Graft-versus-host-disease-associated donor cell engraftment in an F1 hybrid model is dependent upon the Fas pathway.
The graft-versus-host disease (GVHD) generated in BDF1 mice by the injection of spleen cells from the C57BL/6 parental strain induces a direct cell-mediated attack on host lymphohaematopoietic populations, resulting in the reconstitution of the host with donor cells. We examined Fas-Fas ligand (FasL) interactions in donor and host haematopoietic cells over a prolonged period of parental-induced GVHD. Fas expression on bone marrow cells of both donor and host origin increased at 2 weeks. Host cell incubation with anti-Fas antibody induced apoptosis, and the number of haematopoietic progenitor cells decreased. Fas-induced apoptosis by the repopulating donor cells, however, did not increase until 12 weeks, when more than 90% of the cells were donor cells. The expression of various cytokines, such as interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), and FasL gene expression in the bone marrow increased concomitantly. To examine directly whether FasL has a major role in the development of donor cell engraftment, FasL-deficient (gld) mice were used as donors. Injection of B6/gld spleen cells induced significantly less host lymphohaematopoietic depletion, resulting in a failure of donor cell engraftment. Furthermore, injection of IFN-gamma gene knockout (gko) B6 spleen cells failed to augment Fas and FasL expression in recipient mice, resulting in a failure of donor cell engraftment. This suggests that the induction of apoptosis by Fas-FasL interactions in host cells may contribute to a reconstitution of the host with donor cells and that donor-derived IFN-gamma plays a significant role for Fas-FasL interactions in host cells during parental-induced GVHD.
Iwasaki
T
T
The Second Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Hamano
T
T
Saheki
K
K
Kuroiwa
T
T
Kataoka
Y
Y
Takemoto
Y
Y
Ogata
A
A
Fujimoto
J
J
Kakishita
E
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D053938:DNA Fragmentation; D053222:Fas Ligand Protein; D005260:Female; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000637:transplantation; D019014:fas Receptor / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D019014:fas Receptor; D007371:Interferon-gamma