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: 7683038
• 负责人: RAKESH K. SINDHI
• 金额: $ 39.36万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683038
• 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; 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; 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; Time; Toxic effect; Translating; Transplant Recipients; Transplantation; Work; case control; caspase-3; cohort; experience; gene function; genetic variant; genome-wide; histocompatibility gene; immunoreactivity; immunoregulation; improved; indexing; liver transplantation; mRNA Expression; novel; peripheral blood; programs; prospective; response; thymocyte; transmission process; uptake

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 regulatory- suppressive 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 MHC- region 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) locus- specific 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.

该项目的长期目标是最大限度地减少每个器官的排斥反应和免疫抑制剂的毒性。 接受肝移植（LTx）的儿童。 LTx 前淋巴细胞去除可以避免使用类固醇并降低 需要他克莫司免疫抑制。如果更好地理解潜在机制，它们可能是 用于减少药物最小化期间​​的进一步原发排斥反应（50%）和复发排斥反应（30%） 该协议。初步工作使我们假设供体特异性低反应性和监管- 在儿科 LTx 中，以高度可变的时间间隔实现抑制效果，并在治疗后出现早期排斥反应。 无类固醇的淋巴细胞消耗免疫抑制。我们进一步假设这种变异性 免疫调节与扩展 MHC 中的单核苷酸多态性 (SNP) 模式相关 区域基因促进增殖、凋亡、记忆和 B 细胞依赖性功能。一项临床试验于 我们中心将在用 5 mg/kg 兔抗人胸腺细胞耗尽后给予不含类固醇的他克莫司 为 80 名 LTx 儿童提供球蛋白 (rATG)。拟议的机械附录研究将需要一系列 所有儿童在 LTx 之前以及之后 1、3 和 12 个月时的外周血样本。具体目标是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 以及每个儿童的抗 HLA alto 抗体，2. 分布在 14 名儿童中的 29 个 SNP 的 LTx 前特征 MHC 基因，其初步分布模式在排斥者之间显着不同（活检证明） LTx 后 60 天的拒绝者）和非拒绝者。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，并且其传播不同 拒绝者和非拒绝者之间的显着差异，将用于识别具有传输的候选基因座 不平衡测试，以及 3. 通过 a) 测量来验证结果组内的潜在候选基因/位点 CFSE-MLR 检测 T 细胞和 B 细胞亚群中供体特异性增殖/凋亡/记忆反应，b) 整体 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) 位点- 候选位点的特定基因表达 (mRNA) c)。如果成功的话，研究结果的未来应用可能 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。

项目成果

Predicting Cellular Rejection With a Cell-Based Assay: Preclinical Evaluation in Children.

• DOI: 10.1097/tp.0000000000001076
• 发表时间: 2017-01
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Ashokkumar C;Soltys K;Mazariegos G;Bond G;Higgs BW;Ningappa M;Sun Q;Brown A;White J;Levy S;Fazzolare T;Remaley L;Dirling K;Harris P;Hartle T;Kachmar P;Nicely M;OʼToole L;Boehm B;Jativa N;Stanley P;Jaffe R;Ranganathan S;Zeevi A;Sindhi R
• 通讯作者: Sindhi R

Antithymocyte globulin facilitates alloreactive T-cell apoptosis by means of caspase-3: potential implications for monitoring rejection-free outcomes.

• DOI: 10.1097/tp.0000000000000289
• 发表时间: 2015-01
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Ashokkumar C;Sun Q;Ningappa M;Higgs BW;Mazariegos G;Zeevi A;Sindhi R
• 通讯作者: Sindhi R

Profile of the Pleximmune blood test for transplant rejection risk prediction.

用于预测移植排斥风险的 Pleximune 血液测试概况。

• DOI: 10.1586/14737159.2016.1139455
• 发表时间: 2016
• 期刊: Expert review of molecular diagnostics
• 影响因子: 5.1
• 作者: Sindhi,Rakesh;Ashokkumar,Chethan;Higgs,BrandonW;Levy,Samantha;Soltys,Kyle;Bond,Geoffrey;Mazariegos,George;Ranganathan,Sarangarajan;Zeevi,Adriana
• 通讯作者: Zeevi,Adriana

A network-based approach to identify expression modules underlying rejection in pediatric liver transplantation.

• DOI: 10.1016/j.xcrm.2022.100605
• 发表时间: 2022-04-19
• 期刊: CELL REPORTS MEDICINE
• 影响因子: 14.3
• 作者: Ningappa, Mylarappa;Rahman, Syed A.;Higgs, Brandon W.;Ashokkumar, Chethan S.;Sahni, Nidhi;Sindhi, Rakesh;Das, Jishnu
• 通讯作者: Das, Jishnu