The Risks and Opportunities of Homeostatic Repopulation

稳态增殖的风险和机遇

• 批准号: 10214492
• 负责人: Stuart Johnston Knechtle
• 金额: $ 243.43万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10214492
• 关键词: Acute; Allogenic; Antibodies; Antigens; Automobile Driving; Award; B cell repertoire; B-Lymphocytes; Calcineurin; Cardiovascular Diseases; Cause of Death; Cell Cycle; Cell Death; Cells; Cellular biology; Cessation of life; Chronic; Clinical; Cyclophosphamide; Cytomegalovirus; Data; Disease; Dose; Effector Cell; Engraftment; Evaluation; Event; Exogenous Factors; Exposure to; Goals; Graft Rejection; Growth; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunologics; Immunosuppression; Immunosuppressive Agents; Impairment; Individual; Indolent; Infection; Intravenous Immunoglobulins; Isoantibodies; Kidney Transplantation; Knowledge; Life; Lymphocyte; Lymphocyte Depletion; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Methodology; Modeling; Monoclonal Antibodies; Morphology; Neoadjuvant Therapy; Organ; Organ Donor; Organ Transplantation; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Plasma Cells; Plasmapheresis; Pre-Clinical Model; Predisposition; Principal Investigator; Process; Proliferating; Protocols documentation; Radiation; Regulatory Element; Regulatory T-Lymphocyte; Research; Residual state; Risk; Role; Shapes; Specificity; Steroids; Structure of germinal center of lymph node; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Tissue Donors; Transplant Recipients; Transplantation; Viral; Viral Antigens; Work; alemtuzumab; antibody-mediated rejection; antiproliferative agents; base; desensitization; end-stage organ failure; experience; improved; inhibitor/antagonist; isoimmunity; kidney allograft; memory acquisition; memory process; nonhuman primate; novel; novel therapeutic intervention; polyclonal antibody; premature; preservation; prevent; programs; reconstitution; response; rituximab; secondary lymphoid organ; side effect; thymocyte; transplant model; tumor-immune system interactions

ABSTRACT – Overall Thousands of patients benefit each year from the lifesaving impacts of organ transplantation, but this benefit is hampered by the requirement of preventing rejection of the donor graft. Establishing immunologic tolerance in organ transplant recipients using life-long immunosuppressive therapy, in particular, the lymphocyte depletion immunosuppression strategy has been a critical component of all successful approaches. Following lymphocyte depletion, immune cells proliferate to fill the newly created gap in the immune repertoire, a process referred to as homeostatic repopulation. During this process the immune microenvironment critically influences the ensuing immunologic repertoire and can detour the response to allogeneic donor tissue either toward rejection or tolerance. We propose that the post-depletional fate of lymphocytes depends on its differentiation state, its exposure to antigen, and the effect of exogenous factors driving or inhibiting its growth. Within this context, we advance a generalizable framework for repopulation: recollective homeostasis, positing that the lymphocyte repertoire at any given time is determined by an ongoing process of memory acquisition and deletion. Importantly, depletion accelerates turnover, creating an intense period of opportunity during which we propose this process can be manipulated, exploiting relative differences in cell susceptibility to create, over time, a state of sustained allospecific hypo-responsiveness. This proposal seeks to capitalize on this window of opportunity to reshape the immune repertoire towards tolerance through the work of two interrelated projects investigating specific repopulation events supported by an administrative core and a scientific core for immune profiling. Project 1 will focus on depletional T lymphocyte repopulation, while Project 2 will focus on B lymphocyte/plasma cell/antibody modulation. These projects are scientifically distinct but are interactive in methodologies and mechanisms. Specifically, both projects will employ our major histocompatibility complex (MHC)-defined, nonhuman primate (NHP) renal transplantation model that provides rigorous translational evaluation of potential novel tolerance induction strategies. Homeostatic repopulation is a central theme in our work that serves to generalize our approach beyond tolerance protocols, to broader immunosuppressant- and viral-induced lymphopenic states. This proposal will also improve upon our understanding of the role of costimulation blockade and the drug belatacept in tolerance induction; their ability to enhance the specificity and tolerability of anti-rejection therapy and to downregulate alloantibody has been a longstanding focus of our research. Our proposed studies will build on two decades of collaborative experience investigating both depletion and costimulation blockade in NHPs. The knowledge gained from these studies will further our understanding of tolerance mechanisms in NHPs and humans, extend our understanding of T and B cell biology, and deepen our understanding of transplant immunosuppression.

摘要--总体 每年有数以千计的患者从器官移植挽救生命的影响中受益，但这种好处是 受阻于防止供体移植物排斥反应的要求。在中国建立免疫耐受 器官移植受者使用终生免疫抑制疗法，特别是淋巴细胞耗竭 免疫抑制策略一直是所有成功方法的关键组成部分。跟随 淋巴细胞耗尽，免疫细胞增殖，以填补免疫谱系中新产生的缺口，这是一个过程 称为动态平衡再繁殖。在这一过程中，免疫微环境对 随后的免疫学谱系，并可以绕开对同种异体供体组织的反应 拒绝或容忍。我们认为淋巴细胞耗竭后的命运取决于其分化。 状态、其对抗原的暴露以及推动或抑制其生长的外源因素的影响。在这个范围内 在此背景下，我们提出了一个可推广的再种群框架：回忆性动态平衡，假设 任何给定时间的淋巴细胞能力是由记忆获得和持续过程决定的 删除。重要的是，耗尽加速了营业额，创造了一个激烈的机会时期，在此期间，我们 提出这个过程是可以操纵的，利用细胞易感性的相对差异来创造， 时间，一种持续的同种异体低反应状态。这项提议寻求利用这一窗口 通过两个相互关联的项目的工作重塑免疫系统以实现耐受性的机会 在免疫管理核心和科学核心的支持下，调查具体的再繁殖事件 侧写。项目1将侧重于耗竭的T淋巴细胞再繁殖，而项目2将侧重于B淋巴细胞 淋巴细胞/浆细胞/抗体调节。这些项目在科学上是不同的，但在 方法论和机制。具体地说，这两个项目都将采用我们的主要组织相容性复合体 (MHC)定义的非人类灵长类(NHP)肾移植模型，提供严格的翻译 潜在的新的耐受诱导策略的评估。动态平衡的重新繁殖是我们的一个中心主题 这项工作旨在推广我们的方法，超越耐受性方案，推广到更广泛的免疫抑制剂--以及 病毒引起的淋巴细胞减少状态。这项建议还将改善我们对 共刺激受体阻滞剂和药物贝拉泰普诱导耐受能力的研究 而抗排斥治疗的耐受性和下调同种异体抗体一直是我们 研究。我们提议的研究将建立在20年来研究两者的合作经验的基础上 NHP中的耗竭和共刺激阻断。从这些研究中获得的知识将进一步促进我们的 了解NHP和人类的耐受机制，扩大我们对T和B细胞的理解 生物学，并加深我们对移植免疫抑制的理解。