B-CELL CHANGES ASSOCIATED WITH HIV-1 THROMBOCYTOPENIA

描述（改编自申请人摘要） 申请人表现出了一种不同寻常的联系， 一组HIV-1感染者的无关血液学异常 个体 HIV-1血清阳性、血小板减少的个体显示 他们的B细胞亚群有明显的改变虽然B细胞数量 正常人外周血CD5+细胞比例及其绝对数均为 CD5-B细胞的绝对数量明显减少。 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 可归因于CD4或CD8细胞数量、CD4/CD8比值的变化，或 淋巴细胞绝对计数与疾病严重程度和AZT无关 治疗 申请人认为， 血小板减少症和异常B细胞分布发生， 偶然事件 他们的建议旨在调查 协会 三种可能的解释将被审查：（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 将对感染患者进行与B反应的自身抗体检测 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 HIV-1 + ITP患者的血小板。 如果抗B细胞抗体 他们将确定CD5 + B细胞如何逃避这种自身免疫性疾病， 反应 (2)这些异常可能是HIV-1的直接影响 造血前体或细胞上的感染， B细胞和巨核细胞的发育。 长期骨 骨髓细胞培养和短期克隆培养将用于 研究了病毒、HIV-1感染细胞和血清对HIV-1感染的影响， B细胞的发育。(3)淋巴造血的变化可能是 这是由CD4 + T细胞缺乏或CD4 + T细胞缺乏引起的调节异常的结果。 细胞或过量的CD8 + T细胞。 已知T细胞衍生的细胞因子 对MK和B细胞的发育都有深远的影响。 的相对 CD5+亚群的T细胞独立性可能是其持续存在的原因。 这一可能性将使用两个模型系统进行研究。 在第一个， 将从未感染的受试者中选择的人细胞群 转移至免疫缺陷（SCID）小鼠。将使用细胞分选 分离高度富集的CD5+和CD5-B细胞群，或其 前体以及表达CD4或CD8的T细胞群。 将注射这些群体的各种组合， 确定B细胞亚群的存活率。 在第二个模型中， 将尝试在完全鼠模型中再现该现象。 系统同样，将通过以下步骤制备必需表型的细胞： 细胞分选并注射到SCID小鼠中，但在该模型中， 从同基因小鼠中转移，消除了 组织不相容性的问题会混淆 问题研究

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.