Interleukin-12 (IL-12) and IL-18 Are Important in Innate Defense against Genital Herpes Simplex Virus Type 2 Infection in Mice but Are Not Required for the Development of Acquired Gamma Interferon-Mediated Protective Immunity

Respiratory syncytial virus-induced bronchiolitis has been linked to the development of allergy and atopic asthma. IL-12 and possibly IL-18 are central mediators orchestrating Th1 and/or Th2 immune responses to infection. To determine a possible role for IL-12 in regulating the immune response to acute respiratory syncytial virus infection, IL-12p40 gene-targeted (IL-12p40−/−) and wild-type mice were intratracheally infected with respiratory syncytial virus, and lung inflammatory and immune responses were assessed. Lung inflammation and mucus production were increased in the airways of IL-12p40−/− mice as compared with those of wild-type mice, concurrent with increased levels of the Th2 effector cytokines IL-5 and IL-13. Respiratory syncytial virus clearance and levels of Th1 effector cytokine IFN-γ were not altered. Interestingly, IL-18, another mediator of IFN-γ production, was significantly increased in the lungs of IL-12p40−/− mice early during the course of infection. Abrogation of IL-18-mediated signaling in IL-12p40−/− mice further enhanced Th2 immune response and mucus production in the airways during respiratory syncytial virus infection but failed to modulate IFN-γ production or viral clearance. These findings implicate a role for IL-12 and IL-18 in modulating respiratory syncytial virus-induced airway inflammation distinct from that of viral clearance.

Section: Discussionsupporting

confidence: 81%

IL-12p40 and IL-18 Modulate Inflammatory and Immune Responses to Respiratory Syncytial Virus Infection

Wang

Bao

Rosenberger

et al. 2004

“…However, IFN-␥ responses in the lymphoid organs appeared to be dominant. We and others have previously documented the critical importance of IFN-␥ response for immune protection against genital herpes infection in mice (23)(24)(25)(26). Furthermore, we could show that mice immunized with gD plus ␣-GalCer had high levels of gD-specific IgG Abs in their sera and vaginal extracts.…”

Section: Discussionsupporting

confidence: 54%

The Mucosal Adjuvant Effect of α-Galactosylceramide for Induction of Protective Immunity to Sexually Transmitted Viral Infection

Lindqvist

Persson

Thörn

et al. 2009

Self Cite

Development of mucosal adjuvants to generate immunity in the female genital tract may have important implications for the development of vaccines to counter sexually transmitted infections. α-Galactosylceramide (α-GalCer) is presented by CD1d molecule on APCs to invariant Vα14+ NKT (iNKT) cells, which upon activation rapidly produce large amounts of immunomodulatory cytokines, leading to activation of a variety of innate and adaptive immune cells. Here, we assessed whether α-GalCer could act as a mucosal adjuvant for induction of protective immunity against genital herpes. We found that intranasal immunization with HSV-2 glycoprotein D (gD) in combination with α-GalCer elicits strong systemic gD-specific IgG Ab response as well as lymphoproliferative response with a mixed Th1/Th2 cytokine profile in the spleen, mediastinal lymph nodes, and genital lymph nodes. Importantly, such an immunization scheme conferred complete protection against an otherwise lethal vaginal HSV-2 challenge. We could also show that intravaginal immunization with gD plus α-GalCer generates potent gD-specific lymphoproliferative and IFN-γ responses in the genital lymph nodes and spleen. Furthermore, the vaginally immunized mice developed a strong systemic and mucosal IgG Ab response and protection against vaginal HSV-2 challenge. The mucosal adjuvant effect of α-GalCer was found to be mediated via CD1d molecule and appeared to be independent of the usage of the adaptor molecule MyD88. To our knowledge, this is the first report on the mucosal adjuvant effect of α-GalCer for induction of protective immunity against a sexually transmitted pathogen.

“…In contrast, neutralization of IL-12p40 in BALB/c mice was found to significantly diminish the antiviral CTL response to the more virulent A/PR/8 strain of influenza virus (16). On the other hand, although both cytokines were found to be important for control of HSV-2 by innate immunity, neither was needed for generation of adaptive immune effector mechanisms (17). Finally, neither IL-12p40 nor IL-18 were found to be necessary for the control of respiratory syncytial virus infection or IFN-␥ production, although both cytokines contributed to limiting lung inflammation and Th2 responses (18).…”

Section: P Roduction Of the Th1 Cytokine Ifn-␥ By Nk And T Cells Is Cmentioning

confidence: 99%

IL-12p40 and IL-18 Play Pivotal Roles in Orchestrating the Cell-Mediated Immune Response to a Poxvirus Infection

Wang

Chaudhri

Jackson

et al. 2009

A strong cell-mediated immune response is critical for controlling viral infections and is regulated by a number of cytokines, including IL-12 and IL-18. Indeed, some viruses have evolved to specifically target these pathways to counter the host immune response. Orthopoxviruses, including ectromelia virus, encode immune evasion molecules that specifically target IL-18 and IFN-γ. We hypothesized that IL-12 and IL-18 are pivotal for induction of IFN-γ production and subsequent generation of an effective host response to ectromelia virus infection. In this study, we demonstrate that absence of both IL-12p40 and IL-18 resulted in increased susceptibility to infection that was associated with skewing of the cytokine response to Th2 and a reduction in NK and CTL responses. The decrease in CTL response correlated with a defect in CD8+ T cell proliferation and lower numbers of virus-specific CD8+ T cells. Lack of either IL-12p40 and/or IL-18 was also associated with reduced numbers of CD8+ T cells at sites of infection and with an increase in the numbers of splenic T regulatory cells. Taken together, our data indicate that IL-12p40 and IL-18 act in concert and play an important antiviral role through the up-regulation of IFN-γ production and cell-mediated immune responses.