Mechanism of action of antibody to capsular polysaccharide in Cryptococcus neoformans infection
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Cryptococcus neoformans is an encapsulated fungus that causes meningoencephalitis in patients with AIDS. Several mAbs have been generated that bind the glucuronoxylomannan (GXM) component of cryptococcal polysaccharide capsule. These mAbs are protective in various murine models of cryptococcosis and are being studied for therapeutic use. We describe studies designed to explore mechanisms by which cell-mediated and humoral immunity mediate protective efficacy against C. neoformans infection.;We first examined the regulation of capsule growth and epitope expression during infection. Using a panel of GXM-specific Abs in combination with immunofluorescence and electron microscopy, we found that certain staining patterns were associated with specific binding locations within the capsule. These epitopes were preserved during infection. Organ-associated differences in capsule thickness were present with a relative order of lung < brain < in vitro, indicating that the local environment has important effects on capsule synthesis.;Subsequent studies were performed exploring host factors contributing to the efficacy of Ab therapy for cryptococcosis. Mice deficient in inducible nitric oxide synthase (NOS2-/-) were more susceptible to infection and exhibited remarkably different cytokine and cellular recruitment patterns compared to parental mice. MAb was not protective in these mice, suggesting that NO is necessary for Ab efficacy. B cell-deficient mice also exhibited enhanced susceptibility to cryptococcal infection and were not protected by Ab administration. These results suggest that B cells may contribute to the host response in a manner other than Ab production. Additional studies showed that protective or disease-enhancing characteristics of mAbs were dependent on the strain of mouse used. These results highlight a role of host genetics in the efficacy of mAb therapy.;In summary, our studies suggest that the mechanism of mAb-mediated protection against C. neoformans is extremely complex and is dependent on variables not previously known to be involved in Ab efficacy. MAb administration appears to have a wide range of effects on the inflammatory response as defined by pulmonary cellular composition and cytokine/chemokine expression. These results have important implications for the development of passive Ab therapy and may lead to new strategies for prevention and therapy of C. neoformans infections.
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