PATHOGENESIS AND TREATMENT OF APLASTIC ANEMIA

再生障碍性贫血的发病机制和治疗

• 批准号: 3843328
• 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/3843328
• 关键词: aplastic anemia; blood disorder chemotherapy; bone marrow disorder; clinical trials; cyclosporines; globulins; hematopoietic growth factor; human subject; human therapy evaluation; immunohematology; immunosuppression; immunotherapy; interferons; interleukin 3; 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, excessive lymphokine production, and decreased natural killer cells. We have recently established that aplastic anemia following hepatitis is non-C as well as non-A, non-B, and we have initiated chimpanzee inoculation studies and seroepidemiologic studies for hepatitis E. The immunophysiology of aplastic anemia has been investigated through gene amplification studies of RNA in bone marrow. We have found that the majority of patients presenting with aplastic anemia have detectable gamma-interferon mRNA in extracted bone marrow. Gamma-interferon mRNA is not found in normal individuals, in patients who have received multiple blood transfusions, or in patients with other forms of bone marrow failure. Gamma- interferon RNA predominates in the bone marrow of patients with aplastic anemia, not in this peripheral blood. In clinical studies, we have initiated a trial of intensive immunosupprccession consisting of combined anti-thymocyte globulin and cyclosporine. Preliminary response rates are approximately 70%, considerably higher than hematologic improvement rates observed with anti-thymocyte globulin treatment alone. For growth factors, we are continuing to treat patients with Diamond- Blackfan anemia with interleukin-3, after having observed significant durable and clinical remissions in 2/6 patients with congenital pure red cell aplasia. A trial of stem cell factor, a novel human interleukin, is scheduled to begin shortly in patients with severe refractory aplastic anemia. Finally, we have proposed a unifying model for post- aplastic anemia paroxysmal nocturnal hemoglobinuria and myelodysplasia based upon the diverse activities of cytotoxic lymphocytes.

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，淋巴因子的过度产生， 自然杀伤细胞减少 我们最近确定， 肝炎后再生障碍性贫血是非C型以及非A型，非B型， 我们已经开始了黑猩猩接种研究， 戊型肝炎的血清流行病学研究 免疫生理学 再生障碍性贫血已通过基因扩增研究 RNA在骨髓中。 我们发现大多数病人 患有再生障碍性贫血的患者， 抽取骨髓 γ-干扰素mRNA在正常人中未发现， 在接受多次输血的患者中， 或其他形式的骨髓衰竭患者。 伽马- 再生障碍性贫血患者骨髓中干扰素RNA占优势 贫血，不是在外周血中。 在临床研究中， 启动了一项强化免疫抑制试验， 联合抗胸腺细胞球蛋白和环孢霉素。 初步答复 率约为70%，远高于血液学检查 用单独的抗胸腺细胞球蛋白治疗观察到的改善率。 对于生长因子，我们继续用钻石治疗患者- 布莱克凡贫血与白细胞介素-3，后有观察显着 2/6例先天性纯红患者的持久和临床缓解 细胞再生障碍 干细胞因子，一种新的人类白细胞介素， 计划开始不久， 再生障碍性贫血 最后，我们提出了一个统一的模型后， 再生障碍性贫血阵发性睡眠性血红蛋白尿和骨髓增生异常 基于细胞毒性淋巴细胞的不同活性。