lung allograft; mTOR inhibition; mortality; next generation; nonhuman primate; novel; novel strategies; post-transplant; preservation; prevent; stem cells; success

PROJECT SUMMARY / ABSTRACT Heart transplantation represents the best therapeutic option for patients with end-stage cardiac disease. However, while one-year success rates are reasonable, heart transplant recipients encounter high rates of morbidity and mortality, both from allograft rejection and from immunosuppression-associated toxicities. Given these issues, the ultimate goal is immune tolerance induction, which promises life-long graft acceptance without chronic immunosuppression. While tolerance to kidneys has been achieved in non-human primates (NHPs) and in humans with transient mixed chimerism, the same protocols have failed to induce tolerance to heart (and lung) allografts. Importantly, although lung allografts will not be studied in this Project, our recent findings in lung recipients provide proof of principle that durable mixed chimerism can be achieved in NHP thoracic allograft recipients which results in long term tolerance. This represents a major advance. However, this first success employed agents that are not currently clinically available, and conferred ongoing risks of graft-versus-host disease (GVHD) and of post-transplant lymphoproliferative disorder. These data, along with murine studies, suggest that durable mixed chimerism represents a robust platform for thoracic organ tolerance induction, but that improved strategies are needed, with a focus on preventing GVHD, preserving protective immunity, and rapid clinical translation. In this Project, we will address three major hurdles in translating durable chimerism- based strategies for heart transplant tolerance to the clinic: (A) Controlling graft versus host disease (GVHD) during chimerism-induction; (B) Developing novel methods of recipient conditioning that are non-genotoxic; and (C) Inducing chimerism using the safest and most efficiently engrafting subset of hematopoietic stem cells. We will do so by completing the following Specific Aims: Specific Aim 1: To induce durable mixed chimerism, optimize Treg homeostasis and preserve protective immunity with OX40L blockade and mTOR inhibition. Specific Aim 2: To develop toxicity-free induction by using antibody-drug conjugate (ADC)-based non-genotoxic conditioning to induce durable mixed-chimerism and transplant tolerance. Specific Aim 3: To induce durable chimerism with a highly purified subset of stem cells capable of rapid multilineage engraftment. If successful, this project will optimize durable chimerism induction strategies for heart allograft tolerance, amenable to immediate clinical translation.

项目摘要/摘要