Dynamics of TCR Repertoire Following Thymus Transplant

胸腺移植后 TCR 的动态变化

• 批准号: 7224913
• 负责人: M. Louise MARKERT
• 金额: $ 36.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-15 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7224913
• 关键词: Allogenic; Allografting; Appearance; Area; Biological Models; Bone Marrow Stem Cell; Bone Marrow Transplantation; CD3 Antigens; CD8B1 gene; Cell Count; Cells; Computer Simulation; DNA Sequence Rearrangement; Data; Defect; Development; DiGeorge Syndrome; Donor person; Enlargement of lymph nodes; Enrollment; Epithelium; Evolution; Exanthema; Excision; Family; Flow Cytometry; Frequencies; Genes; Genetic; Genetic Recombination; Growth; Heart; Homeostasis; Human; Immune; Immunodeficiency and Cancer; Infant; Interleukin-7; Ligands; Lymphatic Diseases; Maintenance; Measures; Modeling; Output; Parathyroid gland; Patients; Pattern; Peptide Signal Sequences; Peptide/MHC Complex; Peripheral; Population; Population Dynamics; Population Growth; Pre-study; Production; Protocols documentation; Publishing; Rate; Regulation; Relative (related person); Research; Research Personnel; Resources; Role; Sampling; Secondary to; Selection Bias; Serum; Signal Transduction; Staging; System; T cell regulation; T-Cell Development; T-Cell Receptor; T-Lymphocyte; Testing; Thinking; Thymus Gland; Time; Tissues; Transplantation; Variant; base; cytokine; density; insight; interest; man; mathematical model; member; postnatal; postnatal human; programs; reconstitution; thymus transplantation

DESCRIPTION (provided by applicant): The long term objective of this proposal is to identify mechanisms regulating human T cell diversity. We propose to do so using a model system of infants with complete DiGeorge syndrome who receive thymic allografts. Infants with DiGeorge syndrome are born with defects in the thymus, heart, and parathyroid glands. Patients with "complete" DiGeorge syndrome have no evidence ofthymic function. Twenty four patients have been treated in a separate, well-established research protocol by transplantation with allogeneic cultured postnatal human thymus. Seventeen patients survive, all with good immune reconstitution and function. The mechanism of T cell development in these patients is host bone marrow stem cells going to the transplanted donor thymic epithelium and developing there into mature host T cells. In the first specific aim, we will examine the mechanisms underlying selection of T cell receptor (TCR) variable-beta gene segments (TCRBV) in newly formed T cells. We hypothesize that early TCRBV usage is biased toward those gene segments that are associated with highly efficient recombination signal sequences (RSS) and toward those that are most proximal to the TCRBJ cluster. We will compare the selection in the early oligoclonal T cell populations, which develop at 3-4 months after transplantation, to those present at 1 year. In aim 3, we will examine T cells in "atypical" complete DiGeorge patients who develop oligoclonal T cells prior to thymus transplantation. These T cells are associated with rash and lymphadenopathy. The same hypothesis will be tested regarding TCRBV selection - that it is based on RSS efficiency and TCRBJ proximity. These T cells develop without thymic input, so the effect of thymic selection on TCRBV usage will be ascertained. In aim 2, we will use mathematical modeling and multivariate statistical analysis of patient data to evaluate the relationship between T cell hemeostasis and TCRBV diversity with emphasis on distinguishing the roles of TCR-specific resources (e.g., MHC-peptide complexes) and TCR non-specific resources, such as IL-7. Thus, this unique model of thymus development will provide insights into development of T cell diversity in man. These findings will have application to thymus and bone marrow transplantation for immunodeficiency and cancer.

描述(由申请人提供)： 这项提议的长期目标是确定调节人类T细胞多样性的机制。我们建议使用接受同种异体胸腺移植的完全性DiGeorge综合征婴儿的模型系统来实现这一点。患有迪乔治综合征的婴儿出生时就有胸腺、心脏和甲状旁腺的缺陷。“完全性”迪乔治综合征患者没有胸腺功能的证据。24名患者通过移植同种异体培养的出生后人类胸腺进行了单独的、完善的研究方案的治疗。17名患者幸存下来，均有良好的免疫重建和功能。这些患者的T细胞发育机制是宿主骨髓干细胞进入移植的供者胸腺上皮，并在那里发育为成熟的宿主T细胞。在第一个特定目标中，我们将研究在新形成的T细胞中选择T细胞受体(TCR)可变β基因片段(TCRBV)的机制。我们假设早期TCRBV的使用偏向于那些与高效重组信号序列(RS)相关的基因片段，以及那些最接近TCRBJ簇的基因片段。我们将比较在移植后3-4个月发育的早期寡克隆性T细胞群体中的选择与在一年时出现的选择。在目标3中，我们将检测胸腺移植前出现寡克隆T细胞的“非典型”完全性DiGeorge患者的T细胞。这些T细胞与皮疹和淋巴结病有关。关于TCRBV的选择将检验相同的假设--它基于RSS效率和TCRBJ近似性。这些T细胞在没有胸腺输入的情况下发育，因此胸腺选择对TCRBV使用的影响将被确定。在目标2中，我们将使用数学建模和患者数据的多元统计分析来评估T细胞血液稳定性和TCRBV多样性之间的关系，重点是区分TCR特异性资源(如MHC-肽复合体)和TCR非特异性资源(如IL-7)的作用。因此，这种独特的胸腺发育模型将为人类T细胞多样性的发展提供洞察力。这些发现将应用于胸腺和骨髓移植治疗免疫缺陷和癌症。