The Risks and Opportunities of Homeostatic Repopulation

稳态增殖的风险和机遇

• 批准号: 9751206
• 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/9751206
• 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; Lymphoid; 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; 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; side effect; thymocyte; transplant model

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 每年有成千上万的患者受益于器官移植的救命作用，但这种好处是有限的。 这受到防止供体移植物排异的要求的阻碍。建立免疫耐受， 器官移植受者使用终身免疫抑制治疗，特别是淋巴细胞耗竭 免疫抑制策略是所有成功方法关键组成部分。以下 当淋巴细胞耗竭时，免疫细胞增殖以填补免疫库中新产生的缺口，这是一个过程。 称为稳态再增殖。在这个过程中，免疫微环境对 随后的免疫库，并可以绕道反应同种异体供体组织， 拒绝或宽容。我们认为，淋巴细胞耗竭后的命运取决于其分化 状态，其暴露于抗原，以及驱动或抑制其生长的外源性因素的影响。在这 背景下，我们提出了一个概括性的框架：回忆稳态，假设， 在任何给定时间的淋巴细胞库都是由正在进行的记忆获得过程决定的， 删除。重要的是，消耗加速了周转，创造了一个密集的机会期，在此期间，我们 我认为这一过程可以被操纵，利用细胞易感性的相对差异， 时间，一种持续的同种异体低反应状态。该提案旨在利用这一窗口， 有机会通过两个相互关联的项目的工作， 调查由免疫管理核心和科学核心支持的特定再增殖事件 侧写项目1将关注耗竭性T淋巴细胞再增殖，而项目2将关注B 淋巴细胞/浆细胞/抗体调节。这些项目在科学上是不同的，但在科学上是互动的。 方法和机制。具体来说，这两个项目将采用我们的主要组织相容性复合体 MHC定义的非人灵长类动物（NHP）肾移植模型，提供了严格的翻译 评价潜在的新的耐受性诱导策略。稳态繁殖是我们研究的中心主题 这项工作有助于将我们的方法推广到更广泛的免疫抑制剂， 病毒诱导的淋巴细胞减少状态。这一建议也将增进我们对以下方面的作用的理解： 共刺激阻断剂和药物贝拉西普在耐受诱导中;它们增强特异性的能力 抗排斥治疗的耐受性和下调同种抗体一直是我们长期关注的焦点。 research.我们提出的研究将建立在二十年的合作经验调查， 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 理解NHP和人类的耐受机制，扩展我们对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。