IL-12 stimulates the development of acute graft-versus-host disease in mice that normally would develop chronic, autoimmune graft-versus-host disease.
The injection of DBA/2 (D2) spleen cells into (C57BL/6 x DBA/2)F1 mice (BDF1) induces a chronic, autoimmune graft-vs-host disease (GVHD) that is characterized by: increased production of Th2-associated cytokines; increased levels of serum Ig, including IgE; increased production of IgG anti-DNA Abs; and no detectable antihost CTL activity. Experiments were performed to determine if treatment with the cytokine IL-12, which stimulates the production of Th1-associated cytokines and inhibits Th2-associated cytokine production, would inhibit humoral autoimmunity in this system. Treatment of mice with 100 ng IL-12 per day for 5 days, starting on the day of cell transfer, resulted in: 1) near complete suppression of autoantibody production; 2) decreased serum Ig levels; 3) detectable donor antihost CTL activity; and 4) greatly reduced numbers of host splenic B and T cells. Treatment of mice with a neutralizing anti-IFN-gamma mAb did not reverse these effects of IL-12. Thirty nanograms per day resulted in reduced numbers of host B cells and reduced serum anti-DNA levels, but no detectable antihost CTL activity. IL-12 treatment initiated 7 days after cell transfer had little effect on the development of autoimmune GVHD. These observations suggest the following: 1) IL-12 inhibits humoral autoimmunity in a murine parent-->F1 GVHD model by inducing the activation of host-reactive CTLs that reject the host immune system. 2) This effect is IFN-gamma-independent. 3) IL-12 needs to be present during the initial differentiation of T cells in this system to have this effect.
Via
C S
CS
Research Service, Loch Raven VA Medical Center, Baltimore, MD.
Rus
V
V
Gately
M K
MK
Finkelman
F D
FD
D000208:Acute Disease; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002478:Cells, Cultured; D002908:Chronic Disease; D003601:Cytotoxicity Tests, Immunologic; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D001323:Autoantibodies; D017252:CD3 Complex; D007376:Interleukin-2; D018664:Interleukin-12; D007371:Interferon-gamma