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Infection and Immunity, June 2005, p. 3668-3676, Vol. 73, No. 6
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.6.3668-3676.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Differential Effects of Total and Partial Neutralization of Tumor Necrosis Factor on Cell-Mediated Immunity to Mycobacterium bovis BCG Infection

Reto Guler, Maria L. Olleros, Dominique Vesin, Roumen Parapanov, and Irene Garcia*

Department of Pathology and Immunology, CMU, Faculty of Medicine, University of Geneva, Switzerland

Received 12 May 2004/ Returned for modification 20 August 2004/ Accepted 27 January 2005

The effects of total and partial inhibition of tumor necrosis factor (TNF) on sensitivity to Mycobacterium bovis BCG infection were investigated by using transgenic mice in which hepatocytes produced different amounts of human soluble TNF receptor 1 (sTNFR1) fused to the Fc fragment of human immunoglobulin G3 that could be detected in the serum. Transgenic mice expressing high serum levels of sTNFR1, neutralizing all circulating TNF, failed to develop differentiated granulomas and bactericidal mechanisms, and they succumbed to BCG infection. sTNFR1 transgenic mice did not activate BCG-induced Th1-type cytokines early in infection, but uncontrolled cytokine release was found late in infection. In this work we also evaluated the effect of partial inhibition of TNF on resistance to BCG infection. Transgenic mice expressing low levels of sTNFR1 were protected against BCG infection, and they developed increased bactericidal mechanisms, such as enhanced inducible nitric oxide synthase activity, increased macrophage activation, and showed higher numbers of liver granulomas early in infection compared to their negative littermates. Our data suggest that while total inhibition of TNF prevented BCG-induced cell-mediated immune responses, partial inhibition of TNF could contribute to macrophage activation, induction of bactericidal mechanisms, and granuloma formation in the early phase of BCG infection.

* Corresponding author. Mailing address: Department of Pathology and Immunology, C.M.U., 1, rue Michel-Servet, CH 1211 Geneva 4, Switzerland. Phone and fax: (41) 22 379 57 46. E-mail: Irene.Garcia-Gabay{at}medecine.unige.ch.

Editor: A. D. O'Brien

Infection and Immunity, June 2005, p. 3668-3676, Vol. 73, No. 6
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.6.3668-3676.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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