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
- 批准号:2576795
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:aplastic anemia artificial immunosuppression autoimmune disorder bone marrow disorder clinical research cytotoxic T lymphocyte gene targeting hematopoiesis hematopoietic stem cells hepatitis histocompatibility typing human subject human therapy evaluation immunohematology lymphokines paroxysmal nocturnal hemoglobinuria phosphatidylinositols tissue /cell culture
项目摘要
Aplastic anemia (AA) and other types of bone marrow failure have clinical
and laboratory features consistent with an autoimmune pathophysiology,
possibly incited by a virus. A majority of patients respond with
hematologic improvement after immunosuppressive therapies. Our
laboratory studies have focused on aspects of the immune pathophysiology
of hematopoietic suppression, the nature of the viral antigen, and the
mechanism of late clonal evolution of aplastic anemia to other diseases,
including myelosyplasia and paroxysmal nocturnal hemoglobinuria (PNH).
In addition, we test new therapies for marrow failure in research
clinical protocols. One form of AA occurs after hepatitis, and we have
completed analysis of combined clinical and laboratory data on 10
patients seen at NIH. Most were young males who suffered seronegative
hepatitis followed by severe marrow failure. The hepatitis was
characterized as non A non B non C and also non G; a role for the novel
GBV- C/hepatitis G agent was excluded here and also in AA in general.
There were strong HLA correlations within the hepatitis/AA population,
especially to Cw7, B7, and DR7, DQ2, and Drw53, and all showed evidence
of cytotoxic lymphocyte activation. Seven patients showed excellent
responses to immunosuppressive therapy. Hepatitis/AA is an
immunologically mediated marrow failure syndrome incited by an unknown
virus. In studies of hematopoiesis in AA, we have measured stem cell
numbers in a surrogate assay called the long-term culture initiating cell
test (LTC-IC). All patients show a marked deficit in stem cell number
on presentation that does not allow prediction of response to
immunosuppressive therapy. LTC-IC also are qualitatively abnormal with
a low capacity to form secondary colonies in culture. Although patients
can recover blood counts without increasing numbers of LTC-IC, several
years after treatment, some patients do have normal numbers of LTC-IC,
suggesting repopulation within the stem cell compartment. Finally, we
have established a knock-out model of hematopoiesis in PNH. Destruction
of the PIG-A gene, required for expression of glycophosphoinositol
(GPI)-linked proteins on the cell surface, adversely affected
embyrogenesis in vitro; however, embyroid body formation was restored,
and hematopoiesis from genetically defective cells was normal, after
coculture of PIG-A- and normal cells.Intercellular protein transfer
could be demonstrated. Studies with red cells also suggest that
GPI-linked proteins can be exchanged by high density lipoproteins. For
human patient samples, there were no differences in hematopoietic colony
formation between normal and GPI-deficient cells. These results suggest
that PNH hematopoiesis has a selective advantage in AA.
再生障碍性贫血(AA)和其他类型的骨髓衰竭有临床
项目成果
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专利数量(1)
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