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.

超过 95% 的患者使用基于钙调神经磷酸酶抑制剂 (CNI) 的长期治疗方案带来的许多并发症抵消了肾移植的巨大益处，但这些并发症会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，并产生显着的影响。共刺激阻断 (CoB)，特别是 CD28-CD80/86 通路抑制，已被证明可以促进同种异体移植物的长期存活，且副作用更少。 CNI 和最近的临床试验表明，淋巴细胞消除促进了基于 CoB 的治疗方案，不仅可以防止排斥反应，还可以促进适应性过程，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耐受。该项目旨在定义淋巴细胞消除的要素。我们已经证明，淋巴细胞耗竭和稳态重新增殖为塑造同种异体反应性免疫库以促进耐受性提供了机会，但也带来了破坏的风险。我们的实验计划旨在了解消除诱导的这两个方面，我们发现治疗性淋巴细胞消除的有效性不是由直接消除 CoB 抗性细胞驱动的。通过刺激淋巴细胞周转和胸腺输出，促进抗原特异性激活诱导的细胞死亡（AICD）从这个角度来看，细胞消除的方法发生了变化，即促进和管理细胞再生（后者）。残余淋巴细胞群对抗原暴露、次级淋巴器官功能和免疫抑制的影响的相对（非绝对）、成熟定义的敏感性控制，我们认为这些因素是易于处理的，并且可以通过治疗来操纵。我们提出 3 个具体目标： 具体目标 1：我们将确定消耗诱导方案（广泛的多克隆或单克隆抗体介导的消耗）对接受肾移植的目标恒河猴的影响移植，比较 CNI 和 mTOR 抑制剂对稳态再增殖的影响，并将这些与 belatacept 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疗对同种异体特异性细胞稳态再增殖的影响。目标 3：我们将定义供体和病毒 (CMV) 抗原暴露对增殖和耐受性的影响，以骨髓或间充质干细胞，并在 CMV 幼稚动物、胸腺照射动物中研究这些方案，所有研究都将得到大力支持，以评估再生库的表型、特异性和功能，我们将与项目 2 合作来确定这些方案的影响。同种抗体形成的操作，并将项目中的结果与项目 2 的结果进行矩阵化，以建立一个范式来指导开发与 CoB 配对的优化消耗方案。