Passive antibody modulation of Cryptococcus neoformans infection in mice

Abstract

Cryptococcus neoformans is an encapsulated fungus that causes a meningoencephalitis in immunosuppresed individuals. Because current therapies against human cryptococcosis only control the disease and do not eradicate the fungus, many AIDS patients die of the acute infection and the survivors must be maintained on lifelong antifungal therapy to prevent a relapse. Passive monoclonal antibodies (mAbs) against glucoronoxylomannan (GXM), the primary component of the C. neoformans polysaccharide capsule, are being tested as one alternative therapy with the hope that they could treat the acute infection and completely eliminate C. neoformans from the chronically infected patient.;Administration of isotype switch variants of a mAb against GXM to mice lethally infected with C. neoformans results in different disease outcomes depending on the isotype. Treatment with IgG1, IgG2a, or IgG2b mAbs prolongs the life of mice with cryptococcal infection whereas IgG3 is either not protective or shortens the lifespans of C. neoformans-infected mice relative to controls. In these studies, we have used this isotype difference and knockout mice to dissect the important elements of immunity that contribute to modulation of cryptococcal infection by passive mAbs.;Using C3 deficient mice to examine the role of complement in passive mAb therapy, we conclude that C3 is not required for passive mAb-mediated protection but does contribute to the enhancement with IgG3. We examine the factors of cellular immunity that contribute to the outcomes of passive antibody therapy with each of the IgG subclasses by using T cell deficient mice and mice lacking various Th1 and Th2 cytokines. We also tested our C. neoformans infection model in Fc receptor knockout mice to determine the contribution of the known Fc receptors in mediating the effects of passive antibody therapy with each of the isotypes.;These experiments have advanced our understanding of isotype interactions with Fc receptors, and suggest that Fc receptors mediate an interface between passive antibodies, cellular immunity and the complement system. This suggests that passive antibodies are recruiting many aspects immune response. Furthermore, we have identified some of the essential elements that comprise the mechanisms of passive mAb modulation of cryptococcal infection in mice.