Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon-γ receptor-deficient hosts

被引:40
作者
Delisle, Jean-Sebastien [1 ,2 ,3 ]
Gaboury, Louis [1 ,4 ]
Belanger, Marie-Pier [1 ]
Tasse, Eliane [1 ]
Yagita, Hideo [5 ]
Perreault, Claude [1 ,2 ,3 ]
机构
[1] Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada
[2] Univ Montreal, Dept Med, Montreal, PQ H3C 3J7, Canada
[3] Hop Maison Neuve Rosemont, Div Hematol, Montreal, PQ H1T 2M4, Canada
[4] Univ Montreal, Dept Pathol Cell Biol, Montreal, PQ, Canada
[5] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 113, Japan
关键词
D O I
10.1182/blood-2007-12-130534
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The immunopathologic condition known as graft-versus-host disease (GVHD) results from a type 1 T-cell process. However, a prototypical type 1 cytokine, interferon-gamma (IFN-gamma), can protect against several manifestations of GVHD in recipients of major histocompatibility complex (MHC)-mismatched hematopoietic cells. We transplanted hematopoietic cells from C3H.SW donors in wild-type (wt) and IFN-gamma-receptor-deficient (IFN-gamma RKO) MHC-matched C57BL/6 recipients. In IFN-gamma RKO recipients, host cells were unresponsive to IFN-gamma whereas wt donor cells were exposed to exceptionally high levels of IFN-gamma. From an IFN-gamma perspective, we could therefore evaluate the impact of a loss-of-function on host cells and gain-of-function on donor cells. We found that lack of IFN-gamma R prevented up-regulation of MHC proteins on host cells but did not mitigate damage to most target organs. Two salient phenotypes in IFN-gamma RKO recipients involved donor cells: lymphoid hypoplasia and hematopoietic failure. Lymphopenia was due to FasL-induced apoptosis and decreased cell proliferation. Bone marrow aplasia resulted from a decreased proliferation of hematopoietic stem/progenitor cells that was associated with down-regulation of 2 genes negatively regulated by IFN-gamma: Ccnd1 and Myc. We conclude that IFN-gamma produced by alloreactive T cells may entail a severe g raft-versus-g raft reaction and could be responsible for cytopenias that are frequently observed in subjects with GVHD.
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页码:2111 / 2119
页数:9
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