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

根据艾滋病毒器官政策平等法(HOPE)，早期研究表明，来自 艾滋病毒携带者捐赠者与艾滋病毒携带者(HIV D+/R+)接受者(HIV D+/R+)扩大捐赠者池，减少等待时间，并产生 极佳的短期患者和移植物存活率。然而，观察到显著的排斥率。 与未感染艾滋病毒的捐赠者(D-)相比，D+受者的感染率有上升的趋势。理解 D+对排斥的影响、潜在的机制以及对长期结果的影响是至关重要的。 HIV D+/R+VS D-/R+KT的高排斥反应有潜在的病毒学和免疫学解释。D+ 肾脏携带艾滋病毒，更有可能携带CMV等其他混合感染。这些病原体可能 引发炎症反应，增强T细胞或抗体(Ab)介导的排斥反应途径。 了解排斥反应的类型和风险因素将有助于改善结果的干预措施，例如艾滋病毒D+ 联合感染的选择标准、免疫抑制或有针对性的监测和预防。 我们建议扩大HOPE，这是一项多中心试验，比较100例HIV D+/R+KT和100例D-/R+KT的结果 KT在15个移植中心。我们将把这个队列与我们之前的HIV D+和D-KT队列结合起来 希望在行动联盟，成立于2015年。在行动中的希望已经积累了大约325个艾滋病毒+KT 迄今为止的接受者；这一较大的队列提供了足够的统计能力来确定艾滋病毒D+的影响 它还将使我们能够确定患者和移植物在5年后的长期结果。 在这项试验中，我们将进行全面的机制研究，以检查T细胞和抗体介导的 排斥途径。我们将量化供者特异性和病毒特异性(HIV CMV)T细胞的变化 在D+和D-受体中，随着时间的推移，有和没有排斥反应的激活诱导标记(AIM)检测。我们会 对分选的AIM+细胞和未分选的T细胞进行β免疫测序，以跟踪T细胞受体的动态变化。 使用VDJ特异性的聚合酶链式反应，我们将量化扩增的克隆，包括KT后的供体或病毒AIM+细胞。 我们还将描述炎症和体液对感染和人类蛋白的反应(供体， 自我)。我们将使用多重电化学发光检测方法来定量&gt；30细胞因子和 趋化因子来表征炎症，噬菌体展示和免疫沉淀测序 表征抗体到&gt；1300个病毒，&gt；14,000个微生物毒素/毒力因子，和&gt；27,000个人自身抗体。 我们的行动希望多中心联盟已经有了既定的记录，成功地完成了 多中心移植试验，包括HIV D+/R+KT。我们将利用我们现有的基础设施来 监督运营、数据管理、分析和安全监控。 总之，拟议的研究将确定艾滋病毒+捐赠者肾脏对排斥反应的影响，将量化 长期结果，并阐明排斥的风险和机制。这一知识可以提高和 扩展HIV D+/R+KT，可以更广泛地提供关于同种免疫的重要见解。

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.