Impact of CCR5 Blockade in HIV+ Kidney Transplant Recipients

CCR5 阻断对 HIV 肾移植受者的影响

• 批准号: 10310958
• 负责人: PETER G STOCK
• 金额: $ 35.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-19 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10310958
• 关键词: Acute; Adult; Affect; Anti-Retroviral Agents; Antigens; Biology; Biopsy; Blood specimen; Bone Marrow Transplantation; CCR5 gene; CD4 Positive T Lymphocytes; Cells; Chemotaxis; Chronic; Clinical; Clinical Trials; Clinical trial protocol document; Communities; Consent; Controlled Clinical Trials; Cytomegalovirus; DNA; Data; Development; Double-Blind Method; Enrollment; Frequencies; General Population; Graft Rejection; Grant; HIV; HIV Infections; HIV Seropositivity; Hepatitis B Virus; Hepatitis C virus; Histologic; Human; Human Herpesvirus 4; Immune; Immune response; Immunity; Immunofluorescence Immunologic; Immunologics; Immunosuppression; In Situ Hybridization; Individual; Infrastructure; Injury; Injury to Kidney; Integrase Inhibitors; Intervention; Iohexol; Kidney; Kidney Transplantation; Lead; Lymphocyte; Measures; Memory; Modification; Nature; Organ Transplantation; Outcome; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Placebos; Plasma; Play; Population; Procedures; Process; RNA; Randomized; Regimen; Renal function; Reporting; Research Personnel; Risk; Role; Safety; Serology; Solid; Specificity; Specimen; Study Subject; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic immunosuppression; Time; Transplant Recipients; Transplantation; United States National Institutes of Health; Viral; Viral reservoir; Virus Diseases; Visceral; antiretroviral therapy; base; chronic infection; defined contribution; effective intervention; graft function; graft vs host disease; improved; inhibitor/antagonist; kidney allograft; novel; novel therapeutics; pathogen; patient population; phase 2 study; post-transplant; prevent; prospective; public health relevance; response; trafficking; transcriptome sequencing; virology

 DESCRIPTION (provided by applicant): Despite considerable refinement in immunosuppressive regimens over the last 25 years and decreased rates of acute rejection following kidney transplantation, long-term transplant outcomes have not improved at the same rate and have remained stagnant. Furthermore, there has been a relative paucity in the development of new immunosuppressive strategies to minimize acute and chronic injury. Maraviroc is a CCR5 inhibitor that may have a novel role in modulating the immune response following transplantation. An ideal setting to test its impact on the alloimmune response is in HIV infected patients undergoing kidney transplantation as maraviroc has known anti-retroviral qualities. This is particularly relevant in that unexpectedly high rejection rates (2-3 fold higher than HIV uninfected recipients) have been reported following kidney transplantation in HIV positive recipients. We hypothesize that CCR5 blockade will minimize immunologic graft injury and improve long-term kidney function. This hypothesis leads to the primary aim, which is to determine the impact of a CCR5 inhibitor (maraviroc) on improving long-term kidney graft function following kidney transplantation in HIV infected recipients. Secondly, some evidence suggests that inhibition of CCR5 could reduce the size of the HIV viral reservoir during long-term antiretroviral therapy in people with HIV. We hypothesize that CCR5 blockade in combination with immunosuppressive therapy used following kidney transplantation will reduce HIV persistence in CD4+ T lymphocytes. Thus, we aim to determine the impact of maraviroc on HIV persistence. Lastly, We hypothesize that the high rate of kidney transplant rejection in HIV+ patients is be due to high frequency of heterologous memory donor-reactive T cells that arise in response to chronic infections in this population which include HIV and a multitude of other co-pathogens such as CMV, EBV, HCV, and HBV. Thus, transplantation in HIV+ patients may provide a unique opportunity to determine the importance of heterologous immunity to transplant outcomes in humans. This leads to the third aim, which is to assess the alloimmune status of HIV+ transplant patients and impact of CCR5 blockade on their alloimmune profile. To achieve these three aims, we propose a prospective, multi-center, double-blind phase II study of kidney transplantation in HIV+ individuals assessing the safety and efficacy of a maraviroc-based antiretroviral regimen given post-transplant. Subjects will be consented and enrolled until 120 eligible subjects are randomized. We will perform mechanistic analysis of the study subjects by testing collected blood samples at defined time points. The R34 grant will allow the investigators to finalize all facets of the clinical trial protocol, procedures for specimen collecion, banking and tracking, for confirming all participating centers, and preparing all necessary study documents and processes.

 描述（由申请人提供）：尽管在过去25年中免疫抑制方案得到了相当大的改进，肾移植后急性排斥反应的发生率也有所下降，但长期移植结局并未以相同的速度改善，并且仍然停滞不前。此外，在开发新的免疫抑制策略以最大限度地减少急性和慢性损伤方面相对缺乏。Maraviroc是一种CCR 5抑制剂，可能在调节移植后的免疫反应中发挥新的作用。测试其对同种免疫反应影响的理想环境是HIV 已知马拉韦罗具有抗逆转录病毒的特性，这是特别相关的，因为出乎意料的高拒绝率（高2-3倍 与未感染HIV的受者相比）。我们假设CCR 5阻断将使移植物免疫损伤最小化，并改善长期肾功能。这一假设导致了主要目的，即确定CCR 5抑制剂（马拉韦罗）对改善HIV感染受者肾移植后长期肾移植功能的影响。其次，一些证据表明，在HIV感染者的长期抗逆转录病毒治疗期间，抑制CCR 5可以减少HIV病毒库的大小。我们推测，肾移植后使用的免疫抑制治疗结合CCR 5阻断将减少HIV在CD 4 + T淋巴细胞中的持续存在。因此，我们的目标是确定马拉韦罗对HIV持续性的影响。最后，我们假设HIV+患者肾移植排斥反应的高发生率是由于该人群中慢性感染（包括HIV和多种其他共病原体，如CMV，EBV，HCV和HBV）引起的异源记忆供体反应性T细胞的高频率。因此，HIV+患者的移植可能提供了一个独特的机会，以确定异源免疫对人类移植结果的重要性。这导致了第三个目标，即评估HIV+移植患者的同种免疫状态以及CCR 5阻断对其同种免疫特征的影响。为了实现这三个目标，我们提出了一个前瞻性，多中心，双盲II期研究肾移植的HIV+个人评估的安全性和有效性的马拉韦罗为基础的抗逆转录病毒治疗方案给予移植后。受试者将获得知情同意并入组，直至120例合格受试者接受随机化。我们将通过在规定的时间点检测采集的血液样本对研究受试者进行机制分析。R34补助金将允许研究者最终确定临床试验方案的所有方面，样本收集，银行和跟踪的程序，确认所有参与中心，并准备所有必要的研究文件和流程。