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 (AA) and other types of bone marrow failure have clinical and laboratory features consistent with an autoimmune pathophysiology, with a diversity of inciting antigens, including viruses, chemicals, and drugs. Whatever its specific etiology, a majority of patients respond with hematologic improvement after immunosuppressive therapies. One important clinical feature of AA is its evolution, sometimes years after normalization of blood counts, to other hematologic diseases such as paroxysmal nocturnal hemoglobinuria (PNH), which derive from clones of hematopoietic stem cells. In the clinic, we have employed a regimen that incorporates mycophenolate mofetil, as well as delayed addition of cyclosporine, to standard antithymocyte globulin, in an effort to induce tolerance in patients with severe aplastic anemia on presentation. With accrual almost complete, hematologic response rates at 3 and 6 months are comparable to those achieved by standard treatment; relapse, evolution, and survival analyses will require longer periods of evaluation. In the laboratory, efforts have concentrated on the incitement of aplastic anemia by an unknown virus (see Z01 HL 02319-14 HB), the aberrant immune response, and the problem of clonal evolution to other hematologic diseases. In efforts to more specifically characterize the immune response, we have utilized the methods of flow cytometry and spectratyping to determine expansion of V-beta TCR families of T cells and skewing of CDR3 expression within expanded families, as indicators of antigen-driven clonal T cell proliferation. Expecially within the CD8 cytotoxic lymphocyte population, we found that a large proportion of aplastic anemia and PNH patients show oligoclonal T cell expansion, and we have identified individual CDR3 sequences within these families. Molecular measurment of CDR3 correlates with disease status pre- and post-immunosuppression, but the patterns differ depending on whether ATG or cyclosphosphamide is used. CDR3 clonotypes are sought as markers of the immune response in patients of similar HLA background. Ultimately, CDR3 regions of interest may be incorporated into recombinant human TCR genes and in turn transduced into immortalized effector cells, for determiantion of antigen specificity. We also have employed DNA chip analysis to examine CD34 hematopoietic cells, both normal and from patients with marrow failure syndromes. Limited numbers of CD34 cells from aplastic anemia cases have been pooled and cRNA pre-amplified. For this disease, target cells show evidence an enhanced genetic program of expression of genes related to immune system activation, apoptosis, and stress, and decreased expression of proliferation genes. While paired cell lines of normal and PNH phenotype show little overall difference in transcriptomes, paired primary CD34 cells from individual patients show marked upregulation of immune and apoptosis genes in the abnormal putative PIG-A-negative population; these results are consistent with our previous cell culture data using similar cell populations. In myelodysplasia, specifically up- and down-regulated genes have been observed for CD34 cells from patients with well-defined cytogenetic abnormalities in myelodysplasia . Trisomy 8, but not monosomy 7, also is associated with immune abnormalities related to hematopoiesis, as cytogenetically abnormal cells are more likely than normal cells to express Fas and to be apoptotic.
再生障碍性贫血(AA)和其他类型的骨髓衰竭具有与自身免疫病理生理学一致的临床和实验室特征,具有多种激发抗原,包括病毒,化学品和药物。无论其具体病因如何,大多数患者在免疫抑制治疗后血液学改善。AA的一个重要临床特征是其演变,有时在血细胞计数正常化后数年,演变为其他血液学疾病,如阵发性睡眠性血红蛋白尿症(PNH),其来源于造血干细胞的克隆。在临床上,我们采用了一种方案,将霉酚酸酯,以及延迟添加环孢霉素,标准的抗胸腺细胞球蛋白,在努力诱导耐受性的严重再生障碍性贫血患者的介绍。随着招募几乎完成,3个月和6个月时的血液学缓解率与标准治疗相当;复发、进展和生存分析将需要更长的评估期。在实验室中,努力集中在由未知病毒引起的再生障碍性贫血(参见Z 01 HL 02319-14 HB)、异常免疫应答和克隆进化为其他血液病的问题上。为了更具体地表征免疫应答,我们已经利用流式细胞术和光谱分析的方法来确定T细胞的V-β TCR家族的扩增和扩增家族内CDR 3表达的偏斜,作为抗原驱动的克隆T细胞增殖的指标。特别是在CD 8细胞毒性淋巴细胞群体中,我们发现很大比例的再生障碍性贫血和PNH患者显示寡克隆T细胞扩增,并且我们已经在这些家族中鉴定了单个CDR 3序列。CDR 3的分子测量与免疫抑制前后的疾病状态相关,但模式不同,这取决于是否使用ATG或环磷酰胺。寻找CDR 3克隆型作为相似HLA背景患者中免疫应答的标志物。最终,可以将感兴趣的CDR 3区掺入重组人TCR基因中,并进而转导到永生化效应细胞中,用于确定抗原特异性。我们还采用DNA芯片分析来检测正常和骨髓衰竭综合征患者的CD 34造血细胞。已合并来自再生障碍性贫血病例的有限数量的CD 34细胞并预扩增cRNA。对于这种疾病,靶细胞显示与免疫系统激活、凋亡和应激相关的基因表达的增强的遗传程序,以及增殖基因表达的降低的证据。虽然正常和PNH表型的配对细胞系在转录组中显示出很小的总体差异,但来自个体患者的配对原代CD 34细胞在异常推定PIG-A阴性群体中显示出免疫和凋亡基因的显著上调;这些结果与我们先前使用类似细胞群体的细胞培养数据一致。在骨髓增生异常中,已经观察到明确的骨髓增生异常细胞遗传学异常患者的CD 34细胞的特异性上调和下调基因。三体8,而不是单体7,也与造血相关的免疫异常有关,因为细胞遗传学异常细胞比正常细胞更可能表达Fas和凋亡。

项目成果

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NEAL S YOUNG其他文献

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

PATHOGENESIS AND TREATMENT OF APLASTIC ANEMIA
再生障碍性贫血的发病机制和治疗
  • 批准号:
    6432684
  • 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:
    6966935
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Immune Pathophysiology of Aplastic Anemia and Immunosuppressive Treatments
再生障碍性贫血的免疫病理生理学和免疫抑制治疗
  • 批准号:
    8746560
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Telomere Diseases
端粒疾病
  • 批准号:
    8558029
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Immune Pathophysiology of Aplastic Anemia and Immunosuppressive Treatments
再生障碍性贫血的免疫病理生理学和免疫抑制治疗
  • 批准号:
    9157323
  • 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:
    7321592
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Immune Pathophysiology of Aplastic Anemia and Immunosuppressive Treatments
再生障碍性贫血的免疫病理生理学和免疫抑制治疗
  • 批准号:
    10685871
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Myelodysplasia
骨髓增生异常
  • 批准号:
    8149587
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Telomeres Diseases
端粒疾病
  • 批准号:
    8149588
  • 财政年份:
  • 资助金额:
    --
  • 项目类别:
Immune Pathophysiology of Aplastic Anemia and Immunosuppressive Treatments
再生障碍性贫血的免疫病理生理学和免疫抑制治疗
  • 批准号:
    8149485
  • 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
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    2023
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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
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    --
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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
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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
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    19H03686
  • 财政年份:
    2019
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    --
  • 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:
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