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Blood. 2014 Dec 11;124(25):3699-708. doi: 10.1182/blood-2014-01-549527. Epub 2014 Oct 23.

IFN-γ causes aplastic anemia by altering hematopoietic stem/progenitor cell composition and disrupting lineage differentiation.

Author information

1
Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD;
2
Laboratory of Animal Science, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD; and.
3
Hematopoiesis and Stem Cell Biology Section, Center for Cancer Research, National Cancer Institute, Frederick, MD.

Abstract

Aplastic anemia (AA) is characterized by hypocellular marrow and peripheral pancytopenia. Because interferon gamma (IFN-γ) can be detected in peripheral blood mononuclear cells of AA patients, it has been hypothesized that autoreactive T lymphocytes may be involved in destroying the hematopoietic stem cells. We have observed AA-like symptoms in our IFN-γ adenylate-uridylate-rich element (ARE)-deleted (del) mice, which constitutively express a low level of IFN-γ under normal physiologic conditions. Because no T-cell autoimmunity was observed, we hypothesized that IFN-γ may be directly involved in the pathophysiology of AA. In these mice, we did not detect infiltration of T cells in bone marrow (BM), and the existing T cells seemed to be hyporesponsive. We observed inhibition in myeloid progenitor differentiation despite an increase in serum levels of cytokines involved in hematopoietic differentiation and maturation. Furthermore, there was a disruption in erythropoiesis and B-cell differentiation. The same phenomena were also observed in wild-type recipients of IFN-γ ARE-del BM. The data suggest that AA occurs when IFN-γ inhibits the generation of myeloid progenitors and prevents lineage differentiation, as opposed to infiltration of activated T cells. These results may be useful in improving treatment as well as maintaining a disease-free status.

PMID:
25342713
PMCID:
PMC4263980
DOI:
10.1182/blood-2014-01-549527
[Indexed for MEDLINE]
Free PMC Article

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