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Blood, 1 September 2008, Vol. 112, No. 5, pp. 2111-2119.
Prepublished online as a Blood First Edition Paper on June 13, 2008; DOI 10.1182/blood-2007-12-130534.
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TRANSPLANTATION
Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon- receptor-deficient hosts
Jean-Sébastien Delisle13,
Louis Gaboury1,4,
Marie-Pier Bélanger1,
Éliane Tassé1,
Hideo Yagita5, and
Claude Perreault13
1 Institute for Research in Immunology and Cancer and
2 Department of Medicine, Université de Montréal, Montréal, QC;
3 Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, QC;
4 Department of Pathology-Cell Biology, Université de Montréal, Montréal, QC; and
5 Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan
The immunopathologic condition known as graft-versus-host disease (GVHD) results from a type I T-cell process. However, a prototypical type I cytokine, interferon- (IFN-), 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--receptor–deficient (IFN-RKO) MHC-matched C57BL/6 recipients. In IFN-RKO recipients, host cells were unresponsive to IFN-, whereas wt donor cells were exposed to exceptionally high levels of IFN-. From an IFN- 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-R prevented up-regulation of MHC proteins on host cells but did not mitigate damage to most target organs. Two salient phenotypes in IFN-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-: Ccnd1 and Myc. We conclude that IFN- produced by alloreactive T cells may entail a severe graft-versus-graft reaction and could be responsible for cytopenias that are frequently observed in subjects with GVHD.
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