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 每年有数千名患者从器官移植的救生影响中受益，但这种好处是 由于需要防止拒绝供体移植物的要求。建立免疫耐受性 器官移植接受者使用终身免疫抑制疗法，尤其是淋巴细胞部署 免疫抑制策略一直是所有成功方法的关键组成部分。下列的 淋巴细胞耗尽，免疫细胞扩散以填补新近产生的免疫毒素间隙，这是一个过程 称为体内平衡重生。在此过程中，免疫微环境严重影响 确保免疫学库，并可以绕开对同种异体供体组织的反应 拒绝或宽容。我们提出，淋巴细胞的排泄后命运取决于其分化 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作用。在此 上下文，我们推进了一个可概括的重生框架：回忆性体内稳态，认为这是 在任何给定时间的淋巴细胞库都是由持续的记忆获取过程和 删除。重要的是，耗尽会加速营业额，创造了一个激烈的机会时期 建议可以操纵此过程，从而利用细胞敏感性的相对差异来创建， 时间，是一种持续的高传播性低反应性的状态。该建议旨在在此窗口上大写 通过两个相互关联的项目的工作，有机会重塑免疫恐惧的宽容 调查由行政核心支持和免疫科学核心支持的特定重生事件 分析。项目1将重点放在耗尽的T淋巴细胞重生上，而项目2将重点放在B上 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 方法和机制。具体来说，这两个项目都将采用我们主要的组织相容性综合体 （MHC）定义的非人类灵长类动物（NHP）肾移植模型，可提供严格的翻译 评估潜在的新型容忍策略。体内稳态重生是我们的中心主题 概括我们的方法超出容忍方案，更广泛的免疫抑制剂和 病毒诱导的淋巴细胞减少状态。该建议还将改善我们对 耐受性诱导中的共刺激封锁和药物Belatacept；他们提高特异性的能力 抗反应疗法的耐受性和下调同种抗体一直是我们的长期重点 研究。我们拟议的研究将基于二十年的协作经验来调查两者 NHP中的耗竭和共刺激阻滞。从这些研究中获得的知识将进一步 了解NHP和人类的耐受性机制，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。