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13-10-2011 | Immunology | Article

Novel immunotherapy developed for allergic diseases


Free abstract

MedWire News: US researchers have developed a novel antigen (Ag)-specific immunotherapy that could be used to treat allergic diseases, such as peanut allergies and asthma.

The study, conducted in mice, shows that treatment with Ags coupled to splenocytes (SPs) can block the T-helper (Th)2 cell response.

"CD4+ Th2 cells are important regulators of allergy through production of cytokines that induce B cell class-switching to immunoglobulin (Ig)E, thereby priming mast cells, as well as eosinophil and basophil maturation - cells important in the effector phase of the allergic cascade," explain Stephen Miller (Northwestern University, Chicago, Illinois) and colleagues.

Immunotherapy is an effective therapeutic approach for many allergic diseases but requires long dose-escalation periods and has a high risk for adverse reactions, particularly in food allergy, they add.

New methods to safely induce Ag-specific tolerance could therefore improve the clinical approach to allergic disease.

Miller and team have previously demonstrated that intravenous administration of peptides attached to the surface of syngeneic splenic leukocytes (known as Ag-coupled SPs [Ag-SPs]) with the chemical cross-linking agent ethylene-carbodiimide, safely and efficiently induce Ag-specific immune tolerance in Th1/Th17-mediated autoimmune disease.

In the present study, the researchers investigated whether Ag-SPs may also induce tolerance in Th2-mediated mouse models of allergic asthma and peanut allergy.

In the allergic asthma model, the team administered ovalbumin-coupled SPs (OVA-SPs) prior to each of two sensitizations with OVA in alum adjuvant, which provokes an immune response in the lungs. Myelin basic protein-coupled SPs (MBP-SPs) were used as a control treatment.

Analysis of bronchoalveolar lavage fluid showed that OVA-SP-treated mice had significantly lower levels lung eosinophilia than the mice treated with MBP-SP (approx 25,000 vs 175,000 eosinophils/ml).

Furthermore, compared with MBP-SP-treated mice, OVA-SP-treated mice had significantly lower levels the Th2-associated cytokines interleukin (IL)-4 (10 vs 55 pg/ml) and IL-5 (50 vs 220 pg/ml). The systemic allergic response was also inhibited in the OVA-SP group, as demonstrated by reduced blood eosinophil concentrations (60,000 vs 190,000 eosinophils/ml) and serum OVA-specific IgE levels (180 vs 800 ng/ml), compared with the MBP-SP group.

In the peanut allergy model, the researchers administered whole peanut extract coupled SPs (WPE-SPs) prior to sensitization. For this series of experiments, bovine serum albumin-coupled SPs (BSA-SPs) were used as a control treatment.

Fifteen minutes after oral challenge with WPE, mice treated with WPE-SP showed significantly decreased symptom scores compared with BSA-WP-treated mice.

In addition, WPE-SPs significantly prevented core temperature decreases commonly associated with anaphylaxis, and reduced mouse mast cell protease 1 - a product of mast cell activation - secretion into the serum, compared with BSA-SPs.

As in the allergic asthma model, WPE-SP treatment also significantly reduced systemic allergic responses.

The researchers also investigated whether Ag-SP could be used in a therapeutic context.

They administered the Ag-SP after the animals were sensitized to OVA or WE, and found that each respective treatment resulted in a significant reduction in Th2-mediated cytokine release.

Importantly, mice previously sensitized with WPE showed no anaphylactic symptoms upon treatment with WPE-SP.

"Collectively, our data demonstrate that Ag-SP treatment can induce protective Ag-specific tolerance in models of Th2-mediated immune responses and presents an attractive means of developing a safe and effective therapy to prevent and treat allergic disease," Miller and co-authors conclude in the Journal of Immunology.

By Laura Dean

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