PATHOGENESIS AND TREATMENT OF APLASTIC ANEMIA

再生障碍性贫血的发病机制和治疗

基本信息

项目摘要

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.
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, 可能是被病毒感染的 再生障碍性贫血患者表现为 细胞毒性T细胞和过量淋巴因子活化的证据 产生,特别是γ-干扰素和光毒素或肿瘤 坏死因子 大多数患者的血液学反应 免疫抑制疗法改进。 再生障碍性贫血的一些病例 是肝炎的前兆 我们的研究集中在 造血抑制的免疫病理生理学, 一种新的肝炎病毒对这种疾病的作用,以及临床研究。 以前我们发现γ-干扰素的一种作用机制 是诱导Fas抗原途径的程序性细胞死亡。 我们 现在证明骨髓细胞上Fas表达增加, 从再生障碍性贫血患者体内,这意味着这是一个 疾病的重要过程。 抑制性分子的局部作用 已经通过使用重组DNA技术来表达 将γ-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 在抑制造血方面比外源性干扰素更有效,和 干扰素的分泌伴随着细胞凋亡以及干扰素分泌的阻断。 CD 34+造血细胞之间的细胞周期。 干扰素以及 肿瘤坏死因子广泛影响造血,从原始细胞 到晚期的祖先 干细胞的数量,在长期的测量中, 术语培养和起始细胞测定,在所有 严重再生障碍性贫血患者,尽管 血液学恢复 这些结果表明股骨柄不可逆丢失 免疫系统攻击的结果。 我们发现了一本小说 黄瘟病毒剂在血液中的几个病人与 肝炎/再生障碍综合征,以及其他再生障碍患者 贫血 该病毒在再生障碍性贫血病因学中的作用 仍有待最后确定。 最后,在一项干细胞研究中, 因子作为治疗难治性再生障碍性贫血,我们已经观察到一个 接受干细胞治疗的患者中有临床意义的应答 分化生长因子,粒细胞集落 刺激因子和促红细胞生成素。

项目成果

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N S YOUNG其他文献

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{{ truncateString('N S YOUNG', 18)}}的其他基金

PAROVIRUS
细小病毒
  • 批准号:
    3942851
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
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
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
PAROVIRUS (HUMAN) B19
细小病毒(人)B19
  • 批准号:
    3858051
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
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
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
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
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
VIRUSES AND HEMATOPOEIESIS
病毒和造血作用
  • 批准号:
    6162707
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
LYMPHOCYTES AND LMYPHOKINES IN APLASTIC ANEMIA
再生障碍性贫血中的淋巴细胞和淋巴细胞因子
  • 批准号:
    3942850
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
LYMPHOCYTES AND LMYPHOKINES IN APLASTIC ANEMIA
再生障碍性贫血中的淋巴细胞和淋巴细胞因子
  • 批准号:
    3966619
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
PATHOGENESIS AND TREATMENT OF APLASTIC ANEMIA
再生障碍性贫血的发病机制和治疗
  • 批准号:
    2576795
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
B19 PARVOVIRUS AND ADENO-ASSOCIATED VIRUS
B19 细小病毒和腺相关病毒
  • 批准号:
    3757656
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:

相似海外基金

Immune escape mechanisms in BCOR/BCORL1 mutant hematopoietic stem cells from patients with aplastic anemia
再生障碍性贫血患者 BCOR/BCORL1 突变型造血干细胞的免疫逃逸机制
  • 批准号:
    23K15297
  • 财政年份:
    2023
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
A Phase III Randomized Trial Comparing Unrelated Donor Bone Marrow Transplantation with Immune Suppressive Therapy for Newly Diagnosed Pediatric and Young Adult Patients with Severe Aplastic Anemia
一项针对新诊断患有严重再生障碍性贫血的儿童和年轻成人患者进行非亲缘供体骨髓移植与免疫抑制治疗比较的 III 期随机试验
  • 批准号:
    10722602
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
A Phase III Randomized Trial Comparing Unrelated Donor Bone Marrow Transplantation with Immune Suppressive Therapy for Newly Diagnosed Pediatric and Young Adult Patients with Severe Aplastic Anemia
一项针对新诊断患有严重再生障碍性贫血的儿童和年轻成人患者进行非亲缘供体骨髓移植与免疫抑制治疗比较的 III 期随机试验
  • 批准号:
    10368246
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
Eltombopag: Novel Mode of Action on Normal and Aplastic Anemia Hematopoietic Stem Cells
Eltombopag:对正常和再生障碍性贫血造血干细胞的新作用模式
  • 批准号:
    10676888
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
1/2A Phase III Randomized Trial Comparing Unrelated Donor Bone Marrow Transplantation with Immune Suppressive Therapy for Newly Diagnosed Pediatric and Young Adult Patients with Severe Aplastic Anemia
1/2A III 期随机试验,比较无关供体骨髓移植与免疫抑制治疗对新诊断患有严重再生障碍性贫血的儿童和年轻成人患者的影响
  • 批准号:
    10600143
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
The effects of somatic HLA class I allele mutations on antigen presentation in acquired aplastic anemia
体细胞 HLA I 类等位基因突变对获得性再生障碍性贫血抗原呈递的影响
  • 批准号:
    10347646
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
1/2A Phase III Randomized Trial Comparing Unrelated Donor Bone Marrow Transplantation with Immune Suppressive Therapy for Newly Diagnosed Pediatric and Young Adult Patients with Severe Aplastic Anemia
1/2A III 期随机试验,比较无关供体骨髓移植与免疫抑制治疗对新诊断患有严重再生障碍性贫血的儿童和年轻成人患者的影响
  • 批准号:
    10370775
  • 财政年份:
    2022
  • 资助金额:
    --
  • 项目类别:
The effects of somatic HLA class I allele mutations on antigen presentation in acquired aplastic anemia
体细胞 HLA I 类等位基因突变对获得性再生障碍性贫血抗原呈递的影响
  • 批准号:
    10545024
  • 财政年份:
    2022
  • 资助金额:
    --
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Identification of autoantigens presented by specific HLA class I alleles in aplastic anemia
再生障碍性贫血中特定 HLA I 类等位基因呈现的自身抗原的鉴定
  • 批准号:
    19H03686
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Functional analysis of novel genes related to aplastic anemia using mouse models.
使用小鼠模型对与再生障碍性贫血相关的新基因进行功能分析。
  • 批准号:
    19K08297
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
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