PATHOGENESIS AND TREATMENT OF APLASTIC ANEMIA

再生障碍性贫血的发病机制和治疗

• 批准号: 3779565
• 负责人: N S YOUNG
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3779565
• 关键词: aplastic anemia; blood disorder chemotherapy; bone marrow disorder; combination chemotherapy; cyclosporines; globulins; human subject; human therapy evaluation; immunohematology; immunosuppression; immunotherapy; interferon gamma; interleukin 3; lymphokines; messenger RNA; pathologic process; virus antigen

Aplastic anemia and other forms of bone marrow failure have clinical and laboratory features consistent with a possible viral etiology followed by immunological pathophysiology. Aplastic anemia may follow on a viral infection, especially non-A non-B hepatitis. Patients have evidence of activation of cytotoxic lymphocytes, and excessive lymphokine production. During the past year, we have documented that these immunologic abnormalities are more striking when the bone marrow is examined compared to the peripheral blood. For lymphokine production, gamma-interferon mRNA expression, as determined by gene amplification, is prevalent and highly specific for aplastic anemia compared to normal and hematologic control specimens. Lymphotoxin gene expression, although present in normal bone marrow, is also increased in aplastic anemia. Lymphocyte phenotyping of aplastic bone marrow has shown increased cytotoxic lymphocytes, increased natural killer cells, and gamma delta T-cells in the majority of patients with this disease, indicating a broad immunologic response. The explanation for immunological activation in aplastic anemia has been hypothesized to be due to viral antigens. We have established that the hepatitis/aplasia syndrome is non-A non-B non- C. In experiments employing a sophisticated gene amplification methodology, we were unable to demonstrate the presence of novel DNA in fulminant hepatitis (related to hepatitis/aplasia), implicating an RNA rather than DNA virus in these syndromes. Finally, in clinical studies we have continued a program of intensive immunosuppressive therapy consisting of combined antithymocyte globulin and cyclosporin. Response rates continue to be approximately 70% in patients with severe aplastic anemia, higher than the hematologic improvement rates observed with antithymocyte globulin treatment alone. Of note, both children and patients with absolute neutropenia respond at a high rate to this therapy.

再生障碍性贫血和其他形式的骨髓衰竭具有临床和 实验室特征与可能的病毒病因学一致， 免疫病理生理学。 再生障碍性贫血可能是由病毒性贫血引起的。 感染，尤其是非甲非乙型肝炎。 患者有证据表明 细胞毒性淋巴细胞的活化和过度的淋巴因子产生。 在过去的一年里，我们已经证明，这些免疫学 当检查骨髓时， 到外周血中。 产生淋巴因子，γ-干扰素 通过基因扩增确定的mRNA表达是普遍的， 与正常和血液学相比，对再生障碍性贫血具有高度特异性 对照标本。 尽管在哺乳动物中存在着光合毒素基因的表达， 在再生障碍性贫血中也会增加。 淋巴细胞 再生障碍性骨髓的表型分析显示， 淋巴细胞，自然杀伤细胞增加，γ δ T细胞， 大多数患有这种疾病的患者， 免疫反应。 免疫激活的解释 再生障碍性贫血被假设是由于病毒抗原。 我们 已经确定肝炎/再生障碍综合征是非甲非乙型非 C. 在一个复杂的基因扩增实验中， 方法，我们无法证明新DNA的存在， 涉及RNA的暴发性肝炎（与肝炎/再生障碍相关） 而不是DNA病毒 最后，在临床研究中， 我们继续进行强化免疫抑制治疗 由组合的抗胸腺细胞球蛋白和环孢菌素组成。 响应 在严重再生障碍性贫血患者中， 贫血，高于观察到的血液学改善率， 单独抗胸腺细胞球蛋白治疗。 值得注意的是，儿童和 绝对中性粒细胞减少症患者对此反应率高， 疗法