IL-12p40 gene-deficient BALB/c mice exhibit lower weight loss, reduced lung pathology and decreased sensitization to allergen in response to infection with pneumonia virus of mice.

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and pneumonia in infants and pneumonia virus of mice (PVM) causes similar disease. BALB/c mice are highly susceptible, while C57BL/6 mice are more resistant to PVM. IL-12 was significantly more up-regulated in response to PVM infection in BALB/c than in C57BL/6 mice. IL-12p40-deficient neonatal and adult BALB/c mice showed significantly less weight loss than wild-type mice after PVM challenge. The percentage of regulatory T cells, as well as IFN-ß and IL-18 expression, was higher in the lungs of both neonatal and adult IL-12p40-/- mice. Adult IL-12p40-/- mice also showed enhanced TGF-ß and IL-10 expression and reduced inflammatory responses. Furthermore, IL-12p40-/- mice showed decreased sensitization to inhaled cockroach antigen after PVM infection when compared to wild-type mice. In conclusion, these data suggest that a depressed regulatory capacity in BALB/c mice to PVM infection results in enhanced immunopathology and sensitization to allergen.

Blunted inflammatory and mucosal IgA responses to pneumonia virus of mice in C57BL/6 neonates are correlated to reduced protective immunity upon re-infection as elderly mice.

Respiratory syncytial virus is a major cause of bronchiolitis in infants and pneumonia virus of mice (PVM) causes similar disease in mice. The impact of PVM infection in BALB/c and C57BL/6 neonates, and upon re-infection as elderly mice, was compared. As previously shown for adult mice, PVM caused more disease in BALB/c than in C57BL/6 neonates. After PVM-15 infection BALB/c neonates showed higher production of inflammatory mediators, more influx of plasmacytoid dendritic cells and higher IFN-α expression, and more IgA in the lungs than C57BL/6 neonates. After re-infection as elderly, BALB/c mice developed virus neutralizing antibodies in serum and lung, and were protected from clinical disease, whereas C57BL/6 mice did not develop an anamnestic response and were not protected. These results suggest that an effective local innate response, as well as priming of mucosal adaptive responses in neonates after PVM-15 infection is correlated to decreased susceptibility and protection upon re-infection.

Immunogenicity of a bovine herpesvirus 1 glycoprotein D DNA vaccine complexed with bovine neutrophil beta-defensin 3.

Protective efficacy against bovine herpesvirus 1 (BoHV-1) has been demonstrated to be induced by a plasmid encoding bovine neutrophil beta-defensin 3 (BNBD3) as a fusion construct with truncated glycoprotein D (tgD). However, in spite of the increased cell-mediated immune responses induced by this DNA vaccine, the clinical responses of BoHV-1-challenged cattle were not reduced over those observed in animals vaccinated with the plasmid encoding tgD alone; this might have been because the vaccine failed to improve humoral responses. We hypothesized that an alternative vaccine design strategy that utilized the DNA vaccine pMASIA-tgD as a complex with BNBD3 might improve humoral responses while maintaining robust Th1-type cell-mediated responses. C57BL/6 mice were vaccinated with pMASIA-tgD complexed with 0, 0.01875, 0.1875, or 1.875 nmol of a stable synthesized analog of BNBD3 (aBNBD3). The best results were seen in mice immunized with the vaccine composed of pMASIA-tgD complexed to 0.1875 nmol aBNBD3. In this group, humoral responses were improved, as evidenced by increased virus neutralization, tgD-specific early IgG1, and later IgG2a titers, while the strong cell-mediated immune responses, measured based on specific gamma interferon (IFN-γ)-secreting cells, were maintained relative to pMASIA-tgD. Modulation of the immune response might have been due in part to the effect of BNBD3 on dendritic cells (DCs). In vitro studies showed that murine bone marrow-derived DCs (BMDCs) pretreated with aBNBD3 were activated, as evidenced by CD11c downregulation, and were functionally mature, as shown by increased allostimulatory ability. Native, synthetic, and analog forms of BNBD3 were equally capable of inducing functional maturation of BMDCs.

Future considerations for dendritic cell immunotherapy against chronic viral infections.

Dendritic cells (DCs) are multifunctional cells that are pivotal in immune defense. As such they have been explored as vaccine carriers, largely in cancer immunotherapy and against some infectious diseases including HIV and viral hepatitis. However, while the use of DCs as vaccine carrier has shown some promise in cancer immunotherapy, this approach is laborious and is subject to strict quality control, which makes it expensive. Furthermore, in some individuals chronically infected with HIV, HCV and/or HBV the numbers of circulating DCs are reduced and/or their functions impaired. In vivo expansion and mobilization of DCs with Flt3L in combination with antigen and/or adjuvant targeting to critical DC receptors may be a more effective approach to control viral replication in chronically infected HIV, HBV and/or HCV patients than current DC immunotherapy approaches.