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: 10649945
• 负责人: Allan D. Kirk
• 金额: $ 65.75万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10649945
• 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; Disease; Elements; Excision; Fostering; Goals; Graft Rejection; Graft Survival; Health; Hilar; Human; Immune; Immunity; Immunosuppression; Impairment; Isoantibodies; Kidney; Kidney Transplantation; Knowledge; Ligation; Lymphatic; Lymphocyte; Lymphocyte Depletion; MS4A1 gene; Macaca mulatta; Maintenance; Marrow; Mediating; Mesenchymal Stem Cells; Molecular; Monoclonal Antibodies; Organ; Output; PPP3CA gene; Pathway interactions; Patients; Perioperative; Phenotype; Population; Pre-Clinical Model; 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; Testing; Therapeutic; Therapeutic immunosuppression; Thymectomy; Thymus Gland; Time; Transplantation; Viral; Viral Antigens; Virus Diseases; Work; alemtuzumab; base; experience; improved; insight; irradiation; kidney allograft; mTOR Inhibitor; mTOR inhibition; nonhuman primate; novel therapeutic intervention; preservation; prevent; programs; secondary lymphoid organ; side effect; therapeutic effectiveness

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.

肾脏移植的考虑益处被与慢性免疫抑制疗法相关的许多并发症所抵消。超过95％的患者使用了钙调神经磷酸酶抑制剂（CNI）方案，但是这些不加选择的免疫吸收过程，包括促进移植物接受并产生重大副作用的患者。共刺激阻滞（COB），尤其是CD28-CD80/86途径抑制，已被证明可以促进长期的同种同生生存，而副作用少于CNIS，并且最近的临床试验已经促进了基于淋巴细胞的淋巴细胞耗尽，这表明基于COB的淋巴细胞促进了所有方案，而不仅会促进降低适应性的方法，从而促进了适应性的方法，并且会促进适应性的待遇，并促进适应性的方法。 宽容。该项目旨在定义促进基于COB的耐受性的淋巴细胞耗竭的元素。我们已经表明，淋巴细胞的耗竭以及随后的稳态再生，目前有机会塑造同种反应性免疫治疗以偏爱耐受性，但也构成了破坏调节的风险，并引发病毒感染，自身免疫性和激活同种反应性的克隆。我们的实验计划旨在了解耗尽诱导的这两个方面。我们假设热淋巴细胞部署的有效性不是由直接消除COB耐药细胞驱动的，而是通过为淋巴细胞更换和胸腺输出刺激而促进抗原特异性激活诱导的细胞死亡（AICD）。以这种方式观察，耗竭的方法从细胞的进化发生了变化，促进和管理重生，后者由相对（不是绝对），残留淋巴细胞群体的成熟定义的敏感性控制，抗原暴露，二次淋巴机器人功能和免疫抑制作用。我们肯定这些因素是可进行的，并且可以进行热操纵。为了探讨这一点，我们提出了3个具体目的：具体目的1：我们将定义恒河猴猴子在肾脏移植的恒河猴猴子中的耗尽诱导方案（广泛的多克隆或靶向单克隆抗体介导的部署）的影响，将CNIS和MTOR抑制剂抑制对体内抗体的影响以及这些相关的重新构造的效果。具体目标2：我们将定义胸腺或脾切除或辐照对同种特异性细胞的稳态再生的影响。具体目的3：我们将定义供体和病毒（CMV）抗原暴露对再摄取和耐受性的影响，以骨髓或间质干细胞的形式提供延长的供体抗原，并研究CMV的动物，动物，具有胸膜辐射。所有研究都将得到大量的机械支持，以评估重新流行曲目的表型，特异性和功能。将与项目2合作，以定义这些操作对同种抗体形成的影响，并与项目2的项目中的结果矩阵建立范式，以指导开发优化的复制方案与COB配对。