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， 可能是被病毒煽动的。再生障碍性贫血患者显示 细胞毒T细胞活化和淋巴因子过多的证据 产生，尤指产生γ-干扰素和淋巴毒素或肿瘤 坏死因子。大多数患者对血液病有反应 免疫抑制治疗的进展。再生障碍性贫血若干病例报告 在此之前都是肝炎。我们的研究主要集中在 免疫病理生理学与造血抑制的关系 一种新型肝炎病毒对本病的研究以及临床研究。 在此之前，我们展示了伽马干扰素的一种作用机制 诱导细胞程序性死亡的Fas抗原途径。我们 现在证明Fas在骨髓细胞上的表达增加 来自体内的再生障碍性贫血患者，这意味着这是一种 在疾病中起着重要作用。抑制分子的局部效应 已经通过使用重组DNA技术转导 将干扰素基因导入人骨髓基质细胞； 内源性干扰素的产生大约是对照组的100倍 在抑制造血方面比外源性干扰素更有效，以及 干扰素的分泌伴随着细胞凋亡和细胞周期受阻。 CD34+造血细胞间的细胞周期。干扰素以及 肿瘤坏死因子广泛影响原始细胞的造血 献给已故的祖先。干细胞的数量，如长期测量的 定期培养和启动细胞检测，在所有 患有严重再生障碍性贫血并仅有轻微改善的患者 血液学恢复。这些结果表明茎的丧失是不可逆转的。 由于免疫系统的攻击而导致细胞死亡。我们已经确定了一部小说 黄疫病毒制剂在几名患者的血液中 肝炎/再生障碍性贫血综合征以及其他再生障碍性贫血患者 贫血。该病毒在再生障碍性贫血病因学中的作用 仍有待最终确定。最后，在对干细胞的研究中 因子治疗难治性再生障碍性贫血，我们观察到一种 1例接受干细胞移植的患者出现有临床意义的反应 因子后分化生长因子，粒细胞集落 刺激因子和促红细胞生成素。

Aplastic anemia and other types of bone marrow failure have clinical and laboratory features consistent with an autoimmune pathophysiology, possibly incited by a virus. Patients with aplastic anemia show evidence of activation of cytotoxic T cells and excessive lymphokine production, especially of gamma-interferon and lymphotoxin or tumor necrosis factor. A majority of patients respond with hematologic improvement on immunosuppressive therapy. Some cases of aplastic anemia are preceded by hepatitis. Our studies have focused on aspects of the immune pathophysiology of hematopoietic suppression, the relationship of a novel hepatitis virus to this disease, as well as clinical studies. Previously we showed that one mechanism of action of gamma-interferon was induction of the Fas antigen pathway of programmed cell death. We now demonstrate that Fas expression is increased on bone marrow cells from patients with aplastic anemia in vivo, implying that this is an important process in the disease. Local effects of inhibitory molecules have been demonstrated by using recombinant DNA technology to transduce the gamma-interferon gene into human bone marrow stromal cells; endogenous production of interferon was approximately 100-fold more potent than exogenous interferon in suppression of hematopoiesis, and interferon secretion is accompanied by apoptosis as well as a block in cell cycling among CD34+ hematopoietic cells. Interferon as well as tumor necrosis factor broadly affect hematopoiesis, from primitive cells to late progenitors. The numbers of stem cells, as measured in the long term culture and initiating cell assay, is remarkably reduced in all patients with severe aplastic anemia and only modestly improved despite hematologic recovery. These results suggest irreversible loss of stem cells as a result of immune system attack. We have identified a novel flavi-pestivirus agent in the blood of several patients with the hepatitis/aplasia syndrome, as well as in other patients with aplastic anemia. The role of this virus in the etiology of aplastic anemia remains to be definitively determined. Finally, in a study of stem cell factor as treatment for refractory aplastic anemia, we have observed one clinically meaningful response in a patient who received stem cell factor followed by differentiating growth factors, granulocyte-colony stimulating factor and erythropoietin.