IFN‐γ‐mediated efficacy of allergen‐free immunotherapy using mycobacterial antigens and CpG‐ODN

Abstract

Epidemiological and experimental evidence supports the notion that microbial infections that are known to induce Th1-type immune responses can suppress Th2 immune responses, which are characteristics of allergic disorders. However, live microbial immunization might not be feasible for human immunotherapy. Here, we evaluated whether induction of Th1 immunity by the immunostimulatory sequences of CpG-oligodeoxynucleotides (CpG-ODN), with or without culture filtrate proteins (CFP), from Mycobacterium tuberculosis would suppress ongoing allergic lung disease. Presensitized and ovalbumin (OVA)-challenged mice were treated subcutaneously with CpG, or CpG in combination with CFP (CpG/CFP). After 15 days of treatment, airway inflammation and specific T-and B-cell responses were determined. Cell transfer experiments were also performed. CpG treatment attenuated airway allergic disease; however, the combination CpG/CFP treatment was significantly more effective in decreasing airway hyperresponsiveness, eosinophilia and Th2 response. When an additional intranasal dose of CFP was given, allergy was even more attenuated. The CpG/CFP therapy also reduced allergen-specific IgG1 and IgE antibodies and increased IgG2a. Transfer of spleen cells from mice immunized with CpG/CFP also reduced allergic lung inflammation. CpG/CFP treatment induced CFP-specific production of IFN-c and IL-10 by spleen cells and increased production of IFN-c in response to OVA. The essential role of IFN-c for the therapeutic effect of CpG/CFP was evidenced in IFN-c knockout mice. These results show that CpG/CFP treatment reverses established Th2 allergic responses by an IFN-c-dependent mechanism that seems to act both locally in the lung and systemically to decrease allergen-specific Th2 responses.

Bacillus Calmette-Guérin Suppresses Asthmatic Responses via CD4+CD25+Regulatory T Cells and Dendritic Cells

“…A study has reported that the interaction between BCG and toll-like receptor (TLR) 2 on DCs may affect the differentiation of naïve T cell mainly to Th1-like cells with the help of IL-10, IL-12, and so forth 43. In addition, recently, some studies have reported that IFN-γ is essential to suppress allergic responses 44. It would be worth to perform the study of BCG-DCs on damping allergic inflammation in IFN-γ- or TLR2-deficient mice.…”

Immunotherapy of allergic diseases by bacterial products

“…The paper by Fonseca et al . (e‐pub ahead of print: Immunology and Cell Biology (15 March 2011); doi:10.1038/icb.2011.9) reports the effect of two microbial products on a mouse model of asthma 1 . The authors found that treatment with the combination of CpG‐oligodeoxynucloeotides (CpG) and mycobacterial proteins reduced inflammation and airway hyperresponsiveness.…”

“…CpG and mycobacteria have separately been the subject of extensive research for their potential to inhibit allergic diseases, and both types of agent have been tested (separately) in clinical trials of immunotherapy. The paper by Fonseca et al is significant because it demonstrates improved efficacy when the two different agents are combined 1 …”

“…Adjuvants that can increase the efficacy and safety and reduce the treatment regimen of immunotherapy would be very useful. The strategy used in the paper of Fonseca et al 1 has the potential to be adapted for clinical trials in the immunotherapy of allergic diseases.…”

“…There is extensive evidence in mouse models of asthma that therapy with CpG inhibits allergic responses, 2 but most clinical trials of CpG to date have had limited success. It is possible that the use of type A CpG (containing phosphodiester bonds) may be more effective than the more commonly used type B CpG, which have a phosphorothioate backbone, and which were used in the Fonseca et al article 1 . While both type A and type B CpG bind to TLR‐9, they have different effects on their target cells, which in humans are plasmacytoid dendritic cells and B cells.…”