DIFFERENTIAL-EFFECTS OF IL-12 RECEPTOR BLOCKADE WITH IL-12 P40 HOMODIMER ON THE INDUCTION OF CD4(-GAMMA-PRODUCING CELLS() AND CD8(+) IFN)

The role of IL-12 role in regulating Th1/Th2 balance is attributed in part to the ability of this cytokine to induce IFN gamma production by NK and Th1 cells, which in turn promotes Th1 and inhibits Th2 develop ment. In the present study, the requirement for IL-12 in the developme nt of alloantigen-reactive Th1 was assessed by adding neutralizing ant i-IL-12 Abs or the IL-12 receptor antagonist p40 homodimer to primary MLC. The resulting cell populations were assessed for Th1 development by measuring IFN-gamma production upon restimulation with alloantigens . While the addition of anti-IL-12 Abs to primary MLC did not influenc e subsequent cytokine production, addition of p40 homodimer markedly e nhanced, rather than decreased, Th1 development. To determine which T cell population produced enhanced levels of IFN-gamma in response to p 40 homodimer, CD4(+) or CD8(+) T cells were depleted from the MLC. Whi te p40 homodimer was inhibitory to selected CD4(+) Th1 development, it enhanced IFN-gamma production by CD8(+) T cells. To test the in vivo relevance of these findings, mouse heterotopic cardiac allograft recip ients were treated with either p40 homodimer, anti-CD8 mAb, or with bo th p40 homodimer and anti-CD8 mAb, Treatment of allograft recipients w ith p40 homodimer had no effect on the in vivo sensitization of INF-ga mma-producing cells and resulted in accelerated allograft rejection re lative to unmodified recipients, However, p40 homodimer markedly prolo nged allograft survival in mice depleted of CD8(+) T cells. Hence, p40 homodimer stimulates CD8(+) Th1 development in vitro but inhibits CD4 (+) T cell function both in vitro and in vivo.