STAT4 and STAT6 are transcription factors that play crucial roles in respon
ding to IL-12 and IL-4, respectively. STAT4 gene knockout (STAT(4/4)) mice
have markedly reduced Th1 responses and enhanced Th2 responses. STAT6(-/-)
mice show the inverse phenotype. We compared the ability of bone marrow tra
nsplantation (BMT) with the inclusion of spleen cells from STAT6(-/-), STAT
4(-/-), and wildtype (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 i
nduced delayed GVHD mortality compared with WT controls, or compared with c
ombined 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. Recipie
nts of STAT4(-/-) BMT showed signs of GVHD with only initial transient weig
ht loss and later development of severe skin GVHD. Histopathology showed th
at 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 causi
ng intestinal pathology of GVHD. Our studies demonstrate an additive role f
or Th1 and Th2 cells in producing acute GVHD, and suggest a cytokine-direct
ed approach to treating end-organ manifestations of GVHD.