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Adjuvant effects of different TLR agonists on the induction of allergen-specific Th2 responses

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DOI: 10.4236/oji.2012.21003    4,467 Downloads   10,865 Views   Citations

ABSTRACT

Currently different Toll-like receptor (TLR) agonists are tested in humans for their ability to enhance the efficacy of specific immunotherapy (SIT). Recent clinical data suggest that this may be achieved by increasing allergen-specific Th1 responses. However, it is not clear which TLR agonist is best suited to be used in combination with SIT. We tested the ability of five TLR agonists, LTA, poly(I:C), LPS, R848, and CpG-ODN, activating TLR2, 3, 4, 7, and 9, to induce allergen-specific Th1 and suppress allergen-specific Th2 responses in a preclinical setting. Mice were immunized by intraperitoneal injection of ovalbumin (OVA)/Al(OH)3 together with different doses (0.0025, 0.025, 0.25, and 2.5 mg/kg) of agonists followed by two OVA aerosol challenges. The results of these experiments showed, that the suppression of allergen-specific Th2 responses and the induction of Th1 responses dependedon the dose and the agonists used. All TLR agonists increased allergen-specific IgG2a, and with the exception of poly(I:C), reduced allergen-specific IgE levels in the serum. Allergic cutaneous anaphylaxis was also suppressed in mice when LPS or CpG was given together with OVA/alum. The strongest Th1 responses were induced by CpG and poly(I:C), characterized by the presence of IFN-g in the BAL and the highest OVA-specific IgG2a levels in the serum. This study suggests that the TLR9 agonist CpG-ODN and TLR4 agonist LPS have the strongest suppressive effects on the development of aller-gen-specific Th2 responses in mice and CpG-ODN induces the strongest allergen-specific Th1 responses. Therefore these two TLR agonists may be good candidates to combine with allergen in novel SIT formulations in humans.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Duechs, M. , Brunt, J. , Gantner, F. and Erb, K. (2012) Adjuvant effects of different TLR agonists on the induction of allergen-specific Th2 responses. Open Journal of Immunology, 2, 17-24. doi: 10.4236/oji.2012.21003.

References

[1] Barnes, P.J. (2010) New therapies for asthma: Is there any progress? Trends in Pharmacological Sciences, 31, 335-343. doi:10.1016/j.tips.2010.04.009
[2] Walsh, G.M. (2006) Targeting airway inflammation: Novel therapies for the treatment of asthma. Current Medicinal Chemistry, 13, 3105-3111. doi:10.2174/092986706778521779
[3] Holgate, S.T. and Polosa, R. (2008) Treatment strategies for allergy and asthma. Nature Reviews Immunology, 8, 218-230. doi:10.1038/nri2262
[4] Durham, S.R., Walker, S.M., Varga, E.M., Jacobson, M.R., O’Brien, F., Noble, W., Till, S.J., Hamid, Q.A. and Nouri-Aria, K.T. (1999) Long-term clinical efficacy of grass-pollen immunotherapy. New England Journal of Medicine, 341, 468-475. doi:10.1056/NEJM199908123410702
[5] Eifan, A.O., Akkoc, T., Yildiz, A., Keles. S., Ozdemir, C., Bahceciler, N.N. and Barlan, I.B. (2010) Clinical efficacy and immunological mechanisms of sublingual and subcutaneous immunotherapy in asthmatic/rhinitis children sensitized to house dust mite: An open randomized controlled trial. Clinical & Experimental Allergy, 40, 922- 932. doi:10.1111/j.1365-2222.2009.03448.x
[6] Moingeon, P., Batard, T., Fadel, R., Frati, F., Sieber, J. and Overtvelt, L. (2006) Immune mechanisms of allergen specific sublingual immunotherapy. Allergy, 61, 151-165. doi:10.1111/j.1398-9995.2006.01002.x
[7] Tversky, J.R., Bieneman, A.P., Chichester, K.L., Hamilton, R.G. and Schroeder, J.T. (2010) Subcutaneous allergen immunotherapy restores human dendritic cell innate immune function. Clinical & Experimental Allergy, 40, 94-102.
[8] Calamita, Z., Saconato, H., Pela, A.B. and Atallah, N. (2006) Efficacy of sublingual immunotherapy in asthma: systematic review of randomized clinical trials using the Cochrane Collaboration method. Allergy, 61, 1162-1172. doi:10.1111/j.1398-9995.2006.01205.x
[9] Senti, G., Johansen, P., Haug, S., Bull, C., Gottschaller, C., Müller, P., Pfister, T., Maurer, P., Bachmann, M.F. and Graf, N. (2009) Use of A-type CpG oligodeoxynucleotides as an adjuvant in allergen specific immunotherapy in humans: A phase I/IIa clinical trial. Clinical & Experimental Allergy, 39, 562-570. doi:10.1111/j.1365-2222.2008.03191.x
[10] Kündig, T.M., Senti, G., Schnetzler, G., Wolf, C., Prinz, Vavricka, B.M., Fulurija, A., Hennecke, F., Sladko, K., Jennings, G.T. and Bachmann, M.F. (2006) Der p 1 peptide on virus-like particles is safe and highly immunogenic in healthy adults. Journal of Allergy and Clinical Immunology, 117, 1470-1476. doi:10.1016/j.jaci.2006.01.040
[11] Trujillo-Vargas, C.M., Werner-Klein, M., Wohlleben, G., Polte T., Hansen, G., Ehlers, S., Erb, K.J. (2007) Helminth-derived products inhibit the development of allergic responses in mice. American Journal of Respiratory and Critical Care Medicine, 175, 336-344. doi:10.1164/rccm.200601-054OC
[12] Racila, D.M. and Kline, J.N. (2005) Perspectives in asthma: Molecular use of microbial products in asthma prevention and treatment. The Journal of Allergy and Clinical Immunology, 116, 1202-1205. doi:10.1016/j.jaci.2005.08.050
[13] Rolland, J.M., Gardne, L.M. and O'Hehir, R.E. (2009) Allergen-related approaches to immunotherapy. Pharmacology & Therapeutics, 121, 273-284. doi:10.1016/j.pharmthera.2008.11.007
[14] Wohlleben, G. and Erb, K.J. (2006) Immune stimulatory strategies for the prevention and treatment of asthma. Current Pharmaceutical Design, 12, 3281-3292. doi:10.2174/138161206778194114
[15] Trujillo-Vargas, C.M., Mayer, K.D., Bickert, T., Palmetshofer, A., Grunewald, S., Ramirez-Pineda, J.R., Polte, T., Hansen, G., Wohlleben, G. and Erb, K.J. (2005) Vaccinations with T-helper type 1 directing adjuvants have different suppressive effects on the development of allergen-induced T-helper type 2 responses. Clinical & Experimental Allergy, 35, 1003-1013. doi:10.1111/j.1365-2222.2005.02287.x
[16] Kline, J.N., Waldschmidt, T.J., Businga, T.R., Lemish, J.E., Weinstock, J.V., Thorne, P.S. and Krieg, A.M. (1998) Cutting edge: Modulation of airway inflammation by CpG oligodeoxynucleotides in a murine model of asthma. The Journal of Immunology, 160, 2555-2559.
[17] Jahn-Schmid, B., Wiedermann, U., Bohle, B., Repa, A., Kraft, D. and Ebner, C. (1999) Oligodeoxynucleotides containing CpG motifs modulate the allergic TH2 response of BALB/c mice to Bet v 1, the major birch pollen allergen. Journal of Allergy and Clinical Immunology, 104, 1015-1023. doi:10.1016/S0091-6749(99)70083-7
[18] Serebrisky, D., Teper, A.A., Huang, C.K., Lee, S.Y., Zhang, T.F., Schofield, B.H., Kattan, M., Sampson, H.A. and Li, X.M. (2000) CpG oligodeoxynucleotides can reverse Th2- associated allergic airway responses and alter the B7.1/ B7.2 expression in a murine model of asthma. The Journal of Immunology, 165, 5906-5912.
[19] Mo, J.H., Park, S.W., Rhee, C.S., Takabayashi, K., Lee, S.S., Quan, S.H., Kim, I.S., Min, Y.G., Raz, E. and Lee, C.H. (2006) Suppression of allergic response by CpG motif oligodeoxynucleotide house-dust mite conjugate in animal model of allergic rhinitis. American Journal of Rhinology, 20, 212-218.
[20] Redecke, V., Hacker, H., Datta, S.K., Fermin, A., Pitha, P.M., Broide, D.H. and Raz, E. (2004) Cutting edge: Activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. The Journal of Immunology, 72, 2739-2743.
[21] Velasco, G., Campo, M., Manrique, O.J., Bellou, A., Hongzheh, H.E., Arestides, R.S.S., Schaub, B., Perkins, D.L. and Finn, P.W. (2005) Toll-like receptor 4 or 2 agonists decrease allergic inflammation. American Journal of Respiratory Cell and Molecular Biology, 32, 218-224. doi:10.1165/rcmb.2003-0435OC
[22] Sel, S., Wegmann, M., Sel, S., Bauer, S., Garn, H., Alber, G. and Renz, H. (2007) Immunomodulatory effects of viral TLR ligands on experimental asthma depend on the additive effects of IL-12 and IL-10. The Journal of Immunology, 178, 7805-7813.
[23] Gawchik, S.M. and Saccar, C.L. (2009) Pollinex quattro tree: Allergy vaccine. Expert Opinion on Biological Therapy, 9, 377-382. doi:10.1517/14712590802699596

  
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