Could bacterial flagella be used in the treatment of food allergies?

Researchers of the Paul-Ehrlich-Institut succeeded in preventing the development of a food allergy against chicken protein in mice using a fusion protein. This fusion protein consists of the bacterial protein flagellin and ovalbumin, the allergen of the chicken egg white. Moreover, first approaches using the fusion protein for the treatment of an existing allergy turned out to be promising. Research results are reported in the current issue of the Journal of Allergy and Clinical Immunology.

Bacterial flagella are spiral-shaped protein filaments on the surface of the bacteria and enable the movement of free-floating bacteria. Their main component is the protein flagellin which is known to cause immunological reactions in mammals. Dr Stefan Schülke and his colleagues from the Division of Allergology of the Paul-Ehrlich-Institut addressed the question whether the stimulatory effect of flagellin on the immune system could be used for the treatment and/or prevention of allergies. They chose the chicken allergen ovalbumin as a model allergen for their studies. This is of major practical relevance, since there is no established treatment against food allergies to date. Although these allergies are possibly life-threatening, avoiding the substance causing the allergy is still the "treatment of choice".

Bacterium Listeria monocytogenes Source: Elizabeth White, CDC

Flagellin A (flaA), the immune modulating agent the researchers are working with, is derived from the bacterium Listeria monocytogenes. The immune response is triggered via TOLL-like-receptor 5 (TLR 5) recognising flagellin, which is expressed on cells of the innate immune system. TLR5 activation mobilises the immune system. "Our hypothesis was that flagellin can be used to treat allergies when in direct spatial vicinity to the allergen" explained Dr Stephan Scheurer, head of the Section "Recombinant Allergen Therapeutics" of the Paul-Ehrlich-Institut. To achieve spatial vicinity, the researchers fused Flagellin A with the chicken allergen ovalbumin by means of genetic engineering.

At first, Dr Schülke and colleagues investigated the effect of the fusion protein in cell cultures on murine dendritic cells. Dendritic cells control the direction in which the T-lymphocytes of the immune system develop, i.e. whether they develop into cells causing the allergic reaction or cells responsible for normal protective immune responses. The researchers could show that the fusion protein induces the release of the messenger interleukin-10 (IL10). IL10 is produced naturally by the body, and its function is to inhibit overshooting immune responses by acting on T-lymphocytes. The inhibition of such an overshooting immune response is the goal in the treatment of allergies.

In collaboration with junior research groups at the Paul-Ehrlich-Institut, Dr Schülke and his colleagues tested the effect of their fusion protein in mouse cell cultures. The administration of the fusion protein of flagellin and ovalbumin inhibited the activation of the T-lymphocytes, both in cells isolated from allergic mice and in genetically modified cells which specifically recognise ovalbumin, and therefore suppressed the allergic reaction.

Whether an allergy prophylaxis or the therapeutic treatment of an existing allergy actually works, however, must be tested in a live organism. To test the preventive effect against egg white allergy, the scientists injected the fusion protein into mice twice – as a sort of vaccination. Then, the mice were sensitised against chicken allergen. As expected, the non-pre-treated animals developed an allergy with a distinct drop in core body temperature, weight loss and diarrhoea. The animals pre-treated with the fusion protein showed no symptoms – they were protected by the "vaccination". No protective effect was shown, however, if the animals were treated with ovalbumin or flagellin alone or with non-fused flagellin plus ovalbumin in a mixture. "In doing so, we were able to prove that flagellin application results in a shift of the immune response into the desired direction, which, however, is only possible if it is directly linked to the allergen", Schülke explained the results.

First approaches using the fusion protein for the treatment of an established allergy also turned out to be promising. The researchers of the Paul-Ehrlich-Institut are currently working on further studies to improve the efficacy of the treatment and to clarify the underlying mechanisms. In the researchers’ view, fusion proteins consisting of flagellin and allergens are promising candidates for the treatment of patients with IgE-mediated allergies.

"The results of this research project are exciting for our institute in two respects – on the one hand, they may provide new therapeutic options in allergology, and on the other hand, flagellin might become important in the field of the marketing authorisation as an immune modulating agent (adjuvant), and thus for the regulators. Therefore, the combination of basic research and regulatory affairs is of great importance to us" Prof. Stefan Vieths, vice president of the Paul-Ehrlich-Institut emphasised.

Further information:

Schülke S, Burggraf M, Waibler Z, Wangorsch A, Wolfheimer S, Kalinke U, Vieths S, Toda M, Scheurer S (2011): A fusion protein of flagellin and ovalbumin suppresses the TH2 response and prevents murine intestinal allergy.
J Allergy Clin Immunol 128: 1340-1348.
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