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Infection and Immunity, April 2000, p. 1820-1826, Vol. 68, No. 4
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Production of Protective Human Antipneumococcal Antibodies by Transgenic Mice with Human Immunoglobulin Loci

Nina D. Russell,1 Jose R. F. Corvalan,2 Michael L. Gallo,2 C. Geoffrey Davis,2 and Liise-anne Pirofski3,1,3,*

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

Received 28 September 1999/Returned for modification 15 November 1999/Accepted 3 January 2000

Infections with Streptococcus pneumoniae remain a significant cause of morbidity and mortality. To gain insight into structure-function relationships for human antibodies to pneumococcal capsular polysaccharide (PPS), we studied the response of transgenic mice reconstituted with human immunoglobulin loci, XenoMouse, to PPS antigens in a pneumococcal vaccine. Enzyme-linked immunosorbent assays of sera from mice vaccinated with a 23-valent pneumococcal vaccine revealed that they produced serotype-specific human antibodies, with the greatest response being to the PPS of serotype 3 (PPS 3). Molecular sequence analysis of three monoclonal antibodies (MAbs) to PPS 3 generated from lymphoid cells from mice vaccinated with a 23-valent pneumococcal vaccine or a PPS 3-bovine serum albumin conjugate revealed that they all used heavy-chain immunoglobulin genes from the VH3 family, two expressed light chain genes from the human Vkappa 1 family, and one expressed a mouse lambda  light chain. The protective efficacy of the two MAbs was examined in mice. A 10-µg dose of both, and a 1-µg dose of one, significantly prolonged survival from a lethal serotype 3 infection in CBA/N mice. Our data show that XenoMouse mice produced protective, serotype-specific human antibodies to PPS 3, and they lend support to the proposal that these animals represent a useful model to study the human antibody response to PPS antigens.

* Corresponding author. Mailing address: Division of Infectious Diseases, Albert Einstein College of Medicine, 1300 Morris Park Ave., Room 402 Forchheimer Building, Bronx, NY 10461. Phone: (718) 430-2372. Fax: (718) 430-8968. E-mail: pirofski{at}aecom.yu.edu.

Infection and Immunity, April 2000, p. 1820-1826, Vol. 68, No. 4
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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