Alemtuzumab and Regulatory T Cells for Heart Transplant Tolerance in Monkeys

阿仑单抗和调节性 T 细胞对猴子心脏移植耐受的影响

• 批准号: 8690747
• 负责人: Angus W Thomson
• 金额: $ 64.41万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690747
• 关键词: Accounting; Adoptive Transfer; Alloantigen; Animals; Antibodies; Antigens; Autoimmune Responses; Autologous; Biology; CD3 Antigens; CD4 Positive T Lymphocytes; CDW52 gene; Calcineurin; Cardiac; Cardiology; Cells; Cellular Immunology; Chronic; Clinic; Clinical; Clinical Trials; Data; Development; Disease; Effector Cell; Equilibrium; Evaluation; Exhibits; Frequencies; Graft Rejection; Graft Survival; Heart; Heart Transplantation; Human; Immune; Immune response; Immunologic Monitoring; Immunology; Immunosuppression; Immunosuppressive Agents; In Vitro; Incidence; Investigation; Islet Cell; Islets of Langerhans; Length; Lymphocyte; Lymphocyte Depletion; MabCampath; Macaca fascicularis; Macaca mulatta; Mediating; Memory; Methods; Modeling; Monitor; Monkeys; Morbidity - disease rate; Mus; Myosin ATPase; Neoadjuvant Therapy; Organ; Organ Transplantation; Outcome; Patients; Pharmaceutical Preparations; Pharmacotherapy; Primates; Property; Protocols documentation; Regimen; Regulation; Regulatory T-Lymphocyte; Relative (related person); Research; Rodent; Sirolimus; Steroids; T cell response; T cell therapy; T-Cell Depletion; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Therapeutic Agents; Therapeutic immunosuppression; Tissues; To autoantigen; Toxic effect; Transplant Recipients; Transplantation; Universities; Vascular Diseases; Vimentin; alemtuzumab; allograft rejection; base; evidence base; experience; follow-up; graft failure; heart allograft; human disease; immunopathology; immunoregulation; improved; in vivo; innovation; mortality; mycophenolate mofetil; nonhuman primate; novel; preclinical study; prevent; therapeutic development

Our proposed studies will investigate the potential of regulatory T cells (Treg) for the promotion of tolerance to heterotopic heart allografts in cynomolgus monkeys. There is persuasive evidence, based on small animal studies, that depletion of T effector cells prior to the administration of Treg is advantageous to the outcome of Treg-induced immunomodulation. We have developed a T cell-depleting regimen in Indonesian cynomolgus monkeys, using humanized anti-CD52 mAb (alemtuzumab) in combination with mycophenolate mofetil (MMF). CD3[+]T cells can be maintained at very low numbers for periods >4 weeks, and CD4[+] T cells for several months. We have also isolated and successfully expanded monkey Treg and demonstrated their immunomodulatory properties. We hypothesize that posttransplant adoptive transfer of autologous Treg to lymphocyte-depleted hosts, in combination with a course of rapamycin monotherapy, will enhance heart allograft survival and promote tolerance induction. Our proposed investigations have the following Aims: Aim I will determine the Influence of alemtuzumab on heart allograft outcome and host immune reactivity in cynomolgus monkeys; Aim II will assess the impact of polyclonal Treg (either expanded naturally-occurring Treg or induced Treg) on heart allograft outcome and underlying mechanisms in alemtuzumab-treated monkeys and will compare the results with those obtained in Aim I; Aim III will assess the ability of alloantigen-specific Treg to promote heart allograft outcome and underlying mechanisms in alemtuzumab-treated monkeys treated as in Aim I and will compare the results with those in Aims I and II. In each Aim, the Treg will be administered on day 21, after the initial T cell depletion and heart transplantation (day 0); immunosuppressive therapy will be tapered and discontinued at 3 months. Follow-up will be for 6 months post transplant. Outcomes will be monitored by (i) length of graft survival, (ii) incidence of graft vasculopathy (chronic rejection), (iii) development of anti-donor T cell responses, (iv) development of anti-donor antibodies (Abs), (v) development of anti-vimentin and anti-myosin Abs, and T cell responses to these autoantigens, and (vi) assessment of memory T cell responses. In addition, in Aims II and III, we will ascertain the mechanistic basis of the influence of the Treg therapy on host immune reactivity and transplant outcome. These studies will provide definitive information on the ability of adoptively-transferred autologous Treg to induce a state of tolerance or prope tolerance to non-human primate heart allografts, and may provide sufficient data to justify a clinical trial.

我们提出的研究将调查调节性 T 细胞 (Treg) 在促进食蟹猴异位心脏同种异体移植物耐受方面的潜力。基于小动物研究的有说服力的证据表明，在施用 Treg 之前消除 T 效应细胞有利于 Treg 诱导的免疫调节的结果。我们使用人源化抗 CD52 单克隆抗体（阿仑单抗）与吗替麦考酚酯 (MMF) 联合使用，在印度尼西亚食蟹猴中开发了一种 T 细胞消耗方案。 CD3[+]T 细胞可以在超过 4 周的时间内维持在非常低的数量，CD4[+]T 细胞可以维持几个月。我们还分离并成功扩增了猴 Treg 并证明了其免疫调节特性。我们假设，移植后将自体 Treg 过继转移至淋巴细胞耗尽的宿主，并结合雷帕霉素单一疗法，将增强心脏同种异体移植物的存活并促进耐受诱导。我们提出的研究有以下目标： 目标 I 将确定阿仑单抗对食蟹猴心脏同种异体移植结果和宿主免疫反应性的影响；目标 II 将评估多克隆 Treg（扩增的天然 Treg 或诱导 Treg）对接受阿仑单抗治疗的猴子的心脏同种异体移植结果和潜在机制的影响，并将结果与​​目标 I 中获得的结果进行比较；目标 III 将评估同种异体抗原特异性 Treg 促进心脏同种异体移植结果的能力以及按照目标 I 进行阿仑单抗治疗的猴子的潜在机制，并将结果与​​目标 I 和 II 中的结果进行比较。在每个目标中，Treg 将在初始 T 细胞耗竭和心脏移植（第 0 天）后的第 21 天施用；免疫抑制治疗将逐渐减少，并在 3 个月后停止。移植后将进行 6 个月的随访。结果将通过以下方式监测：(i) 移植物存活时间，(ii) 移植物血管病变（慢性排斥）的发生率，(iii) 抗供体 T 细胞反应的发生，(iv) 抗供体抗体 (Abs) 的产生，(v) 抗波形蛋白和抗肌球蛋白 Abs 的产生，以及 T 细胞对这些自身抗原的反应，以及 (vi) 记忆 T 细胞的评估 回应。此外，在目标II和III中，我们将确定Treg治疗对宿主免疫反应和移植结果影响的机制基础。这些研究将提供关于过继转移的自体 Treg 诱导对非人灵长类同种异体心脏移植物耐受或适当耐受状态的能力的明确信息，并可能提供足够的数据来证明临床试验的合理性。