| Budget Amount *help |
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1988: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1987: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
Studies of host defense against infection with Candida albicans have demonstrated roles of humoral immunity (HI) and cell-mediated immunity (CMI). However, their relative contributions in protection against candidiasis remain to be elucidated. We investigated the host defense mechanisms against murine candidiasis, and the possibility of immunotherapy by using recombinant IFN- (rIFN- ) and anti-C__-. albicans mannan monoclonal antibody (MAB), and also combined use of such immunotherapy and antifungal antibiotics. Kinetics of macrophage activation for candidacidal activity and H_2O_2 generation were examined in resident peritoneal macrophages (MP) by stimulating with rIFN- . The pead candidacidal activity occured in 24 hr-stimulated MP and was lost at 72 hr-activated stage. On the other hand, peak H_2O_2 generation occured in MP activated with rIFN- for 72 hr. These results indicate that candidacidal activity of rIFN- -activated MP is based on an oxygen-independent mechanism, and is regu
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lated during activation by rIFN- . The activity of candidacidal factors extracted from lysosomes of 24 hr-stimulated MP was higher than those from untreated controls, whereas factors from 72 hr-stimulated MP did not show any increased activity. These results suggest that candidacidal activity of activated MP is caused either by increased production of normal killing factor(s) or by newly produced killing factor(s) in lysosomes, and that the production of candidacidal factor(s) is regulated in correlation with candidacidal activity of MP, during activation of MP with rIFN- . In the presence of amphotericin B (AMB), activated MP exhibited increased candidacidal activity compared with those without AMB, whereas candidacidal activity of normal MP did not increase in the presence of AMB. When activated MP phagocytized C__-. Albicans in the presence of fresh serum and anti-C__-. Albicans mannan MAb, they exhibited enhanced inhibition of growth of germ tube, whereas effect of MAb was not observed in normal MP. When mice were injected with rIFN- before and after infection with C__-. Albicans, growth of fungi in the kidneys of mice was inhibited. Moreover, growth of fungi in the kidneys of either two groups of rIFN- -administered mice, one was injected with anti-mannan BAb, the other with AMB, were markedly inhibited. These results suggest that host defense mechanisms against candidiasis require cooperation of CMI and HI, although CMI plays a major role, and that combined use of immunotherapy and chemotherapy using rIFN- and anti-mannan BAb, is of great value for control of candidiasis. Less
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