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程度地减少器官排斥和免疫抑制剂毒性 肝移植的儿童（LTX）。前LTX淋巴细胞耗竭允许避免类固醇并降低 需要他克莫司免疫抑制。如果更好地理解了基本机制，它们可能是 用于减少进一步的降低，主要排斥反应（50％）和药物最小化期间​​的反复排斥（30％） 这个协议。初步工作使我们假设捐助者特定的低血压和调节性 在小儿LTX之间以高度可变的间隔实现抑制作用，并在 无类固醇淋巴细胞的免疫抑制。我们进一步假设这种可变性 免疫调节与扩展的MHC-中的单核苷酸多态性（SNP）的模式有关 区域基因扩散，凋亡，记忆和B细胞依赖性功能。一项临床试验 我们的中心将用5 mg/kg兔抗人类胸腺细胞耗尽后施用无类固醇克莫司 Globulin（Ratg）至80名LTX儿童。拟议的机械附录研究将需要串行 LTX前1、3和12个月的所有儿童的外周血样本。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 和每个孩子中的抗HLA中心抗体，2。分布在14中的29个SNP的前LTX表征 MHC基因的初步分布模式在拒绝者之间显着差异（证实活检 在LTX后60天和非拒绝器的拒绝。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，其传播有所不同 在拒绝者和非拒绝器之间，将使用传输来识别候选基因座 不平衡测试和3。通过a）测量结果验证结果组内的潜在候选基因/基因座 CFSE-MLR在T和B细胞亚集中的供体特异性增殖/凋亡/记忆响应，b）整体 基因组mRNA表达以补充SNP关联并最小化假阳性，c） 候选基因座的特定基因表达（mRNA）。如果成功，未来的研究结果可以 改善前LTX药物选择，例如，如果SNP模式预测排斥，则分配类固醇。另外，LTX药物 最小化可以使最小化更安全，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