Kidney Transplantation from Donors with HIV: Impact on Rejection and Long-term Outcomes

艾滋病毒捐献者的肾移植：对排斥和长期结果的影响

• 批准号: 10704333
• 负责人: Christine Marie Durand
• 金额: $ 178.12万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-25 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704333
• 关键词: Antibodies; Autoantibodies; Basic Science; Biological Assay; CD3 Antigens; CD4 Lymphocyte Count; Cells; Cytomegalovirus; Data; Development; Donor person; Enrollment; Ensure; Equity; Event; General Population; Generations; Graft Survival; HIV; Histologic; Hospitalization; Human; Immunologics; Immunoprecipitation; Immunosuppression; Infection; Inflammation; Inflammatory Response; Infrastructure; Intervention; Kidney; Kidney Transplantation; Knowledge; Longterm Follow-up; Mediating; Memory; Modeling; Monitor; Multicenter Trials; Organ; Organ Procurements; Organ Transplantation; Outcome; Pathway interactions; Patients; Persons; Phage Display; Policies; Prophylactic treatment; Proteins; Research; Research Design; Risk; Risk Factors; Safety; Sample Size; Selection Criteria; Sorting; T-Cell Receptor; T-Lymphocyte; Time; Toxin; Transplant Recipients; Transplantation; Viral; Viremia; Virion; Virulence Factors; Virus; Virus Diseases; Wait Time; Work; antibody-mediated rejection; antiretroviral therapy; chemokine; co-infection; cohort; cross reactivity; cytokine; data management; data registry; detection assay; donor-specific antibody; experience; follow-up; graft function; improved; improved outcome; insight; isoimmunity; microbial; novel; operation; pathogen; primary endpoint; response; safety and feasibility; success; transplant centers; trend; trial comparing

Under the HIV Organ Policy Equity (HOPE) Act, early studies show that kidney transplantation (KT) from donors with HIV to recipients with HIV (HIV D+/R+) expands the donor pool, reduces wait-times, and yields excellent short-term patient and graft survival. However, significant rates of rejection were observed with a trend towards higher rates in D+ recipients compared to HIV-uninfected donor (D-) recipients. Understanding the impact of D+ on rejection, underlying mechanisms, and the impact on long-term outcomes is critical. There are potential virologic and immunologic explanations for higher rejection in HIV D+/R+ vs D-/R+ KT. D+ kidneys harbor HIV and are more likely to harbor other co-infections such as CMV. These pathogens may trigger an inflammatory response, enhancing T-cell or antibody(Ab)-mediated pathways of rejection. Understanding the type of rejection and risk factors will inform interventions to improve outcomes, e.g. HIV D+ selection criteria, immunosuppression, or targeted monitoring and prophylaxis for co-infections. We propose Expanding HOPE, a multicenter trial comparing outcomes in 100 HIV D+/R+ KT and 100 D-/R+ KT at 15 transplant centers. We will combine this cohort with prior cohorts of HIV D+ and D- KT from our HOPE in Action Consortium, established in 2015. HOPE in Action has accrued approximately 325 HIV+ KT recipients to date; this larger cohort provides sufficient statistical power to determine the impact of HIV D+ organ on rejection and it will also allow us to determine long-term patient and graft outcomes beyond 5 years. Within this trial, we will perform comprehensive mechanistic studies to examine both T-cell and Ab-mediated rejection pathways. We will quantify changes in donor-specific and viral-specific (HIV CMV) T cells using an activated induced marker (AIM) assay in D+ and D- recipients, with and without rejection, over time. We will perform TCRβ immunosequencing on sorted AIM+ cells vs unsorted T cells to track T cell receptor dynamics. With VDJ-specific PCR, we will quantify expanded clones, including donor or viral AIM+ cells, post-KT. We will also characterize inflammation and the humoral response to infections and human proteins (donor, self). We will use a multiplexed electrochemiluminescence detection assay to quantify >30 cytokine and chemokines to characterize inflammation, and phage display and immunoprecipitation sequencing to characterize Abs to >1300 viruses, >14,000 microbial toxins/virulence factors, and >27,000 human autoAbs. Our HOPE in Action Multicenter Consortium has an established track record, successfully completing multicenter transplantation trials, including HIV D+/R+ KT. We will leverage our existing infrastructure to oversee operations, data management, analysis, and safety monitoring. In summary, the proposed research will determine the impact of HIV+ donor kidneys on rejection, will quantify long term outcomes, and elucidate risks and mechanisms of rejection. This knowledge can improve and expand HIV D+/R+ KT, and can provide important insights about alloimmunity more broadly.

根据艾滋病毒器官政策公平法（Hope）法案，早期研究表明，肾脏移植（KT）来自 对艾滋病毒（HIV D+/r+）接受艾滋病毒的捐助者扩大供体池，减少等待时间和产量 出色的短期患者和移植物存活率。但是，观察到很大的排斥率 与艾滋病毒未感染的供体（D-）接受者相比，D+受体率更高的趋势。理解 D+对排斥，潜在机制以及对长期结果的影响至关重要。 在HIV D+/R+与D-/R+ KT中，有潜在的病毒学和免疫学解释。 D+ 肾脏港口艾滋病毒，更有可能携带其他共同感染，例如CMV。这些病原体可能 触发炎症反应，增强T细胞或抗体（AB）介导的排斥途径。 了解拒绝和风险因素的类型将为您的干预措施提供信息，以改善结果，例如HIV D+ 选择标准，免疫抑制或针对性的监测和预防共同感染。 我们提出了扩大希望，这是一项多中心试验，比较100 HIV D+/R+ KT和100 D-/R+的结果 KT在15个移植中心。我们将将该队列与先前的HIV D+和D- KT相结合 Hope In Action In Consortium，成立于2015年。希望中累积了大约325 HIV+ KT 迄今为止的收件人；这个较大的队列提供了足够的统计能力来确定HIV D+的影响 拒绝的器官，这还将使我们能够确定长期的患者和移植结果超过5年。 在此试验中，我们将进行全面的机械研究，以检查T细胞和AB介导的 拒绝途径。我们将使用A量量化供体特异性和病毒特异性（HIV CMV）T细胞的变化 随着时间的流逝，在D+和D-受体中激活的诱导标记（AIM）测定。我们将 在排序的AIM+细胞与未分类的T细胞上执行TCRβ免疫测序以跟踪T细胞受体动力学。 使用VDJ特异性PCR，我们将量化扩展的克隆，包括供体或病毒AIM+细胞，KT。 我们还将表征注射和对感染和人类蛋白质的体液反应（供体， 自己）。我们将使用多重电化学检测测定法来量化> 30个细胞因子和 趋化因子以表征注射，噬菌体显示和免疫沉淀测序 将ABS特征在> 1300个病毒中，> 14,000个微生物毒素/病毒因素和> 27,000人的自动动作。 我们在行动中的希望多中心财团拥有既定的记录，成功完成 多中心移植试验，包括HIV D+/R+ KT。我们将利用现有的基础设施来 监督操作，数据管理，分析和安全监控。 总而言之，拟议的研究将确定HIV+供体肾脏对拒绝的影响，将量化 长期结果，并阐明排斥的风险和机制。这些知识可以改善，并且 扩展HIV D+/R+ KT，并可以更广泛地提供有关同种免疫性的重要见解。