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）