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 最 患者对免疫抑制的反应是血液学改善。 我们 实验室研究集中在免疫病理生理学， 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。 的研究 肝炎后再生障碍性贫血表明，这是一个 免疫介导的疾病，而没有已知的病毒剂。 分子 研究再生障碍性贫血骨髓的方法， 暴发性肝炎中肝脏的研究现在被应用于 血清阴性急性肝炎患者的血液。 的 免疫学事件通过以下途径加速骨髓衰竭： 造血细胞破坏已经被定义。 最近的观察 包括鉴定合适抑制性细胞因子受体， 造血细胞和细胞内信号转导的表征 γ-干扰素干扰素受体接合后的通路。 一 一种简便测定含苦参碱的药物的实用方法 已经开发了外周血和骨髓淋巴细胞， 可能适用于患者术前和术中的评估 免疫抑制治疗。 晚期克隆性血液病的问题 疾病，尤其是阵发性睡眠性血红蛋白尿， 部分解决的发现，细胞突变的，在 PIG-A基因，以及随之而来的 糖磷酸肌醇连接的膜蛋白，对 一些类型的免疫系统攻击。 两种初级淋巴细胞 患者和细胞系，其中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 不能有效诱导糖磷酸肌醇的细胞毒性， 连接的膜蛋白缺陷细胞。 最后，进一步分析 一个大的患者队列， 由抗胸腺细胞球蛋白组合组成的免疫抑制 环孢霉素显示了再生障碍性贫血治疗的新特点。 强烈的免疫抑制是非常有效的，诱导血液学 约70%的患者有反应。 儿童和患有 极重度中性粒细胞减少，两组相对难治性较多 传统的治疗方法是有效的。 值得注意的是，许多患者 需要继续治疗（通常重新使用环孢菌素），但是， 与白血病相反，“复发”没有副作用， 关于预后

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.