Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets.
STAT4 and STAT6 are transcription factors that play crucial roles in responding to IL-12 and IL-4, respectively. STAT4 gene knockout (STAT4(-/-)) mice have markedly reduced Th1 responses and enhanced Th2 responses. STAT6(-/-) mice show the inverse phenotype. We compared the ability of bone marrow transplantation (BMT) with the inclusion of spleen cells from STAT6(-/-), STAT4(-/-), and wild-type (WT) mice to produce graft-versus-host disease (GVHD) in lethally irradiated MHC-mismatched recipients. Acute GVHD mortality was more rapid when induced by cells from STAT6(-/-) mice than when induced by STAT4(-/-) cells. However, cells from STAT4(-/-) and STAT6(-/-) donors both induced delayed GVHD mortality compared with WT controls, or compared with combined STAT4(-/-) and STAT6(-/-) cells, indicating a contribution of both Th1 cells and Th2 cells to acute GVHD. Recipients of STAT6(-/-) BMT showed evidence of acute GVHD with severe diarrhea and marked weight loss. Recipients of STAT4(-/-) BMT showed signs of GVHD with only initial transient weight loss and later development of severe skin GVHD. Histopathology showed that Th2 responses were required for the induction of both hepatic and severe skin GVHD. In contrast, both Th1 cells and Th2 cells were capable of causing intestinal pathology of GVHD. Our studies demonstrate an additive role for Th1 and Th2 cells in producing acute GVHD, and suggest a cytokine-directed approach to treating end-organ manifestations of GVHD.
Nikolic
B
B
Bone Marrow Transplantation Section, Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02129, USA.
Lee
S
S
Bronson
R T
RT
Grusby
M J
MJ
Sykes
M
M
D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation; D004268:DNA-Binding Proteins / Q000235:genetics; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality; D006183:H-2 Antigens; D007420:Intestine, Large / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity; D011828:Radiation Chimera; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; D012867:Skin / Q000473:pathology; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D013577:Syndrome; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics; D015431:Weight Loss
D004268:DNA-Binding Proteins; D006183:H-2 Antigens; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D015534:Trans-Activators