Depletion, Repopulation and Tolerance in Non-Sensitied Recipients

非敏感受体的消耗、再生和耐受性

• 批准号: 9980790
• 负责人: Allan D. Kirk
• 金额: $ 97.42万
• 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/9980790
• 关键词: Acute; Adjuvant; Alloantigen; Allografting; Animals; Antigens; Antithymoglobulin; Attention; Autoimmunity; Bone Marrow; CD28 gene; CD80 gene; CD8B1 gene; Calcineurin; Calcineurin inhibitor; Cell Adhesion Molecules; Cell Death; Cells; Characteristics; Chimeric Proteins; Chimerism; Chronic; Clinical; Clinical Trials; Cytomegalovirus; Data; Development; Elements; Excision; Fostering; Graft Survival; Hilar; Human; Immune; Immunity; Immunosuppression; Impairment; Isoantibodies; Kidney; Kidney Transplantation; Knowledge; Lead; Ligation; Lymphatic; Lymphocyte; Lymphocyte Depletion; MS4A1 gene; Macaca mulatta; Maintenance; Marrow; Mediating; Mesenchymal Stem Cells; Molecular; Monoclonal Antibodies; Output; PPP3CA gene; Pathway interactions; Patients; Perioperative; Phenotype; Population; Predisposition; Process; Receptor Signaling; Regimen; Regulation; Reporting; Residual state; Resistance; Rhesus; Risk; Shapes; Side; Sirolimus; Specificity; Splenectomy; Steroids; Stimulus; T cell differentiation; T memory cell; T-Cell Receptor; T-Lymphocyte; Therapeutic; Therapeutic immunosuppression; Thymectomy; Thymus Gland; Time; Viral; Viral Antigens; Virus Diseases; Work; alemtuzumab; base; experience; insight; irradiation; kidney allograft; mTOR Inhibitor; mTOR inhibition; nonhuman primate; prevent; secondary lymphoid organ; side effect; therapeutic effectiveness

ABSTRACT – Project 1 (Kirk, Project Lead) Kidney transplantation's considerable benefit is offset by the many complications associated with chronic immunosuppressive therapy. Calcineurin inhibitor (CNI)-based regimens are used by over 95% of patients, but these indiscriminately impair immune processes, including those that facilitate graft acceptance, and produce significant side effects. Costimulation blockade (CoB), particularly CD28-CD80/86 pathway inhibition, has been shown to promote long-term allograft survival with fewer side effects than CNIs, and recent clinical trials have suggested that lymphocyte depletion fosters CoB-based regimens, not only preventing rejection, but fostering adaptive processes that reduce the needs for immunosuppression with time, and promoting allospecific tolerance. This project seeks to define the elements of lymphocyte depletion that foster CoB-based tolerance. We have shown that lymphocyte depletion, and subsequent homeostatic repopulation, present opportunities to shape the alloreactive immune repertoire to favor tolerance, but also poses risks to disrupt regulation, and ignite viral infection, autoimmunity and activation of alloreactive clones. Our experimental plan seeks to understand these two sides of depletional induction. We hypothesize that the effectiveness of therapeutic lymphocyte depletion is NOT driven by direct elimination of CoB-resistant cells, but rather by creating a stimulus for lymphocyte turnover and thymic output, fostering antigen-specific activation induced cell death (AICD). Viewed this way, the approach to depletion changes from cell elimination, to promoting and managing repopulation, the latter controlled by relative (not absolute), maturation-defined susceptibilities of the residual lymphocyte population to the effects of antigen exposure, secondary lymphoid organ function, and immunosuppression. We posit that these factors are tractable, and can be therapeutically manipulated. To explore this, we propose 3 specific aims: Specific Aim 1: We will define the effects of depletional induction regimens (broad polyclonal or targeted monoclonal antibody mediated depletion) in rhesus monkeys undergoing kidney transplantation, comparing the effects of CNIs and mTOR inhibitors on homeostatic repopulation, and relate these to the efficacy of belatacept-induced tolerance. Specific Aim 2: We will define the impact of thymic or splenic resection or irradiation on homeostatic repopulation of allospecific cells. Specific Aim 3: We will define the impact of donor and viral (CMV) antigen exposure on repopulation and tolerance, providing prolonged donor antigen in the form of bone marrow or mesenchymal stem cells, and studying these regimens in CMV naïve animals, animals with thymic irradiation. All studies will be heavily mechanistically supported to assess the phenotype, specificity and function of the repopulating repertoire. We will partner with Project 2 to define the impact of these maneuvers on alloantibody formation, and matrix the results in the Project with those of Project 2 to establish a paradigm to guide the development of an optimized depletional regimen to pair with CoB.

摘要-项目1(Kirk，项目负责人) 肾移植相当大的好处被慢性肾移植的许多并发症所抵消 免疫抑制疗法。超过95%的患者使用基于钙调神经磷酸酶抑制剂(CNI)的方案，但 这些不分青红皂白地损害免疫过程，包括那些促进移植物接受的过程，并产生 严重的副作用。共刺激阻断(COB)，尤其是CD28-CD80/86信号通路的抑制 与CNI相比，CNI被证明能以更少的副作用促进移植物的长期存活，最近的临床试验已经 提示淋巴细胞耗尽促进了以钴为基础的方案，不仅防止了排斥反应，而且促进了 适应过程，随着时间的推移减少对免疫抑制的需求，并促进同种异体特异性 宽容。该项目旨在定义促进基于COB的淋巴细胞耗竭的因素 宽容。我们已经证明，淋巴细胞耗尽，以及随后的动态平衡重新繁殖， 塑造同种异体反应免疫系统以支持耐受性的机会，但也带来了破坏的风险 调节，并点燃病毒感染，自身免疫和同种异体反应克隆的激活。我们的实验计划 试图理解枯竭诱导的这两个方面。我们假设这一方案的有效性 治疗性淋巴细胞耗竭不是由直接消除抗钴细胞驱动的，而是由 刺激淋巴细胞周转和胸腺输出，培养抗原特异性激活诱导细胞 死亡(AICD)。从这个角度来看，耗竭的方法从消除细胞，到促进和 管理再繁殖，后者由相对(而不是绝对)、成熟定义的易感性控制 残留淋巴细胞群对抗原暴露、次级淋巴器官功能和 免疫抑制。我们假设这些因素是容易处理的，并且可以在治疗上进行操纵。至 为了探索这一点，我们提出了三个具体目标：具体目标1：我们将定义耗竭诱导的影响 恒河猴治疗方案(广谱多克隆或靶向单抗介导的耗竭) 肾移植中CNIs和mTOR抑制剂对体内平衡影响的比较 再繁殖，并将这些与贝拉泰塞诱导耐受的疗效相关联。具体目标2：我们将定义 胸腺或脾切除或放射对同种异体细胞内稳态再繁殖的影响。 具体目标3：我们将确定供体和病毒(CMV)抗原暴露对重新繁殖和 耐受性，以骨髓或间充质干细胞的形式提供延长的供体抗原，以及 在CMV幼稚动物身上研究这些方案，胸腺照射的动物。所有的研究都将是繁重的 提供机械支持，以评估重新填充剧目的表型、特性和功能。我们 将与项目2合作，确定这些动作对同种抗体形成的影响，并将 在项目成果与项目2的成果之间建立了一种范型来指导开发优化 与COB配对的耗竭方案。