The interplay between bacillus Calmette-Guérin and Treg cells and its role to prevent or cure inflammatory diseases

Abstract

Clinical evidence indicates that Bacillus Calmette-Guérin (BCG) vaccination exerts anti-inflammatory effects in diseases such as asthma, multiple sclerosis or Type 1 diabetes. Although the exact mechanisms for this activity remain debated, the capacity of mycobacteria to induce regulatory T cells (Tregs) in vivo has been widely reported. However, adverse events associated with live BCG prevent its repeated use, especially in immunocompromised individuals. This article reviews the preclinical data showing a potent, systemic and long-term anti-inflammatory effect in animal models of allergic asthma, inflammatory bowel disease and atherosclerosis with a preparation of BCG inactivated by Extended Freeze-Drying (EFD BCG). It also presents the characteristics of EFD BCG-induced Tregs which play a crucial role in the immunomodulation of various inflammatory diseases. Finally, it compares EFD BCG with other approaches based on the therapeutic use of Tregs in humans.

Keywords::

• bacillus calmette-guérin
• extended-freeze-drying
• foxp3 tregs
• immunotherapy
• inflammatory diseases

Acknowledgements

The authors wish to thank G Marchal and B Vargaftig for their constant support for the EFD BCG project. We are grateful to I Schwartz-Cornil, O Ovchinnikova, M. Bäck, G Hansson, H Bercovier, A Bandeira, J Vanoirbeek for their fruitful implication in the EFD BCG project.

Financial & competing interests disclosure

This paper has been funded by Tolerys. M Lagranderie & PM Guyonvarc’h are shareholders of Tolerys. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Clinical trials assessed an anti-inflammatory effect lasting for several weeks or months after BCG vaccination in several chronic inflammatory diseases (asthma, multiple sclerosis).

• Risks of local and systemic infection are likely to occur if maintenance BCG therapy is required to prevent relapses.

• Heat-killed preparations of mycobacteria have been considered but abandoned during clinical development because of severe local adverse events.

• A preparation of BCG inactivated by extended freeze-drying (EFD BCG) was developed in order to kill mycobacteria without producing toxic derivatives. Protective excipients, such as sodium glutamate, are used to improve survival upon lyophilization for BCG vaccine. By contrast, BCG resuspended in water is inactivated after extensive freeze-drying without adding any lyoprotectant.

• EFD BCG administered subcutaneously exhibits a more pronounced anti-inflammatory effect than live BCG in animal models of allergic manifestations (asthma), autoimmune diseases (IBD) and atherosclerosis.

• EFD BCG’s anti-inflammatory activity relies on the differentiation of naïve T cells toward Tregs, which is dependent upon the recruitment of plasmacytoid dendritic cells (pDCs) in the draining lymph nodes of the site of administration. Indeed, concomitant depletion of pDCs with EFD BCG injection abrogated the activity of the product, whereas delayed depletion of pDCs had not impacted on EFD BCG protective effect in a murine model of asthma.

• Whether EFD BCG-induced Tregs are specific to define antigens remain to be elucidated.

Notes