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Infection and Immunity, March 2007, p. 1424-1435, Vol. 75, No. 3
0019-9567/07/$08.00+0     doi:10.1128/IAI.01161-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Human Immunoglobulin G2 (IgG2) and IgG4, but Not IgG1 or IgG3, Protect Mice against Cryptococcus neoformans Infection

Division of Infectious Diseases, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073,¹ Department of Medicine, David Geffen School of Medicine,² Department of Microbiology, Immunology and Molecular Genetics and the Molecular Biology Institute, University of California, Los Angeles, California 90095³

Received 24 July 2006/ Returned for modification 15 August 2006/ Accepted 27 December 2006

The encapsulated yeast Cryptococcus neoformans is a significant cause of meningitis and death in patients with AIDS. Some murine monoclonal antibodies (MAbs) against the glucuronoxylomannan (GXM) component of the C. neoformans capsular polysaccharide can prolong the lives of infected mice, while others have no effect or can even shorten survival. To date, no one has systematically compared the efficacies of antibodies with the same variable regions and different human constant regions with their unique combination of effector functions in providing protection against murine C. neoformans infection. In the present study, we examined the efficacies of anti-GXM MAbs of the four human immunoglobulin G (IgG) subclasses, which have identical variable regions but differ in their capacities to bind the three types of Fc receptors for IgG (FcR), their abilities to activate complement, and their half-lives. IgG2 and IgG4 anti-GXM prolonged the lives of infected BALB/c mice, IgG3 anti-GXM did not affect animal survival, while mice treated with IgG1 anti-GXM died earlier than mice treated with phosphate-buffered saline or irrelevant isotype-matched MAbs. All MAbs decreased serum GXM in infected animals. Effector pathways traditionally believed to be important in defense against microbes, such as opsonophagocytosis and complement binding, negatively correlated with antibody efficacy. It is generally accepted that human IgG1 has the most favorable combination of effector functions for therapeutic use against infections. Therefore, our findings have significant implications for humanization of the mouse IgG1 currently in clinical trials for cryptococcal meningitis and for the design of antibody therapeutics to treat other infectious diseases as well.

Published ahead of print on 12 January 2007.

Editor: A. Casadevall

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