PATHOGENESIS AND TREATMENT OF APLASTIC ANEMIA

再生障碍性贫血的发病机制和治疗

• 批准号: 3757655
• 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/3757655
• 关键词: CD antigens; amine oxidoreductase; aplastic anemia; apoptosis; artificial immunosuppression; bone marrow; cell adhesion molecules; cytotoxic T lymphocyte; gene induction /repression; globulins; hematopoiesis; hematopoietic stem cells; human subject; human therapy evaluation; human tissue; immunohematology; immunopathology; interferon gamma; lymphokines; nitric oxide; tissue /cell culture; tumor necrosis factor beta; virus diseases

Aplastic anemia and other forms of bone marrow failure have clinical and laboratory features consistent with a possible viral etiology followed by immunological pathophysiology. Patients have evidence of activation of cytotoxic lymphocytes and excessive lymphokine production. Using molecular methods, we have shown that the genes for gamma-interferon and lymphotoxin are over-expressed locally in the bone marrow in patients with aplastic anemia. The bone marrow is also the local site of increased activated cytotoxic lymphocytes. Immunological activation in aplastic anemia may be due to a viral infection. The hepatitis/aplasia syndrome, which is non-A non-B non-C by serology and DNA studies, is the best clinical example of virus-incited marrow failure. However, we have been unable to detect viral sequences using a variety of molecular methodologies in fulminant hepatitis liver specimens of similar serologic and molecular character. The mechanism of interferon suppression of hematopoiesis has been elucidated by study of the Fas system. In tissue culture, gamma interferon induces Fas expression on hematopoietic cells, and activation of the Fas receptor is synergistic with lymphokine suppression of hematopoiesis at multiple stages of differentiation. Program cell death in hematopoiesis may be linked to nitric oxide production, and we have shown that CD34+ cells containing hematopoietic progenitors and stem cells are both susceptible to nitric oxide and contain an inducible nitric oxide synthetase. Finally, in our large clinical trial of intensive immunosuppression in severe aplastic anemia, which has enrolled over 55 patients, we have demonstrated a marked improvement in hematologic responses and survival compared to antithymocyte globulin alone. Therapy has been effective in children and in severely neutrophenic patients.

再生障碍性贫血和其他形式的骨髓衰竭有临床和 实验室特征与可能的病毒病原学一致 通过免疫病理生理学。患者有激活的证据 细胞毒性淋巴细胞和过多的淋巴因子产生。vbl.使用 分子方法，我们已经证明了γ-干扰素和 淋巴毒素在患者骨髓局部过度表达 患有再生障碍性贫血。骨髓也是沙门氏菌 活化的细胞毒性淋巴细胞增多。中国人的免疫激活 再生障碍性贫血可能是由病毒感染引起的。肝炎/再生障碍性贫血 综合征，通过血清学和DNA研究是非A非B非C的，是 病毒引起的骨髓衰竭的最佳临床案例。然而，我们有 无法使用各种分子检测病毒序列 血清学相似的重型肝炎肝标本的方法学研究 和分子特征。干扰素抑制慢性粒细胞白血病的机制 通过对Fas系统的研究，已经阐明了造血的作用。在组织中 培养，γ干扰素诱导造血细胞Fas表达， Fas受体的激活与淋巴因子具有协同作用 在多个分化阶段的造血抑制。 造血过程中程序性细胞死亡可能与一氧化氮有关 产生，我们已经证明CD34+细胞含有造血细胞 祖细胞和干细胞都容易受到一氧化氮和 含有诱导型一氧化氮合酶。最后，在我们的大范围内 强化免疫抑制治疗重型再生障碍性贫血的临床研究 它已经招募了超过55名患者，我们已经展示了一个显著的 血液学反应和存活率的改善 单独使用抗胸腺细胞球蛋白。治疗对儿童和 在严重中性粒细胞缺乏的患者中。