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)F-1 mic e (BDF1) induces a chronic, autoimmune graft-vs-host disease (GVHD) th at is characterized by: increased production of Th2-associated cytokin es; increased levels of serum Ig, including IgE; increased production of Ige anti-DNA Abs; and no detectable antihost CTL activity. Experime nts were performed to determine if treatment with the cytokine IL-12, which stimulates the production of Th1-associated cytokines and inhibi ts Th2-associated cytokine production, would inhibit humoral autoimmun ity 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 compl ete suppression of autoantibody production; 2) decreased serum Ig leve ls; 3) detectable donor antihost CTL activity; and 4) greatly reduced numbers of host splenic B and T cells. Treatment of mice with a neutra lizing anti-IFN-gamma mAb did not reverse these effects of IL-12. Thir ty nanograms per day resulted in reduced numbers of host B cells and r educed serum anti-DNA levels, but no detectable antihost CTL activity. IL-12 treatment initiated 7 days after cell transfer had little effec t on the development of autoimmune GVHD. These observations suggest th e following: 1) IL-12 inhibits humoral autoimmunity in a murine parent --> F-1 GVHD model by inducing the activation of host-reactive CTLs t hat reject the host immune system. 2) This effect is IFN-gamma-indepen dent. 3) IL-12 needs to be present during the initial differentiation of T cells in this system to have this effect.