PATHOGENESIS AND TREATMENT OF APLASTIC ANEMIA

再生障碍性贫血（AA）和其他类型的骨髓衰竭有临床 和实验室特征符合自身免疫病理生理学， 可能是被病毒感染的 大多数患者的反应是 免疫抑制治疗后血液学改善。 我们 实验室研究集中在免疫病理生理学方面 造血抑制，病毒抗原的性质，以及 再生障碍性贫血向其他疾病的晚期克隆进化机制， 包括骨髓增生异常和阵发性睡眠性血红蛋白尿（PNH）。 此外，我们在研究中测试了骨髓衰竭的新疗法， 临床方案。 一种形式的AA发生在肝炎后，我们有 完成了10例患者的临床和实验室数据综合分析 在NIH看到的病人。 大多数是血清反应阴性的年轻男性 肝炎后严重骨髓衰竭 肝炎是 以非A、非B、非C、也非G为特征;小说的一个角色 GBV- C/庚型肝炎因子在这里被排除，一般也在AA中被排除。 在肝炎/AA人群中有很强的HLA相关性， 尤其是Cw 7、B7、DR 7、DQ 2和Drw 53， 细胞毒性淋巴细胞激活的信号 7例患者表现为极好 对免疫抑制治疗的反应。 肝炎/AA是 免疫介导的骨髓衰竭综合征，由未知的 病毒 在再障造血的研究中，我们测量了干细胞 称为长期培养起始细胞的替代试验中的数量 LTC-IC测试 所有患者的干细胞数量都明显不足 无法预测对以下疾病的反应的介绍 免疫抑制治疗 LTC-IC也是定性异常， 在培养物中形成次级菌落的能力低。 虽然患者 可以在不增加LTC-IC数量的情况下恢复血细胞计数， 在治疗后数年，一些患者的LTC-IC数量正常， 表明在干细胞区室中的再增殖。 最后我们 建立了PNH造血功能基因敲除模型。 毁灭 PIG-A基因，表达糖磷酸肌醇 （GPI）连接的蛋白质在细胞表面，不利地影响 体外胚胎发生;然而，胚状体形成恢复， 基因缺陷细胞的造血功能正常， PIG-A-细胞和正常细胞的共培养。 可以证明。 对红细胞的研究还表明， GPI连接的蛋白质可以被高密度脂蛋白交换。 为 在人类患者样本中，造血集落没有差异 正常和GPI缺陷细胞之间的形成。 这些结果表明 PNH造血在AA中具有选择性优势。

Aplastic anemia (AA) and other types of bone marrow failure have clinical and laboratory features consistent with an autoimmune pathophysiology, possibly incited by a virus. A majority of patients respond with hematologic improvement after immunosuppressive therapies. Our laboratory studies have focused on aspects of the immune pathophysiology of hematopoietic suppression, the nature of the viral antigen, and the mechanism of late clonal evolution of aplastic anemia to other diseases, including myelosyplasia and paroxysmal nocturnal hemoglobinuria (PNH). In addition, we test new therapies for marrow failure in research clinical protocols. One form of AA occurs after hepatitis, and we have completed analysis of combined clinical and laboratory data on 10 patients seen at NIH. Most were young males who suffered seronegative hepatitis followed by severe marrow failure. The hepatitis was characterized as non A non B non C and also non G; a role for the novel GBV- C/hepatitis G agent was excluded here and also in AA in general. There were strong HLA correlations within the hepatitis/AA population, especially to Cw7, B7, and DR7, DQ2, and Drw53, and all showed evidence of cytotoxic lymphocyte activation. Seven patients showed excellent responses to immunosuppressive therapy. Hepatitis/AA is an immunologically mediated marrow failure syndrome incited by an unknown virus. In studies of hematopoiesis in AA, we have measured stem cell numbers in a surrogate assay called the long-term culture initiating cell test (LTC-IC). All patients show a marked deficit in stem cell number on presentation that does not allow prediction of response to immunosuppressive therapy. LTC-IC also are qualitatively abnormal with a low capacity to form secondary colonies in culture. Although patients can recover blood counts without increasing numbers of LTC-IC, several years after treatment, some patients do have normal numbers of LTC-IC, suggesting repopulation within the stem cell compartment. Finally, we have established a knock-out model of hematopoiesis in PNH. Destruction of the PIG-A gene, required for expression of glycophosphoinositol (GPI)-linked proteins on the cell surface, adversely affected embyrogenesis in vitro; however, embyroid body formation was restored, and hematopoiesis from genetically defective cells was normal, after coculture of PIG-A- and normal cells.Intercellular protein transfer could be demonstrated. Studies with red cells also suggest that GPI-linked proteins can be exchanged by high density lipoproteins. For human patient samples, there were no differences in hematopoietic colony formation between normal and GPI-deficient cells. These results suggest that PNH hematopoiesis has a selective advantage in AA.