| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2004: ¥2,000,000 (Direct Cost: ¥2,000,000)
|
|---|
| Research Abstract |
Pneumococcus is a leading causative bacterium in community-acquired pneumonia. Recently, increase in the drug-resistant pneumococcus is getting in a clinical problem. Aged people, infant and patients with asplenia and chronic cardiopulmonary diseases frequently suffer from severe and refractory infection. In these individuals, vaccination with capsular polysaccharides is required, but its effectiveness is not satisfactory. On this background, it is important to fully understand the host defense mechanism against pneumococcal infection.
In this study, we have studied the role of innate immune lymphocytes, especially NKT cells and γδ T cells and contribution of Th1-related cytokines to their function in pneumococcal infection using a mouse model. Manipulations suppressing Th1-related cytokines by genetic disruption of IL-12 and administration of neutralizing anti-IFN-γ mAb resulted in the impairment of host defense, which was well correlated with decreased production of MIP-2 and TNF-α an
… More
d attenuated accumulation of neutrophils at the infected sites. These data indicated a critical role of Th1-related cytokines in the neutrophil-mediated host defense to this infection. Mice genetically lacking NKT cells, γδ T cells and Vγ4+γδ T cells, a major γδ T cell subset in lungs, (Jα18KO, CdKO and Vγ4KO, respectively) were highly susceptible to pneumococcal infection. In these mice, synthesis of MIP-2 and TNF-α and accumulation of neutrophils in the infected lungs were significantly reduced, when compared to those in wild-type (WT) mice. The impairment of host defense and neutrophilic inflammatory responses in Ja18KO mice was almost completely recovered by administration of rIFN-γ or liver mononuclear cells (LMNC) from WT mice, whereas LMNC from IFN-γKO mice did not show such effect. By contrast, the recovery effects of rIFN-γ administration were not remarkable in Vγ4KO mice.
In conclusion, innate immune lymphocytes, particularly NKT cells, were found to deeply contribute to the neutrophil-mediated host defense against pneumococcal infection through the production of IFN-γ. These findings provide an important basic implication in the development of more efficient vaccine for this infection. Less
|
