Thymic Transplantation in Complete DiGeorge Syndrome

完全性迪乔治综合征的胸腺移植

• 批准号: 7931554
• 负责人: M. Louise MARKERT
• 金额: $ 46.49万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7931554
• 关键词: Address; Adult; Affinity; Age; Alleles; Alloantigen; Allogenic; Allografting; Antibiotics; Antigen-Presenting Cells; Apoptosis; Binding; Binding Sites; Biology; CD28 gene; CD3 Antigens; CD8B1 gene; Cell Count; Cell Death; Cell Proliferation; Cell physiology; Characteristics; Complex; DNA Sequence Rearrangement; Data; Defect; Dendritic Cells; DiGeorge Syndrome; Education; Etiology; Evaluation Research; Excision; Family; Flow Cytometry; Fluorescent Dyes; Grant; HLA A*0201 antigen; Histocompatibility Antigens Class I; Homeostasis; Immune; Immunity; Immunoglobulin Variable Region; Immunologic Deficiency Syndromes; In Vitro; Infant; Interferon Type II; Iodine; Joints; Laboratories; Length; Life; Long-Term Survivors; Lymphopenia; MHC Class I Genes; Medical; Memory; Mitochondria; Mutate; Outcome; Output; Patients; Peptides; Peripheral; Peripheral Blood Mononuclear Cell; Phytohemagglutinins; Pilot Projects; Population; Positron-Emission Tomography; Production; Proliferating; Propidium; RNA; Research Subjects; Role; Signal Transduction; Staining method; Stains; T memory cell; T-Cell Development; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Transplant Recipients; Transplantation; Virus Diseases; Water; base; beta Chain Antigen T Cell Receptor; improved; novel; peripheral blood; postnatal; premature; prevent; prophylactic; protein expression; receptor; receptor binding; reconstitution; research study; response; senescence; telomere; thymus transplantation

This 5 year competing application describes an opportunity to explore the long term outcomes of thymus transplantation in detail, with particular focus on the role of thymic activity and T cell function. Over the last 15 years, our laboratory has established that thymus transplantation is a successful therapeutic strategy for infants born with complete DiGeorge anomaly who are athymic and thus have a fatal immunodeficiency. Thymus transplantation results in host T cell reconstitution and survival of approximately 75% of subjects. We now will address unanswered questions about the basic biology of thymus transplantation in our long term survivors. Questions include the following, 1) why do T cell numbers remain in the 10th percentile after subjects reconstitute T cell numbers and function? 2) Does the thymus undergo senescence soon after transplantation with resulting low thymic output or, alternatively, is homeostasis altered due to premature apoptosis? 3) Are host T cells restricted to host HLA or to the HLA of the unmatched thymus donor? Lastly, it appears that there are some subclinical defects in T cell function. We will ask whether these differences are due to the lymphopenia of the subjects or are due to an inherent defect resulting from thymus transplantation. To address these questions, we will pursue three aims. The first specific aim will assess the etiology of low T cell numbers after transplantation. Thymic output will be investigated by deuterated water loading and quantification of signal joint to ¿ T cell receptor rearrangement excision circle ratios. The length of thymic function after thymus transplantation will be assessed using positron emission tomography (PET) scans. Studies of apoptosis will address whether peripheral apoptosis contributes to the low T cell numbers found in subjects with complete DiGeorge anomaly. The second specific aim will assess the binding of T cell receptors to MHC by tetramer experiments. The binding to class I and class II tetramers will be compared between subjects with and without matching to the thymus donor and by comparing complete DiGeorge anomaly subjects to those with partial DiGeorge anomaly and healthy adults. The third specific aim focuses on T cell function. Studies are planned to distinguish the general effects of lymphopenia from potential inherent defects in the T cells after thymus transplantation. The T cell defects include the lack of or low level of T cell response to insoluble CD3, low numbers of T cells, and low interferon gamma (IFN-¿) production by T cells. By comparing the outcomes of the experiments from complete DiGeorge subjects to those with partial DiGeorge anomaly, who have lymphopenia, we can determine if thymus transplantation across an MHC barrier contributes to defects in T cell functioning after transplantation.

这5年的竞争应用程序描述了一个探索长期结果的机会， 详细介绍了胸腺移植，特别着重于胸腺活性和T细胞功能的作用。 在过去的15年里，我们的实验室已经确定胸腺移植是一种成功的方法。 先天性完全性DiGeorge畸形婴儿的治疗策略 致命的免疫缺陷胸腺移植导致宿主T细胞重建和移植物存活 约75%的受试者。我们现在要解决一些未解之谜， 胸腺移植在我们的长期幸存者身上。问题包括：1）为什么T细胞 在受试者重建T细胞数量和功能后，数量仍保持在第10百分位数？（二） 移植后胸腺是否很快衰老导致胸腺输出量降低， 或者，体内平衡是否由于过早凋亡而改变？3)宿主T细胞是否仅限于 宿主HLA还是不匹配的胸腺供体的HLA？最后，似乎有一些 T细胞功能的亚临床缺陷。我们会问，这些差异是否是由于 淋巴细胞减少症或由于胸腺移植导致的固有缺陷。 为了解决这些问题，我们将追求三个目标。第一个具体目标将评估 移植后T细胞数量减少的病因。胸腺输出将通过氘代 水负荷和与T细胞受体重排切除环信号连接的定量 比率。胸腺移植后胸腺功能的长度将使用正电子 发射断层扫描（PET）。细胞凋亡的研究将解决外周细胞凋亡是否 导致在具有完全DiGeorge异常的受试者中发现的低T细胞数量。的 第二个具体目标是通过四聚体实验评估T细胞受体与MHC的结合。 与I类和II类四聚体的结合将在具有和不具有的受试者之间比较。 匹配胸腺供体，并通过比较完全DiGeorge异常受试者与 部分DiGeorge异常和健康成人。第三个具体目标集中在T细胞功能上。 计划进行研究以区分淋巴细胞减少症的一般影响和潜在的固有缺陷 在胸腺移植后的T细胞中。T细胞缺陷包括缺乏或低水平的T细胞 对不溶性CD 3的反应，T细胞数量少，T细胞产生的干扰素γ（IFN-γ）低。通过比较来自完全DiGeorge受试者与具有淋巴细胞减少症的部分DiGeorge异常受试者的实验结果，我们可以确定穿过MHC屏障的胸腺移植是否有助于移植后T细胞功能的缺陷。