Interleukin-4 plays a dominant role in Th1- or Th2-like responses during the primary immune response to the hapten penicillin

Despite a large number of studies on the Th1/Th2 balance during immune response to pathogens or protein antigens, little is known concerning the early events which regulate Th1/Th2 differentiation following a single injection of haptenic compounds. In this work, we studied how two mouse strains with different MHC haplotypes, SJL (H-2(s)) and Balb/c (H-2(d)), could develop different primary immune responses to subcutaneously injected benzylpenicillin coupled to tetanus toroid (BPO-TT). The SJL mice showed a high BPO-specific IgG1 response that was maximum on day 10 and no BPO-specific IgG2a response. In contrast, Balb/c mice showed a high BPO-specific IgG2a response on days 15 and 22 and a weak IgG1 production. In SJL mice, the response to BPO-TT was characterized by a very early and high IL-4 mRNA expression. In Balb/c, a delayed and weaker expression of IL-4 mRNA was observed. Kinetics of IL-2 and IFN-gamma mRNA expression were comparable in both strains, but IFN-gamma mRNA expression was higher in SJL than in Balb/c. In vivo neutralization of IL-4 induced a significant BPO-specific IgG2a production and a two-fold reduction of IgG1 production in SJL mice while it accelerated production of BPO-specific IgG2a in Balb/c mice. In addition, studies of IL-12 p40 and IL-10 mRNA expression following immunization with BPO-TT showed a greater IL-12 p40 mRNA expression in Balb/c mice and a slightly higher IL-10 mRNA expression in SJL. Taken together, our data suggest that Th1 or Th2 differentiation in primary immune responses to haptenic compounds such as penicillin may be driven by the kinetics and the level of IL-4 production rather than by the level of IFN-gamma. Additional cytokines such as IL-10 and IL-12 are likely to contribute to the regulation of this response.