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Infection and Immunity, August 2004, p. 4810-4818, Vol. 72, No. 8
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.8.4810-4818.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Protective and Nonprotective Human Immunoglobulin M Monoclonal Antibodies to Cryptococcus neoformans Glucuronoxylomannan Manifest Different Specificities and Gene Use Profiles

Robert W. Maitta,1 Kausik Datta,1 Qing Chang,1 Robin X. Luo,2 Bradley Witover,3 Krishanthi Subramaniam,3 and Liise-anne Pirofski1,3*

Departments of Microbiology and Immunology,1 Medicine, Division of Infectious Diseases, Albert Einstein College of Medicine, Bronx, New York 10461,3 Abgenix Inc., Fremont, California 945552

Received 22 March 2004/ Returned for modification 15 April 2004/ Accepted 19 April 2004

The features of protective murine antibodies to the Cryptococcus neoformans capsular polysaccharide glucuronoxylomannan (GXM) have been rigorously investigated; however, the characteristics of protective human antibodies to GXM have not been defined. We produced monoclonal antibodies (MAbs) from XenoMouse mice (transgenic mice that express human immunoglobulin M [IgM], IgG2, and {kappa}) which were immunized with a C. neoformans serotype D strain 24067 GXM-diphtheria toxoid conjugate. This study reports the specificity and efficacy of three human IgM MAbs, G14, G15, and G19, generated from these mice. Each MAb was specific for GXM, but G14 and G19 had different specificity based on their binding to serotype A strain H99 and SB4 GXMs, to which G15 did not bind. Nucleic acid sequence analysis revealed that G15 uses VH3-64 in the germ line configuration. G14 and G19 use VH6-1, which has somatic mutations. All of the MAbs use V{kappa} DPK22/A27. Studies of MAb efficacy in BALB/c mice showed that administration of 0.1 mg, but not 1 or 0.01 mg, of G15 prolonged survival against lethal C. neoformans strain 24067 challenge, whereas G14 and G19 were not protective at any dose. This panel of MAbs illustrates that serotype D GXM has epitopes that elicit human antibodies that can be either protective or nonprotective. Our findings suggest that VH gene use may influence GXM specificity and efficacy, and they provide insights into the possible contribution that VH gene use may have in resistance and susceptibility to cryptococcosis.

* Corresponding author. Mailing address: Room 709, Forchheimer Bldg., Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2372. Fax: (718) 430-2292. E-mail: pirofski{at}aecom.yu.edu.

Editor: T. R. Kozel

Infection and Immunity, August 2004, p. 4810-4818, Vol. 72, No. 8
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.8.4810-4818.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Datta, K., Lees, A., Pirofski, L.-a. (2008). Therapeutic Efficacy of a Conjugate Vaccine Containing a Peptide Mimotope of Cryptococcal Capsular Polysaccharide Glucuronoxylomannan. CVI 15: 1176-1187 [Abstract] [Full Text]  
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