Requirements and mechanisms of alloantigen-induced cardiac allograft survival by cDC1s

cDC1同种异体抗原诱导心脏同种异体移植物存活的要求和机制

基本信息

批准号：
10744193
负责人：
Samantha Leigh Schroth
金额：
$ 4.32万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744193
关键词：
Acute Adult Affect Alloantigen Allograft Tolerance Allografting Anti-Inflammatory Agents Antibodies Antigen-Presenting Cells Antigens Apoptotic Biological Response Modifiers CD8-Positive T-Lymphocytes Cell Therapy Cell physiology Cells Childhood Chimerism Chronic Coupled Data Dendritic Cells Development Diabetes Mellitus Disparate Echocardiography Evaluation Exposure to Flow Cytometry Genetic Transcription Graft Rejection Graft Survival Growth Heart Transplantation Heart failure Histology Immune Immune Tolerance Immune response Immune system Immunologics Immunosuppression Immunosuppressive Agents In Vitro Inflammatory Infusion procedures Instruction Interleukin-6 Investigation Malignant Neoplasms Manuals Mediating Mediator Metabolic Methods Mitochondria Modeling Molecular Molecular Profiling Morbidity - disease rate Mus Operative Surgical Procedures Organ Transplantation Palpation Pathology Pathway interactions Patient Care Patients Peripheral Pharmaceutical Preparations Physiological Play Population Prevalence Process Reporting Research Role Signal Pathway Signal Transduction Solid Splenocyte Surface T cell response T-Cell Proliferation T-Lymphocyte TNF gene TNFSF5 gene Techniques Testing Transplant Recipients Transplantation Up-Regulation Validation Vascular Diseases Work adaptive immune response allograft rejection arm central tolerance cytokine experience graft failure heart allograft improved in vivo infancy inflammatory milieu kidney dysfunction mortality mouse model nonhuman primate novel peripheral tolerance post-transplant prevent programmed cell death ligand 1 programs response single-cell RNA sequencing standard of care transcriptional reprogramming transcriptomics transplant model uptake

Acute Adult Affect Alloantigen Allograft Tolerance Allografting Anti-Inflammatory Agents Antibodies Antigen-Presenting Cells Antigens Apoptotic Biological Response Modifiers CD8-Positive T-Lymphocytes Cell Therapy Cell physiology Cells Childhood Chimerism Chronic Coupled Data Dendritic Cells Development Diabetes Mellitus Disparate Echocardiography Evaluation Exposure to Flow Cytometry Genetic Transcription Graft Rejection Graft Survival Growth Heart Transplantation Heart failure Histology Immune Immune Tolerance Immune response Immune system Immunologics Immunosuppression Immunosuppressive Agents In Vitro Inflammatory Infusion procedures Instruction Interleukin-6 Investigation Malignant Neoplasms Manuals Mediating Mediator Metabolic Methods Mitochondria Modeling Molecular Molecular Profiling Morbidity - disease rate Mus Operative Surgical Procedures Organ Transplantation Palpation Pathology Pathway interactions Patient Care Patients Peripheral Pharmaceutical Preparations Physiological Play Population Prevalence Process Reporting Research Role Signal Pathway Signal Transduction Solid Splenocyte Surface T cell response T-Cell Proliferation T-Lymphocyte TNF gene TNFSF5 gene Techniques Testing Transplant Recipients Transplantation Up-Regulation Validation Vascular Diseases Work adaptive immune response allograft rejection arm central tolerance cytokine experience graft failure heart allograft improved in vivo infancy inflammatory milieu kidney dysfunction mortality mouse model nonhuman primate novel peripheral tolerance post-transplant prevent programmed cell death ligand 1 programs response single-cell RNA sequencing standard of care transcriptional reprogramming transcriptomics transplant model uptake

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项目摘要

PROJECT SUMMARY/ABSTRACT Heart transplantation is currently the only treatment for advanced stage heart failure and as such, the volume of transplants performed globally continues to increase. Advances in surgical technique and available immunosuppression have improved patient survival acutely, however the same cannot be said years after transplantation. Immune mediated pathologies such as chronic allograft vasculopathy result in graft failure and significant morbidity from prolonged use of immunosuppressant medication including renal dysfunction, diabetes, and malignancy, continue to be experienced by patients. Therefore, improved strategies to promote survival of the cardiac allograft are necessary. A great deal of research has sought to identify the cellular actors responsible for cardiac allograft rejection and tolerance. In the setting of rejection, the adaptive immune response has emerged in a leading role, specifically CD4+ and CD8+ T cells. Importantly, T cells are not solo performers but instead require instruction provided by antigen presenting cells, predominantly dendritic cells (DCs). Once considered a homogenous population, DCs are now recognized for their distinct ontogeny and functional roles which determine DC subset identity. Conventional DC 1 cells (cDC1s) are powerful mediators of the immune response and have been shown to be critical for the promotion of central tolerance. Yet no work on the subset specific role of cDC1s in solid organ transplantation has been performed and our understanding of cDC1s in peripheral tolerance remains in its infancy. Importantly, my preliminary data implicate cDC1s as necessary in donor-induced tolerization strategies that result in long term cardiac allograft survival. Tolerization strategies utilizing infused donor antigen and costimulation blockade (CoB) produce long term cardiac allograft survival in murine and nonhuman primate models, though little is known as to how exposure of donor alloantigen influences tolerance induction. This proposal hypothesizes that during a donor-induced tolerance strategy, the cDC1 subset is necessary to promote peripheral immunological hyporesponsiveness towards cardiac allografts through processing of alloantigen, modulation of surface marker expression, and metabolic transcriptional reprogramming. This hypothesis will be tested using mouse models of cDC1 deletion and heterotopic heart transplantation alongside functional (palpation, echocardiography) and cellular (flow cytometry, histology) analysis. Additionally, single-cell transcriptomics of splenic DCs after in vivo allo- and iso- infusion in the presence of CoB coupled with in vitro experimentation will help unveil cDC1 specific programming that promote a tolerogenic allospecific response. Thus, the proposed studies will identify targetable pathways to enhance immunologic tolerance and improve cardiac allograft survival.

项目摘要/摘要心脏移植是目前唯一用于晚期心力衰竭的治疗方法，因此全球进行的移植物继续增加。手术技术的进步和可用免疫抑制急性地改善了患者的生存，但是几年后不能说。移植。免疫介导的病理（例如慢性同种异体血管病）导致移植衰竭和长期使用免疫抑制剂药物（包括肾功能障碍，糖尿病，和恶性，患者继续经历。因此，改进了促进生存的策略心脏同种异体移植是必要的。大量研究试图确定负责心脏同种异体拒绝和的细胞参与者宽容。在排斥反应的情况下，自适应免疫反应已出现在领导作用中，特别是 CD4+和CD8+ T细胞。重要的是，T细胞不是独奏表演者，而是需要由抗原呈现细胞，主要是树突状细胞（DC）。一旦被视为同质人口，DCS 现在，以确定直流子集身份的独特的跨发育和功能作用而被认可。常规DC 1细胞（CDC1）是免疫反应的强大介体，已被证明是对于促进中心容忍至关重要。然而，在固体器官中CDC1的子集特异性作用尚无作用已经进行了移植，我们对外围耐受性中Cdc1的理解仍然存在婴儿期。重要的是，我的初步数据暗示了供体诱导的公差策略的必要这导致长期心脏同种异体移植生存。使用注入供体抗原和共刺激阻滞（COB）的耐受策略长期产生鼠和非人类灵长类动物模型中的心脏同种异体移植生存供体同具有影响耐受性诱导。该提议假设在捐赠者引起的期间耐受性策略，CDC1子集是促进外周免疫学所必需的通过处理同种异体对心脏同种异体移植的反应不足，调制表面标记表达和代谢转录重编程。该假设将进行检验使用CDC1缺失和异位心脏移植的小鼠模型与功能（palpation，palpation，超声心动图）和细胞（流式细胞仪，组织学）分析。另外，单细胞转录组学体内异胞体同质和同in-在存在的cob和体外实验的情况下的脾脏DC将会帮助揭示CDC1特定的编程，以促进耐受性的外旋响应。因此，提议研究将确定可靶向的途径，以增强免疫学耐受性并改善心脏同种异体移植的存活率。