Dynamics of TCR Repertoire Following Thymus Transplant

胸腺移植后 TCR 的动态变化

• 批准号: 6893711
• 负责人: M. Louise MARKERT
• 金额: $ 38.5万
• 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/6893711
• 关键词: CD3 molecule; DiGeorge' s syndrome; T cell receptor; T lymphocyte; cell differentiation; cell growth regulation; cell population study; cell proliferation; clinical research; developmental genetics; family genetics; flow cytometry; gene mutation; genetic recombination; homologous transplantation; human subject; infant human (0-1 year); interleukin 7; major histocompatibility complex; mathematical model; polymerase chain reaction; 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）：