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: 9751632
• 负责人: PETER G STOCK
• 金额: $ 276.41万
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751632
• 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; Immunosuppressive Agents; In Situ Hybridization; Individual; Infrastructure; Injury; 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; Serological; 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)：尽管在过去的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有所下降，但长期移植结果并没有以同样的速度改善，仍然停滞不前。此外，在开发新的免疫抑制策略以将急性和慢性损伤降至最低方面，也相对较少。马拉韦罗是一种CCR5抑制剂，可能在调节移植后的免疫反应方面具有新的作用。测试其对同种免疫反应的影响的理想环境是在艾滋病毒中 作为马拉韦罗接受肾移植的感染患者具有已知的抗逆转录病毒特性。这一点尤其相关，因为出乎意料的高拒绝率(高出2-3倍 据报道，在艾滋病毒阳性接受者的肾移植后发生了(比未感染艾滋病毒的接受者更多的)。我们推测，阻断CCR5将最大限度地减少免疫移植物损伤，并改善长期肾功能。这一假设引出了主要目的，即确定CCR5抑制剂(马拉韦罗)在改善HIV感染受者肾移植后长期肾功能方面的影响。其次，一些证据表明，在艾滋病毒携带者的长期抗逆转录病毒治疗期间，抑制CCR5可能会减少艾滋病毒病毒库的大小。我们假设，肾移植后联合应用CCR5阻断和免疫抑制治疗将降低HIV在CD4+T淋巴细胞中的持久性。因此，我们的目标是确定马拉韦罗对艾滋病毒持久性的影响。最后，我们假设，HIV+患者肾移植排斥反应的高发生率是由于在该人群中出现了高频率的异种记忆供者反应性T细胞，这些T细胞是对包括HIV和许多其他共病原体如CMV、EBV、丙型肝炎病毒和乙肝病毒在内的慢性感染的反应。因此，HIV+患者的移植可能提供了一个独特的机会来确定异种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CCR5阻断对他们同种免疫状况的影响。为了实现这三个目标，我们提出了一项前瞻性、多中心、双盲的II期HIV+患者肾移植研究，评估基于马拉韦罗的抗逆转录病毒方案在移植后给予的安全性和有效性。受试者将被同意并登记，直到120名符合条件的受试者被随机分配。我们将通过在指定的时间点测试采集的血液样本来对研究对象进行机械分析。R34拨款将使研究人员能够最终确定临床试验方案的所有方面，样本收集、储存和跟踪的程序，确认所有参与中心，并准备所有必要的研究文件和过程。