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: 10214495
• 负责人: Allan D. Kirk
• 金额: $ 85.48万
• 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/10214495
• 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） 肾移植的巨大益处被慢性肾脏病相关的许多并发症所抵消。 超过 95% 的患者使用基于钙调神经磷酸酶抑制剂 (CNI) 的治疗方案，但是 这些不加区别地损害免疫过程，包括促进移植物接受的免疫过程，并产生 共刺激阻断（CoB），特别是 CD28-CD80/86 通路抑制，已被证实具有显着的副作用。 与 CNI 相比，它可以促进同种异体移植物的长期存活，且副作用更少，最近的临床试验表明 表明淋巴细胞耗竭促进基于 CoB 的治疗方案，不仅可以防止排斥反应，还可以促进 随着时间的推移减少免疫抑制需求的适应性过程，并促进同种异体特异性 该项目旨在定义促进基于 CoB 的淋巴细胞消除的要素。 我们已经证明存在淋巴细胞耗竭和随后的稳态重新增殖。 塑造同种异体免疫系统以促进耐受的机会，但也带来了破坏的风险 调节，并引发病毒感染、自身免疫和同种反应性克隆的激活。 我们试图理解耗尽感应的这两个方面。 治疗性淋巴细胞清除不是由 CoB 耐药细胞的直接消除驱动的，而是由 刺激淋巴细胞更新和胸腺输出，促进抗原特异性激活诱导细胞 从这个角度来看，消除细胞的方法发生了变化，从细胞消除到促进和死亡。 管理再繁殖，后者由相对（而非绝对）、成熟定义的易感性控制 残余淋巴细胞群对抗原暴露、次级淋巴器官功能的影响，以及 我们认为这些因素是易于处理的，并且可以通过治疗来控制。 为了探索这一点，我们提出了 3 个具体目标： 具体目标 1：我们将定义耗尽感应的影响 恒河猴治疗方案（广泛多克隆或靶向单克隆抗体介导的耗竭） 接受肾移植，比较 CNI 和 mTOR 抑制剂对体内平衡的影响 重新填充，并将这些与贝拉西普诱导的耐受性的功效联系起来。 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稳态再增殖的影响。 具体目标 3：我们将定义供体和病毒 (CMV) 抗原暴露对繁殖和繁殖的影响 耐受性，以骨髓或间充质干细胞的形式提供长期的供体抗原，以及 在未接触 CMV 的动物、接受胸腺照射的动物中研究这些方案的所有研究都将进行大量研究。 机械支持评估再生库的表型、特异性和功能。 将与项目 2 合作确定这些操作对同种抗体形成的影响，并用矩阵表示 该项目的结果与项目 2 的结果一起建立了一个范式来指导优化的开发 与 CoB 配对的耗尽方案。