Scientists at the Center of Allergy and Environment (ZAUM) at Technical University of Munich and Helmholtz Zentrum München say they have succeeded in isolating, identifying, and analyzing a protein that the larvae of a roundworm (Heligmosomoides polygyrus) use to trick the immune system of their host to survive.

Hpb glutamate dehydrogenase activates various immunoregulatory metabolic pathways. These pathways ensure the formation of anti-inflammatory mediators in the immune cells of the host organism. At the same time the number of inflammatory mediators is reduced.

The team published its study “An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products” in Science Translational Medicine.

“Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma. Helminth products have been suggested as remedies against inflammatory diseases, but their effects on eicosanoids are unknown. Here, we show that larval products of the helminth Heligmosomoides polygyrus bakeri (HpbE), known to modulate type-2 responses, trigger a broad anti-inflammatory eicosanoid shift by suppressing the 5-lipoxygenase pathway, but inducing the cyclooxygenase (COX) pathway,” write the investigators.

“In human macrophages and granulocytes, the HpbE-driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E2 (PGE2) and IL-10] and suppressed chemotaxis. HpbE also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition.

“Intranasal treatment with HpbE extract attenuated allergic airway inflammation in mice, and intranasal transfer of HpbE-conditioned macrophages led to reduced airway eosinophilia in a COX/PGE2-dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1α (HIF-1α), and Hpb glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in HpbE. Hpb GDH activity was required for anti-inflammatory effects of HpbE in macrophages, and local administration of recombinant Hpb GDH to the airways abrogated allergic airway inflammation in mice.”

“Thus, a metabolic enzyme present in helminth larvae can suppress type-2 inflammation by inducing an anti-inflammatory eicosanoid switch, which has important implications for the therapy of allergy and asthma.”

“The ability of Hpb glutamate dehydrogenase to weaken the immune response makes it a promising candidate for treatment of chronic airway inflammation,” says Julia Esser-von Bieren, PhD, a researcher at the Center.

Respiratory illnesses such as allergic asthma are often the result of an over-reaction by the immune system due to an overproduction of inflammatory mediators known as leukotrienes, which can trigger asthma attacks. However, the medications currently given to patients, usually cortisone, hardly have any effect on these mediators at all, she adds.

The scientists used a mouse model of allergic asthma to successfully show that the larval protein can be used to suppress inflammatory reactions. Investigations using human cell cultures also provided encouraging results, according to Esser-von Bieren.

“We paid particular attention to the effects on certain human immune cells known as macrophages. Constant activation of macrophages results in chronic inflammation,” she explains. “By adding Hpb glutamate dehydrogenase we were able to significantly reduce the pro-inflammatory activity of the macrophages. Here the substance turns out to have greater efficacy than cortisone.”

However, Esser-von Bieren points out that there is still a long way to go before a finished medication can be produced.

“We’re in the pre-clinical phase and still have to address a number of questions, for example how the worm protein is received by cells in the respiratory tract and what the overall effects on the human immune system are,” she explained.

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