PATHOGENESIS AND TREATMENT OF APLASTIC ANEMIA

再生障碍性贫血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。多数 患者对免疫抑制的反应是血液学改善。我们的 实验室研究的重点是这种疾病的免疫病理生理学。 疾病，一种假定的病毒抗原的鉴定及其机制 晚期克隆性血液病综合征的发展。对中国传统文化的研究 肝炎后再生障碍性贫血表明，这是一种 免疫介导性疾病，没有已知的病毒剂。分子 再生障碍性贫血和再生障碍性贫血的骨髓研究方法 重型肝炎的肝脏样本现在正被应用于 血清阴性的急性肝炎患者的血液。这个 导致骨髓衰竭的免疫学事件通过 对造血细胞的破坏进行了定义。最近的观察结果 包括识别适当抑制性细胞因子受体 造血细胞及其细胞内信号转导特性 干扰素受体结合后的信号转导途径。一个 一种简便测定细胞因子含量的实用方法 外周血和骨髓淋巴细胞已经开发出来， 可适用于患者术前和术中的评估 免疫抑制治疗。晚期克隆血液学的问题 疾病，特别是阵发性睡眠性血红蛋白尿， 部分地解决了这一问题，因为发现具有突变的细胞 PIG-A基因以及由此导致的PIG-A基因缺失 糖基磷脂醇连接的膜蛋白，不容易感染 某些类型的免疫系统攻击。两个初级淋巴细胞都来自 患者和一种细胞系，对于该细胞系，配对的正常和突变株是 已经被用来证明T细胞和自然杀伤细胞 不能有效地诱导糖基磷脂醇的细胞毒性- 连接膜蛋白缺陷细胞。最后，进一步分析了 一大群患者统一接受强化治疗 由抗胸腺细胞球蛋白组合组成的免疫抑制 环孢素显示了治疗再生障碍性贫血的新特点。 强化免疫抑制非常有效，可引发血液系统疾病 约70%的患者有反应。无论是儿童还是患者 极重度中性粒细胞减少症，两组比较难治较多 常规的治疗形式，都是有效的。值得注意的是，许多患者 需要继续治疗(通常是环孢素的再治疗)， 与白血病不同，“复发”不会产生不良影响。 对预后的影响。

Aplastic anemia and other types of bone marrow failure have clinical and laboratory features consistent with an autoimmune pathophysiology. Most patients respond with hematologic improvement to immunosuppression. Our laboratory studies have focused on the immune pathophysiology of this disease, identification of a putative viral antigen, and the mechanism of development of late clonal hematologic syndromes. Studies of the post-hepatitis aplastic anemia have shown that this is an immunologically-mediated disease without a known viral agent. Molecular methods developed for the study of bone marrow in aplastic anemia and of liver in fulminant hepatitis are now being applied to specimens of blood from patients with seronegative acute hepatitis. The immunological events that precipitate bone marrow failure through hematopoietic cell destruction have been defined. Recent observations include identification of appropriate inhibitory cytokine receptors on hematopoietic cells and characterization of the intracellular signaling pathway after gamma-interferon interferon receptor engagement. A practical method for the convenient assay of cytokine-containing peripheral blood and bone marrow lymphocytes has been developed which may be applicable to the evaluation of patients before and during immunosuppressive treatment. The problem of late clonal hematologic diseases, especially paroxysmal nocturnal hemoglobinuria, has been partly resolved with the discovery that cells with mutations in the PIG-A gene, and consequent absent expression of glycophosphoinositol-linked membrane proteins, are not susceptible to some types of immune system attack. Both primary lymphocytes from patients and a cell line, for which paired normal and mutant strains are available, have been used to show that T cells and natural killer cells are not effective in inducing cytotoxicity in glycophosphoinositol- linked membrane protein-deficient cells. Finally, further analysis of a large cohort of patients uniformly treated with intensive immunosuppression consisting of a combination of anti-thymocyte globulin and cyclosporine has revealed new features of treated aplastic anemia. Intensive immunosuppression is highly effective, inducing hematologic responses in about 70% of patients. Both children and patients with extremely severe neutropenia, two groups relatively refractory to more conventional forms of treatment, are responsive. Of note, many patients require continued treatment (usually reinstitution of cyclosporine) but, in contrast to the leukemias, "relapse" does not have an adverse effect on prognosis.