Submitted December 21, 2007
Accepted May 29, 2008
GVHD causes failure of donor hematopoiesis and lymphopoiesis in IFN-
receptor-deficient hosts
Jean-Sebastien Delisle, Louis Gaboury, Marie-Pier Belanger, Eliane Tasse, Hideo Yagita, and Claude Perreault*
Department of Medicine, Universite de Montreal, Montreal, QC, Canada
Department of Pathology-Cell Biology, Universite de Montreal, Montreal, QC, Canada
Institute for Research in Immunology and Cancer, Universite de Montreal, Montreal, QC, Canada
Department of Immunology, Jutendo University School of Medicine, Tokyo, Japan
Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada
* Corresponding author; email: c.perreault{at}videotron.ca.
Graft-versus-host disease (GVHD) immunopathology 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-, while 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 upregulation 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 downregulation of two 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.
