权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

B-CELL CHANGES ASSOCIATED WITH HIV-1 THROMBOCYTOPENIA

与 HIV-1 血小板减少症相关的 B 细胞变化

基本信息

批准号：
2518487
负责人：
ROSS S BASCH
金额：
$ 29.72万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-09-30 至 2000-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2518487
关键词：
B lymphocyte CD5 molecule CD8 molecule SCID mouse autoantibody cell sorting cytokine hematopoiesis human immunodeficiency virus 1 immune complex megakaryocytes phenotype receptor expression thrombocytopenia

项目摘要

DESCRIPTION (Adapted from the applicant's abstract) The applicants have demonstrated an unusual association of apparently unrelated hematological abnormalities in a group of HIV-l infected individuals. HIV-l seropositive, thrombocytopenic individuals showed marked alterations in their B-cell subsets. Although B-cell numbers were normal, both the proportion of CD5+ cells and their absolute number were increased and the absolute number of CD5- B-cells were markedly reduced. In some patients 90 percent of the circulating B-cells were CD5+ (normal=18.2 + 2.3%). The alteration in the B-cell subsets was neither attributable to changes in CD4 or CD8 cell number, CD4/CD8 ratio, or absolute lymphocyte count nor to severity of disease nor to AZT treatment. The applicants suggest that it is improbable that the association of thrombocytopenia and aberrant B-cell profile occurred through happenstance. Their proposal is designed to investigate the basis of the association. Three possible explanations will be examined: (1) Both the abnormalities could be consequences of an autoimmune response, associated with the prevalence of CD5+ B cells, and directed against either the mature cells or their progenitors in the marrow. Sera from infected patients will be assayed for autoantibodies reactive with B cells and platelets or their progenitors. The applicants will also seek cell-bound autoantibodies or immune complexes similar to those found on platelets of patients with HIV-1 + ITP. If anti-B-cell antibodies are found, they will determine how CD5+ B-cells escape this autoimmune response. (2) The abnormalities could be a direct effect of HIV-l infection on either a hematopoietic precursor or a cell necessary for the development of B-cells and megakaryocytes. Both long term bone marrow cell cultures and short-term clonal cultures will be used to study the effects of virus, HIV-l infected cells and serum on the development of B-cells. (3) The changes in lympho-hematopoiesis could be a result of dysregulation induced by either the deficiency of CD4+ T- cells or the excess of CD8+ T-cells. T-cell derived cytokines are known to have profound effects on both MK and B-cell development. The relative T-independence of the CD5+ subset may account for their persistence. This possibility will be examined using two model systems. In the first, selected populations of human cells from uninfected subjects will be transferred to immunodeficient (SCID) mice. Cell sorting will be used to isolate highly enriched populations of CD5+ and CD5- B-cells, or their precursors as well as T-cell populations expressing either CD4 or CD8. Various combinations of these populations will be injected and the survival of the B-cell subsets determined. In the second model, an attempt will be made to reproduce the phenomenon in a totally murine system. Again, cells of the necessary phenotypes will be prepared by cell sorting and injected into SCID mice, but in this model only cells from syngeneic mice will be transferred, eliminating the possibility that problems of histo-incompatibility will confound the developmental studies.

描述（改编自申请人的摘要）申请人表现出一种不寻常的关联，显然一组 HIV-1 感染者中不相关的血液学异常个人。 HIV-1 血清阳性、血小板减少的个体表现出 B 细胞亚群发生显着改变。尽管 B 细胞数量 CD5+细胞比例及其绝对数均正常增加，CD5-B细胞的绝对数量显着减少。在一些患者中，90% 的循环 B 细胞是 CD5+ （正常=18.2 + 2.3%）。 B 细胞亚群的改变既不是归因于 CD4 或 CD8 细胞数量、CD4/CD8 比率的变化，或绝对淋巴细胞计数、疾病严重程度、AZT 治疗。申请人认为该协会不太可能成立血小板减少症和异常 B 细胞谱发生于偶然事件。他们的提议旨在调查该法案的基础协会。将研究三种可能的解释：（1）两者这些异常可能是自身免疫反应的结果，与 CD5+ B 细胞的流行相关，并针对骨髓中的成熟细胞或其祖细胞。血清来自感染患者将检测与 B 反应的自身抗体细胞和血小板或其祖细胞。申请人还将寻求细胞结合的自身抗体或免疫复合物类似于在 HIV-1 + ITP 患者的血小板。如果抗 B 细胞抗体发现后，他们将确定 CD5+ B 细胞如何逃避这种自身免疫回复。 (2) 这些异常可能是 HIV-1 的直接影响造血前体或造血所需细胞的感染 B 细胞和巨核细胞的发育。两者都是长期骨骨髓细胞培养和短期克隆培养将用于研究病毒、HIV-1感染细胞和血清对 B 细胞的发育。 (3)淋巴造血的变化 CD4+ T- 缺乏引起的失调的结果细胞或过量的 CD8+ T 细胞。 T细胞衍生的细胞因子是已知的对 MK 和 B 细胞发育产生深远影响。亲戚 CD5+ 子集的 T 独立性可能是其持续存在的原因。将使用两个模型系统来检验这种可能性。在第一个中，来自未感染受试者的选定人类细胞群将被转移到免疫缺陷（SCID）小鼠体内。将使用细胞分选分离高度富集的 CD5+ 和 CD5- B 细胞群或其前体细胞以及表达 CD4 或 CD8 的 T 细胞群。这些人群的各种组合将被注射，并且确定 B 细胞亚群的存活率。在第二个模型中，将尝试在完全小鼠中重现该现象系统。同样，将通过以下方式制备具有必要表型的细胞细胞分选并注射到 SCID 小鼠中，但在该模型中仅注射细胞来自同系小鼠的将被转移，消除了可能性组织不相容性问题将扰乱发育研究。