title: IFN-γ causes aplastic anemia by altering hematopoietic stem/progenitor cell composition and disrupting lineage differentiation.
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.
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD;
authors.forename: Fan-ching
authors.initials: FC
authors.lastname: Lin
authors.affiliation: Laboratory of Animal Science, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD; and.
authors.forename: Megan
authors.initials: M
authors.lastname: Karwan
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD;
authors.forename: Bahara
authors.initials: B
authors.lastname: Saleh
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD;
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Hodge
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD;
authors.forename: Tim
authors.initials: T
authors.lastname: Chan
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD;
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Boelte
authors.affiliation: Hematopoiesis and Stem Cell Biology Section, Center for Cancer Research, National Cancer Institute, Frederick, MD.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Keller
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, Frederick, MD;
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
mesh_terms: D000741:Anemia, Aplastic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D016026:Bone Marrow Transplantation / Q000379:methods; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology*; D004920:Erythropoiesis / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D007371:Interferon-gamma