Predictors for drug selection and minimization in pediatric liver transplantation

小儿肝移植药物选择和最小化的预测因子

• 批准号: 7251717
• 负责人: RAKESH K. SINDHI
• 金额: $ 37.21万
• 依托单位: CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251717
• 关键词: child rearing; children; clinical research; genes; genome; immunosuppression; liver transplantation; lymphocyte; measurement; parents

DESCRIPTION (provided by applicant): The long term goal of this project is to minimize organ rejection and immunosuppressant toxicity, in each child with liver transplantation (LTx). Pre-LTx lymphocyte depletion permits steroid avoidance and lowers need for Tacrolimus immunosuppression. If underlying mechanisms were better understood, they could be used to reduce further, primary rejection (50%) and recurrent rejection during drug minimization (30%) on this protocol. Preliminary work leads us to hypothesize that donor-specific hyporeactivity and regulatorysuppressive effect are achieved at highly variable intervals among pediatric LTx with early rejection after steroid-free lymphocyte-depleting immunosuppression. We further hypothesize that this variability in immune-modulation is associated with patterns of single nucleotide polymorphisms (SNP) in extended MHCregion genes subserving proliferation, apoptosis, memory and B-cell-dependent functions. A clinical trial at our center will administer steroid-free Tacrolimus after depletion with 5 mg/kg rabbit anti-human-thymocyte globulin (rATG) to 80 children with LTx. The proposed mechanistic addendum study will entail serial peripheral blood samples from all children before and at 1, 3, and 12 months post-LTx. Specific aims are 1. Longitudinal characterization of donor-specific alloreactivity, T-reg/suppressor cells (CD4+CD25+, CD8+28-), and anti-HLA alto-antibodies in each child, 2. Pre-LTx characterization of 29 SNPs distributed among 14 MHC genes, whose preliminary distribution patterns differ significantly between rejectors (biopsy-proven rejection at 60 days post-LTx), and non-rejectors. This will be done in 80 children and their biologic parents. SNPs showing > or < 50% expected transmission from parents to rejectors and whose transmission differs significantly between rejectors and non-rejectors, will be used to identify candidate loci with the transmission disequilibrium test, and 3. Validate potential candidate genes/loci within outcome groups, by a) measuring donor-specific proliferative/apoptotic/memory responses in T- and B-cell subsets by CFSE-MLR, b) whole genome mRNA expression to complement SNP associations, and minimize false-positives, and c) locusspecific gene expression (mRNA) for candidate loci c). If successful, future application of study results could improve pre-LTx drug selection, e.g., allocating steroids if SNP patterns predict rejection. Also, post-LTx drug minimization could be made safer, e.g., when T-reg/T-sup appear.

描述（由申请人提供）：该项目的长期目标是在每个患有肝移植（LTX）的孩子中最大程度地减少器官排斥和免疫抑制剂毒性。 LTX前淋巴细胞耗竭允许避免类固醇，并降低了他克莫司免疫抑制的需求。如果更好地理解潜在的机制，则可以使用它们来减少进一步的原发性排斥（50％）和在药物最小化期间​​的反复排斥（30％）。初步工作使我们假设我们在小儿LTX之间在高度可变的间隔内实现了供体特异性的缺乏性和调节性抑制效应，而无类固醇淋巴细胞抑制免疫抑制后早期排斥。我们进一步假设免疫调节中的这种变异性与扩展的MHCRegion基因中的单核苷酸多态性（SNP）的模式有关，从而扩增了增殖，凋亡，记忆和依赖B细胞的依赖性功能。我们中心进行的一项临床试验将在5 mg/kg兔抗人胸腺细胞球蛋白（RATG）耗尽后，对80名LTX儿童进行耗竭后的无类固醇克莫司。拟议的机械附录研究将在LTX后1、3和12个月中涉及所有儿童的串行外周血样本。具体目的是1。供体特异性同种异体反应性，T-REG/抑制细胞（CD4+CD25+，CD8+28-）的纵向表征和每个儿童中的抗HLA Alto抗体，2个。在14个MHC基因之间分布了29个SNP的Pre-LTX表征，其分布模式之间的分布分布（他们的分布量显着差异） LTX后）和非拒绝器。这将在80个孩子及其生物父母中完成。 SNP显示>或<50％的预期从父母到拒绝者的传播，其传播在被拒绝者和非置换器之间显着不同，将用于通过传播不平衡测试来识别候选基因座，3。验证结果中的潜在候选基因/基因座在结果中，通过a）测量供体特异性/apoptotic/apoptotic/apoptotic/memory反应的t-cell be cell be），b）t-cell befe befe b）补充SNP关联并最小化假阳性，以及c）候选基因座的locuss特异性基因表达（mRNA）。如果成功，未来的研究结果可能会改善LTX药物的选择，例如，如果SNP模式预测排斥，则分配类固醇。同样，可以使LTX后的药物最小化可以更安全，例如，当出现T-REG/T-SUP时。