Mechanisms of Allogeneic Stem Cell Education in SCID

SCID 中同种异体干细胞教育的机制

• 批准号: 7897678
• 负责人: REBECCA H BUCKLEY
• 金额: $ 39万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897678
• 关键词: Address; Age; Age-Months; Alloantigen; Allogeneic Bone Marrow Transplantation; Allogenic; Antibodies; Apoptosis; Autoimmunity; Biological Assay; Bone Marrow; Bone Marrow Cells; Bone Marrow Stem Cell; Bone Marrow Transplantation; CD3 Antigens; Cell Count; Cell Therapy; Cell physiology; Cells; Cessation of life; Characteristics; Chimera organism; Clonality; Color; Cytometry; Data; Defect; Development; Diagnosis; Education; Engraftment; Flow Cytometry; Funding; Genes; Genetic; Genetic Recombination; Genotype; Goals; Hematopoietic stem cells; Human; Human Development; Immune; Incidence; Infant; Infection; Janus kinase 3; Length; Life; Ligase; Longevity; Longitudinal Studies; Marrow; Measures; Methods; Mixed Lymphocyte Culture Test; Molecular; Monitor; Monoclonal Antibodies; Mutation; Natural Killer Cells; Output; PTPRC gene; Parents; Patients; Phenotype; Population; Prophylactic treatment; Research; Resistance; Resistance to infection; Resources; Role; Severe Combined Immunodeficiency; Sorting - Cell Movement; Staining method; Stains; Stem cells; Surface; Survival Rate; Survivors; Syndrome; T-Lymphocyte; Testing; Thymus Gland; Time; Tin; Transplantation; Treatment Efficacy; V(D)J Recombination; Viral; Virus Diseases; Work; abstracting; adenosine deaminase; adenosine deaminase deficiency; artemis; cell type; chemotherapy; conditioning; cytokine; experience; gene therapy; graft vs host disease; immune function; interest; magnetic beads; reconstitution; stem; stem cell therapy; telomere; transplantation typing

Modified Project 0 The overall goal of the proposed research is to further elucidate mechanisms of allogeneic stem cell education goal the proposed research in patients with severe combined immunodeficiency (SCID) given transplants of rigorously T cell-depleted HLAwith severe combined immunodeficiency HLAidentical or haploidentical related bone marrow cells without pre-transplant chemotherapy or post-transplant identical haploidentical related marrow cells without pre-transplant chemotherapy post-transplant PI has administered the 161 such graft-versus-host disease (GVHD) prophylaxis. The P1 has administered the latter therapy to 161 such infants graft-versus-host disease (GVHD) prophylaxis. rate of 77%. (16 HLA-identical, 145 haploidentical) over the past 26.4 years, with an overall survival rate of 77%. Aim 1) To HLA-identical, 145 haploidentical) over the 26.4 years, with an 1) To investigate the possible roles of elevated percentages of double negative and y8 T cells in the longterm investigate the possible roles of elevated percentages of double negative and yB T cells in the longterm functions ON immune reconstitution of these SCID chimeras. We will characterize the phenotypes and functions of DN and immune reconstitution of these SCID chimeras. We will characterize the y6 T cells after allogeneic stem cell therapy in SCID using monoclonal antibodies and multi-color flow yB cells after allogeneic stem cell therapy in SCIO using monoclonal antibodies and multi-color flow cytometry, cellular cytokine staining and assays of T cell and T cell function. The hypothesis to be tested is that cytometry, cellular cytokine staining and assays of I development of elevated percentages of double negative and y6 T in these SCID chimeras postthe development of elevated percentages of double negative and yB T cells in these SCID chimeras posttransplantation may be beneficial to these chimeras by increasing their resistance to infection, 2) transplantationmay be beneficial to these chimeras by 1) increasing their resistance to infection, 2) maintaining tolerance of the genetically donor T cells to host alloantigens in the setting of half-matched marrow of half-matched marrow maintaining tolerance of the genetically their overall successful immune transplants, 3) reducing the incidence autoimmunity, and transplants, 3) reducing the incidence of autoimmunity, and 4) contributing to their overall successful immune various molecular of reconstitution. Aim 2) To examine why the immune reconstitution differs in the various molecular forms of reconstitution. Aim 2) To examine why the immune reconstitution differs in SCID. SCIDs with adenosine deaminase deficiency and VDJ recombination defects have lower than normal T SCID. SCIDs with adenosine deaminase deficiency and VDJ recombination defects have lower than normal T cell numbers and function and lower thymic output post-transplantation than SCIDs of other molecular types. cell numbers and function and lower thymic output post-transplantation than SCIDs of other molecular types. of the various molecular types of approach this question, we plan to To approach this question, we plan to measure telomere length in the T cells of the various molecular types of SCID and to examine for abnormal apoptosis and homeostatic proliferation. The hypothesis is that the thymus the thymus SCID and to examine for abnormal apoptosis proliferation. number and that the T cells have a of some molecular types of SCIO is less able to produce T cells in normal number and that the T cells have a molecular types of SCID is maintained proliferation. 3) To investigate shorter lifespan but that circulating T cells are maintained by homeostatic proliferation. Aim 3) To investigate lifespan but that circulating T whether the decline in natural killer (NK) cell function in X-SCID and Jak3-deficient SCID is compensated for SCIO is compensated whether the decline in natural killer (NK) by the development of normally functioning NKT cells. The approach would be to analyze these NKT cells for cells. The approach would be to analyze these cells for the phenotype and function other unique surface markers characteristic of this type of cell, and to characterize the phenotype and function unique surface markers characteristic cell, hypothesis be tested is that there is these cells. We will also examine for clonality of these cells. We will also examine for clonality or the lack of it. The hypothesis to be tested is that there is cells and 2) that, instead, something missing in the microenvironment in that does not permit survival something missing in the microenvironment in that does not permit survival of NK cells and 2) that, instead, molecular NKT cells develop as a compensatory mechanism that protects SCIDs with those two molecular types from NKT cells develop as a compensatory mechanism that protects SCIDs with be pursued in as many severe viral infections. Because this a longitudinal study, the three aims severe viral infections. Because this isis a longitudinalstudy, the three aims will be pursued in as many returning or new chimeras who are available during the two years of support, with the intent to show returning or new chimeras who are available during the two years of support, with feasibility of the proposed methods to address the hypotheses and to generate sufficient data to proposed methods address hypotheses and generate data feasibility permit application for further support. application for further (Op 0)-N 0-0 .O-., -Ow 3o�n�1 nip --� Sam ..� -M, (�A O�< -550 0_q (Op __j .-� 'C7 .n_. w01 fl, tin

修改后的项目 0 拟议的研究的总体目标是进一步阐明同种异体干细胞教育目标的机制，拟议的严重合并免疫缺陷性（SCID）的患者的拟议研究具有严格的T细胞耗尽的HLA，具有严重的免疫缺陷性HLAALAAIDICENTIC HLAAIDICTION或单倍性相关的无关骨骼的骨骼固定性或邮政为良好的骨骼化学疗法，而无需先生的骨骼化学疗法，则提出了严格的T细胞耗尽的HLA。移植前化学疗法移植后PI已施用161种此类移植物抗宿主病（GVHD）的预防。 P1已对161例此类婴儿移植物抗宿主病（GVHD）预防进行了治疗。率为77％。 （在过去的26.4年中，（16 HLA），145个单倍体），总生存率为77％。目的1）在26。4年中，在145个单倍词中，1）在长期中研究了双重阴性和Y8 T细胞比例升高的作用，研究了长期功能在长期功能中可能升高的双重和Yb T细胞比例在这些Scid Chimeras的免疫分配中的作用。我们将表征这些SCID嵌合体的DN和免疫宪法的表型和功能。我们将使用单克隆抗体和多色干细胞在SCIO中使用单克隆抗体和多色流式细胞术，细胞细胞因子和T细胞细胞功能的分析来表征使用单克隆抗体和多色流量YB细胞在SCIO进行SCID后SCID中的Y6 T细胞表征Y6 T细胞。要检验的假说是，在这些SCID嵌合体中，这些SCID嵌合体的细胞仪，细胞细胞因子染色以及I开发双重阴性和y6 t的升高百分比，在这些SCID嵌合在这些SCID嵌合体中的升高百分比升高的发展后，通过这些SCID嵌合在这些SCID嵌合会在这些转移后通过这些奇物群增强其抵抗，以使其有益于这些嵌合体，从而有益于这些奇物膜，以使其有益于这些奇物，并有助于这些嵌合体，这些嵌合体具有2），这些嵌合体的感染能力，这些嵌合体有益于这些嵌合体，这些嵌合体的感染构成，这些嵌合体有益于这些嵌合体，该嵌合体的感染构成，以下是2），这些嵌合体的感染构成，构层的构架，构造的构造，是有益于这些嵌合体， 2）在遗传供体T细胞中保持容忍度托管同型物质的耐受性在半匹配的骨髓的环境中保持遗传上成功的免疫移植的耐受性，3）降低各种自动免疫性，并降低各种自动化的事件，并降低自动化事件，4）4）重构分子。目标2）研究为什么免疫学重构在各种分子形式的重建形式中有所不同。目的2）检查为什么免疫学重构在SCID中有所不同。具有腺苷脱氨酶缺乏症和VDJ重组缺陷的SCID低于正常T SCID。与其他分子类型的SCID相比，患有腺苷死亡酶缺乏症和VDJ重组缺陷的SCID低于正常T细胞数量和功能和胸腺输出量低。在这个问题的各种分子类型中，我们计划解决这个问题，我们计划测量SCID的各种分子类型的T细胞中的端粒长度，并检查异常的细胞凋亡和稳态增殖。假设是胸腺胸腺scID并检查异常凋亡增殖。数量并且T细胞具有某些分子类型的SCIO的A较少能力产生正常数的T细胞，并且T细胞具有分子类型的SCID，可以通过稳态增殖来维持。目的3）研究寿命，但是循环t是否可以补偿X-SCID和JAK3缺陷SCID中天然杀伤（NK）细胞功能的下降是否能否通过正常运行的NKT细胞的发展来补偿SCIO。该方法是分析这些NKT细胞的细胞。该方法是分析这些细胞的表型和功能的这些细胞的其他独特表面标记，并表征表型和功能独特的表面标记的特征性细胞，可以检验的假设是有这些细胞。我们还将检查这些细胞的克隆性。我们还将检查克隆性或缺乏克隆性。要检验的假说是有细胞和2），相反，微环境中缺少某些东西，在这种情况下不允许生存在微环境中缺少的东西，因为它不允许允许NK细胞的生存和2）分子NKT细胞作为一种远离nkt sciD sciD sciD的NKT细胞而发展的NK细胞的生存，而这些机制与NKT相关的机制发展，而NKT类型也可以在NKT中发育，而NKT细胞也可以在NKT中发展，而NKT细胞则具有nkt sciD，而NKT细胞则是NKT细胞的发展，而NKT细胞则是NKT细胞发展的，而NKT细胞则具有NKT细胞的发展。病毒感染。 Because this a longitudinal study, the three aims will be pursued in as many returning or new chimeras who are available during the two years of support, with the intent to show returning or new chimeras who are available during the two years of support, with feasibility of the proposed methods to address the hypotheses and to generate sufficient data to proposed methods address hypotheses and generate data feasibility permit application for further support.申请进一步支持 （OP 0）-n 0-0 .O-。， - ow 3o。1nip - � 山姆 ..� -m， （A o < -550 0_Q （OP __J .- 'C7 .n_。 W01 佛罗里达州 锡

项目成果

The long and the short of telomeres in bone marrow recipient SCID patients.

• DOI: 10.1007/s12026-010-8192-8
• 发表时间: 2011-04
• 期刊: IMMUNOLOGIC RESEARCH
• 影响因子: 4.4
• 作者: Sarzotti-Kelsoe, Marcella;Daniell, Xiaoju G.;Whitesides, John F.;Buckley, Rebecca H.
• 通讯作者: Buckley, Rebecca H.