Acute, lethal graft-versus-host disease in an F1-hybrid model using grafts from parental-strain, T-cell receptor-delta gene knockout donors.
Gammadelta T cells have been implicated in the pathogenesis of acute graft-versus-host disease (GVHD). We therefore performed experiments to determine whether mortality from GVHD is reduced in C57BL/6 x DBA/2 F1-hybrid (BDF1-hybrid) mice when parental strain, T-cell receptor-delta (TCRdelta) knockout (KO) donors are used. We compared mortality, weight loss, interferon-gamma (IFN-gamma) production and cytotoxic activity in recipients of either wild-type or TCRdelta KO grafts. In both groups there was significant weight loss and an identical level of mortality. Elevated IFN-gamma levels were present in both groups, but recipients of TCRdelta KO grafts produced twice as much as recipients of wild-type grafts. Elevated natural killer (NK) and NK-like activity was also seen in both. These results demonstrate that TCRdelta KO grafts can induce GVHD as severe as that seen in recipients of wild-type grafts, a finding that is at odds with studies demonstrating reduced mortality when gammadelta T cells are purged from donor mice. We suggest that the inconsistency may lie in the higher levels of IFN-gamma seen with TCRdelta KO grafts and that the protection afforded by the absence of gammadelta T cells in the graft is overwhelmed by the higher levels of IFN-gamma.
Ellison
C
C
Department of Immunology, University of Manitoba, Winnipeg, Canada.
Gartner
J
J
D000208:Acute Disease; D000818:Animals; D016923:Cell Death; D005260:Female; D018390:Gene Targeting; D019676:Genes, T-Cell Receptor delta / Q000235:genetics*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000166:cytology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout / Q000235:genetics; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D019737:Transplants / Q000009:adverse effects*; D014407:Tumor Cells, Cultured / Q000378:metabolism; D015431:Weight Loss / Q000276:immunology
D007371:Interferon-gamma