Effect of interleukin 12 neutralization on host resistance and gamma interferon production in mouse typhoid

Abstract

Innately resistant (Ity r) A/J mice infected with the virulent Salmonella typhimurium C5 strain suppress the early exponential bacterial growth in the reticuloendothelial system toward the end of the first week of infection, with spleen and liver bacterial counts reaching a plateau phase. In vivo administration of neutralizing anti-interleukin-12 (IL-12) antibodies did not affect early bacterial growth in the tissues (days 1 to 3) but impaired the establishment of the plateau, with higher spleen and liver counts by day 7 of the infection in anti-IL-12 treated mice than in untreated controls. Gamma interferon (IFN-␥) was detectable in the sera and spleen homogenates of both control and anti-IL-12-treated mice on days 3 and 7 of the infection. Noticeably, IFN-␥ levels were significantly lower in anti-IL-12 treated mice than in control animals. Splenocytes from uninfected A/J mice released IFN-␥ in response to concanavalin A (ConA) or to S. typhimurium C5. In vitro IL-12 neutralization dramatically impaired the IFN␥ response to S. typhimurium but not to ConA. Splenocytes harvested from infected anti-IL-12 treated mice on day 7 of the infection produced significantly lower amounts of IFN-␥ upon in vitro stimulation with ConA and with a Salmonella protein-rich extract than did cells from similarly infected untreated control animals. Spleen cells from infected mice showed lower proliferative (mitogenic) responses to ConA and to a Salmonella soluble extract than did cells from uninfected mice. In vivo anti-IL-12 treatment significantly restored the ability of splenocytes from infected mice to proliferate in response to the antigens and ConA. In vivo neutralization of IL-12 in innately susceptible BALB/c mice (Ity s) immunized with a live attenuated aromatic-dependent Salmonella vaccine reduced host resistance to virulent oral challenge with S. typhimurium C5. Thus, in primary Salmonella infections, IL-12 mediates the suppression of growth of virulent salmonellae in the reticuloendothelial system, positively modulates IFN-␥ production, and is involved in the immunosuppression which accompanies the acute stages of the disease. IL-12 also contributes to host resistance to virulent organisms in secondary infections.

Immunity to intestinal pathogens: lessons learned from Salmonella

“…As these mice resist secondary infection, this model also allows for antibody-mediated depletion of cell populations or cytokines to assess the role of these in Salmonella immunity. These experiments have confirmed the importance of both CD4 + and CD8 + T cells during protective immunity and demonstrated that IL-12, IFN-c, TNF-a, and iNOS each play important roles in mediating bacterial killing (8,9,85,86). It is surprising therefore that the adoptive transfer of spleen cells from immune to na€ ıve mice is insufficient to transfer protective immunity (11).…”

Salmonella, the host and disease: a brief review

“…As is clear from the data of human patients IL-12 is important to control Salmonella infections. 112 This may relate to IFN-g function, as IL-12 is a potent activator of IFN-g production. However, it may also be in part due to IFN-g independent IL-23mediated effects as discussed above.…”

Novel IL-12 family members shed light on the orchestration of Th1 responses

“…Role of the IL-12 family members in infectious diseases IL-12 has a key role in protection against intracellular protozoan, fungal and bacterial infections [4,5,40,52,53] ( Table 2). The role of IL-12 in protection and pathology during viral infections depends on the type of virus [54 -57].…”