DESCRIPTION (Adapted from the applicant's abstract): Cryptococcus neoformans is a fungus that causes a lethal meningoencephalomyelitis in immunosuppressed individuals. Since anti-fungal agents alone do not clear the infection, mouse monoclonal antibodies (mabs) have been generated to the capsular polysaccharide of the fungus. In the course of studying the protective potential of a large library of these mabs in vivo in both immunocompetent and immunoincompetent mice, we have identified protective, non-protective and enhancing antibodies. We have shown that the ability of the antibodies to modulate the infection depends upon the isotype, epitope specificity and state of the effector cells. In particular, IgG3 mabs do not prolong the life of the animals, and in certain situations can enhance the infection, while IGGI, IgG2b and IgG2a isotype switch variants of these mab can prolong the life of the animal. This suggests that the FcRs on effector cells are also playing a role. In determining the efficacy of these antibodies in vivo. Furthermore, CD4+ and CD8+ T cells and interferon-y play a role in the ability of the passively administered antibodies to modulate infection. Preliminary experiments reveal that the different effects of IgG3 and IGGI can also be observed in vitro with primary macrophages. We propose here to do in vitro and in vivo experiments with genetically defective mice to learn why antibodies of different isotypes modulate the infection of mice with C neoformans in different ways. It is hoped that these studies will provide new insights into the mechanism of action of antibodies in preventing and treating infection with C neoformans, and perhaps other encapsulated organisms.
|Effective start/end date||5/1/99 → 4/30/05|
- National Institute of Allergy and Infectious Diseases: $381,738.00
- National Institute of Allergy and Infectious Diseases: $416,704.00
- National Institute of Allergy and Infectious Diseases: $404,703.00
- National Institute of Allergy and Infectious Diseases: $393,051.00
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