Longitudinal assessment of CMV and BK virus immunity in renal transplant patients

描述（由申请人提供）：本提案概述了一项为期2年的计划，用于肾移植受者中BK病毒（BKV）免疫发病机制的调查研究。肾移植药物的一个主要临床障碍是BKV引起的多瘤病毒相关性肾病（PVAN）的发生，在移植后阶段，BK病毒血症（13%）和PVAN（8%）的发生率很高。确保移植物存活的最佳免疫抑制必须与感染风险相平衡。抗体水平是疾病风险或抗病毒治疗反应的不良预测指标，基于病毒DNA PCR的检测无法提供有关免疫状态的直接信息。然而，目前还没有细胞免疫监测试验在临床上用于肾移植受者。为了填补这一空白，我们将使用四种高度优化的多色流式细胞术（PFC）测定法，旨在评估成熟亚群中的CD 4和CD 8 T细胞应答：CEF肽库（CD 8应答的HLA I类限制性表位），念珠菌CASTA（CD 4活性），CMV pp 65和IE-1肽库（主要是CD 8）和BKV肽库（CD 4，CD 8）。我们将对120例肾移植患者进行纵向免疫监测（第0、4、12、24和48周）。由于很少有此类PFC测定报告此类抗原特异性T细胞应答的稳健测量，因此我们的目标是客观地定量免疫重建的移植后早期（0-3个月）和晚期（6-12个月）的CD 4/CD 8 T细胞应答。通过客观和纵向量化抗原特异性免疫应答，我们的最终目标是填补科学知识和临床实践中的空白，用于免疫抑制和化学预防方案的个体滴定，以改善移植临床护理和结果

DESCRIPTION (provided by applicant): This proposal outlines a 2-year plan for investigative research into the immunopathogenesis of BK virus (BKV) in renal transplant recipients. A major clinical barrier to renal transplant medicine is the occurrence of polyomavirus-associated nephropathy (PVAN) due to BKV, with significant occurrences of BK viremia (13%) and PVAN (8%) in the post-transplant period. Optimal immunosuppression to ensure graft survival must be balanced with infectious risk. Antibody levels are poor predictors of risk of disease or response to antiviral therapy and viral DNA PCR-based assays provide no direct information on the immune status. However, there are currently no cellular immune monitoring assays in clinical use for renal transplant recipients. To fill this gap, we will use four highly optimized polychromatic flow cytometry (PFC) assays designed to assess CD4 and CD8 T cell responses within maturational subsets: CEF peptide pool (HLA class I restricted epitopes for CD8 responses), Candida CASTA (CD4 activity), CMV pp65 & IE-1 peptide pools (primarily CD8) and BKV peptide pools (CD4, CD8). We will perform longitudinal immune monitoring in 120 patients following renal transplantation (weeks 0, 4, 12, 24, & 48). Because few such PFC assays report robust measurements of such antigen specific T cell responses, we will aim to objectively quantify CD4/CD8 T cell responses in the early (0-3 month) and late (6-12 month) post-transplant periods of immune reconstitution. By objectively and longitudinally quantifying antigen specific immune responses, we ultimately aim to fill gaps in scientific knowledge and clinical practice for the individual titration of immunosuppressive and chemoprophylaxis regimens to improve transplant clinical care and outcomes