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Infection and Immunity, April 2003, p. 1887-1896, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.1887-1896.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Intranasal Immunization with Recombinant Lactococcus lactis Secreting Murine Interleukin-12 Enhances Antigen-Specific Th1 Cytokine Production

Luis G. Bermúdez-Humarán,1,2 Philippe Langella,1* Naima G. Cortes-Perez,2 Alexandra Gruss,1 Reyes S. Tamez-Guerra,2 Sergio C. Oliveira,3 Odila Saucedo- Cardenas,4 Roberto Montes de Oca-Luna,2* and Yves Le Loir1,{dagger}

Unité de Recherches Laitières et de Génétique Appliquée, INRA, Domaine de Vilvert, 78352 Jouy en Josas cedex, France,1 Laboratorio de Inmunología y Virología, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza,2 Centro de Investigación Biomédica, Instituto Mexicano del Seguro Social, Monterrey, Nuevo León, Mexico,4 Laboratorio de Immunologia Doenças Infecciosas, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG-ICB), Belo Horizonte, Minas Gerais, Brazil3

Received 2 December 2002/ Returned for modification 6 January 2003/ Accepted 13 January 2003

Interleukin-12 (IL-12), a heterodimeric cytokine, plays an important role in cellular immunity to several bacterial, viral, and parasitic infections and has adjuvant activity when it is codelivered with DNA vaccines. IL-12 has also been used with success in cancer immunotherapy treatments. However, systemic IL-12 therapy has been limited by high levels of toxicity. We describe here inducible expression and secretion of IL-12 in the food-grade lactic acid bacterium Lactococcus lactis. IL-12 was expressed as two separate polypeptides (p35-p40) or as a single recombinant polypeptide (scIL-12). The biological activity of IL-12 produced by the recombinant L. lactis strain was confirmed in vitro by its ability to induce gamma interferon (IFN-{gamma}) production by mouse splenocytes. Local administration of IL-12-producing strains at the intranasal mucosal surface resulted in IFN-{gamma} production in mice. The activity was greater with the single polypeptide scIL-12. An antigen-specific cellular response (i.e., secretion of Th1 cytokines, IL-2, and IFN-{gamma}) elicited by a recombinant L. lactis strain displaying a cell wall-anchored human papillomavirus type 16 E7 antigen was dramatically increased by coadministration with an L. lactis strain secreting IL-12 protein. Our data show that IL-12 is produced and secreted in an active form by L. lactis and that the strategy which we describe can be used to enhance an antigen-specific immune response and to stimulate local mucosal immunity.

* Corresponding authors. Mailing address for Philippe Langella: Unité de Recherches Laitières et de Génétique Appliquée, INRA, Domaine de Vilvert, 78352 Jouy en Josas cedex, France. Phone: 33 01 34 65 20 83. Fax: 33 01 34 65 20 65. E-mail: langella{at}jouy.inra.fr.

* Mailing address for R. Montes de Oca Luna: Laboratorio de Inmunología y Virología, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo León, Mexico. Phone: 52 8 3 76 43 19. Fax: 52 8 3 52 42 12. E-mail: rmontesd@ccr.dsi.uanl.mx" LOCATOR-TYPE="EMAIL">langella@jouy.inra.fr. Mailing address for R. Montes de Oca Luna: Laboratorio de Inmunología y Virología, Facultad de Ciencias Biológicas, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo León, Mexico. Phone: 52 8 3 76 43 19. Fax: 52 8 3 52 42 12. E-mail: rmontesd{at}ccr.dsi.uanl.mx.

Editor: J. T. Barbieri

{dagger} Present address: Laboratoire de Microbiologie INRA ENSAR UMR1055 65, Rennes cedex, France.

Infection and Immunity, April 2003, p. 1887-1896, Vol. 71, No. 4
0019-9567/03/$08.00+0     DOI: 10.1128/IAI.71.4.1887-1896.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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