Molecular Characterization of C Neoformans Antibodies

  • Casadevall, Arturo (PI)

Project: Research project

Project Details

Description

DESCRIPTION (provided by applicant): Cryptococcus neoformans is an important fungal pathogen that is a relatively frequent cause of life-threatening
infections in patients with impaired immunity. Current therapy is
unsatisfactory because the available antifungal agents often fail to eradicate
the infection in immunocompromised individuals with cryptococcosis. Although
cellular immunity is critically important for controlling and eradicating C.
neoformans infections there is overwhelming evidence from several independent
laboratories that humoral immunity can also make a decisive contribution to
host defense. A novel approach to therapy is to administer antibodies to the
polysaccharide capsule as adjunctive immunotherapy. A murine monoclonal
antibody (mAb) that binds to capsular polysaccharide is currently in clinical
evaluation. The relationship between antibody structure and efficacy against C.
neoformans appears to be extremely complex. Antibody specificity, isotype and
amount have each been shown to be important variables in protective efficacy.
In the past funding period this research program identified several amino acid
residues that conferred a protective specificity, discovered a new mechanism
for IgM-mediated phagocytosis, and re-discovered prozone-like effects in a
passive protection experiments. This competing renewal application proposes to
continue molecular studies to ascertain the structural determinants and
mechanisms of antibody efficacy against C. neoformans. The proposed work takes
advantage of a well defined system to explore important questions of antibody
function. Three specific Aims are proposed: 1. To identify the VH structural
motifs required for protection against Cryptococcus neoformans; 2. To establish
the mechanism and consequences of complement-independent IgM-mediated
phagocytosis of C. neoformans; and 3. To establish the mechanism for
prozone-like effects in passive antibody protection experiments. These studies
are expected to yield new insights on fundamental aspects of antibody function
as well as practical information for the development of second generation
antibody reagents for human therapy.
StatusFinished
Effective start/end date12/1/932/28/07

Funding

  • National Institute of Allergy and Infectious Diseases: $244,613.00
  • National Institute of Allergy and Infectious Diseases: $250,500.00
  • National Institute of Allergy and Infectious Diseases: $250,500.00

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