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素

基本信息

批准号：
7289728
负责人：
RAKESH K. SINDHI
金额：
$ 35.08万
依托单位：
CHILDREN'S HOSP PITTSBURGH/UPMC HLTH SYS
依托单位国家：
美国
项目类别：
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/7289728
关键词：
Addendum Adverse effects Allografting Antibodies Antigen Presentation Antigen-Presenting Cells Apoptosis Apoptotic Appearance B-Lymphocyte Subsets B-Lymphocytes Biological Biopsy Blood specimen CD3 Antigens CD4 Positive T Lymphocytes CD40 Ligand CD8B1 gene Candidate Disease Gene Cell Death Cells Child Childhood Class Clinical Trials Coculture Techniques Color Complement Data Data Set Drug resistance Enrollment Enzyme-Linked Immunosorbent Assay Esters Event Flow Cytometry Frequencies Future Gene Expression Genes Genetic Genetic Polymorphism Genome Globulins Goals Helper-Inducer T-Lymphocyte Histocompatibility Human Immune Immunosuppression Immunosuppressive Agents Individual Inhibition of Apoptosis Label Lymphocyte Lymphocyte Depletion Lymphocyte Subset Measurement Measures Memory Memory B-Lymphocyte Messenger RNA Molecular Monitor Organ Oryctolagus cuniculus Outcome Parents Pathway interactions Patients Pattern Pediatric Hospitals Peptides Peripheral Blood Lymphocyte Pharmaceutical Preparations Pharmacodynamics Pharmacogenomics Polymerase Chain Reaction Population Positioning Attribute Protocols documentation Recurrence Relative (related person)Research Personnel Risk Sampling Scanning Schedule Single Nucleotide Polymorphism Solid Steroids Suppressor-Effector T-Lymphocytes T-Lymphocyte Tacrolimus Testing Therapeutic immunosuppression Time Toxic effect Translating Transplant Recipients Transplantation Work case control caspase-3 cohort day experience gene function genetic variant histocompatibility gene immunoreactivity immunoregulation improved indexing liver transplantation mRNA Expression novel peripheral blood programs prospective response thymocyte transmission process uptake

项目摘要

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最大限度地减少每个接受肝移植（LTx）的儿童的器官排斥和免疫抑制剂毒性。 LTx 前淋巴细胞去除可以避免使用类固醇并降低对他克莫司免疫抑制的需求。如果更好地理解潜在机制，它们可用于进一步减少该方案中药物最小化期间的原发排斥反应（50%）和复发排斥反应（30%）。初步工作使我们推测，在无类固醇的淋巴细胞耗竭免疫抑制后出现早期排斥反应的儿科 LTx 中，供者特异性低反应性和调节抑制作用是在高度可变的时间间隔内实现的。我们进一步假设，免疫调节的这种变异性与扩展 MHC 区域基因中的单核苷酸多态性 (SNP) 模式有关，这些基因促进增殖、凋亡、记忆和 B 细胞依赖性功能。我们中心的一项临床试验将在 80 名患有 LTx 的儿童中使用 5 mg/kg 兔抗人胸腺细胞球蛋白 (rATG) 后给予不含类固醇的他克莫司。拟议的机制附录研究将需要在 LTx 之前以及之后 1、3 和 12 个月时采集所有儿童的连续外周血样本。具体目标是 1. 每个儿童供体特异性同种异体反应性、T-reg/抑制细胞（CD4+CD25+、CD8+28-）和抗 HLA alto 抗体的纵向表征，2. 29 个 SNP 的 LTx 前表征分布在 14 个 MHC 基因中，其初步分布模式在排斥者之间存在显着差异（LTx 后 60 天活检证明排斥），以及非拒绝者。这项研究将在 80 名儿童及其亲生父母身上进行。 SNP 显示 > 或 < 50% 的预期从父母到排斥者的传播，并且其传播在排斥者和非排斥者之间显着不同，将用于通过传播不平衡测试来识别候选基因座，以及 3. 验证结果组内的潜在候选基因/基因座，通过 a) 通过 CFSE-MLR 测量 T 细胞和 B 细胞亚群中供体特异性增殖/凋亡/记忆反应，b) 全基因组 mRNA 表达以补充 SNP 关联，并最大限度地减少假阳性，以及 c) 候选位点 c) 的位点特异性基因表达 (mRNA)。如果成功，未来研究结果的应用可以改善 LTx 前的药物选择，例如，如果 SNP 模式预测排斥反应，则分配类固醇。此外，LTx 后药物最小化可以变得更安全，例如，当 T-reg/T-sup 出现时。