18 Feb 2020

Findings may boost hay fever therapy

L-R: Dr Craig McKenzie, Prof Robyn O'Hehir,
Associate Professor Menno van Zelm
by Anne Crawford

Allergen immunotherapy is the only treatment to modify the natural course of allergy to ryegrass pollen – or spring hay fever – rather than just alleviating symptoms. Treatment involves repeated exposure of patients to allergen extracts either by injection or tablet, ‘training’ the immune system to clear these allergens without generating an allergic response.

But it’s not known exactly how this immunotherapy works.

Central Clinical School researchers have added a piece to this puzzle with the finding that one antibody in particular, subclass IgG2, could be more important than previously thought in the allergen-specific immunotherapy. Their study, published in Allergy, yielded findings that may prove beneficial in both administering the treatment and improving the treatment itself.

The study was led by Associate Professor Menno van Zelm from the Department of Immunology and Pathology and Professor Robyn O'Hehir AO who heads the Department of Allergy, Clinical Immunology and Respiratory Medicine. First co-authors are the Department of Immunology and Pathology’s Dr Craig McKenzie and Dr Jorn Heeringa, Erasmus University Medical Center (Erasmus MC), the Netherlands.

Ryegrass pollen allergy is the major cause of seasonal allergic rhinitis in south-eastern Australia, affecting about 15% of the population, or 3.1 million people.

The researchers recruited 29 patients from the Alfred Allergy Clinic. The participants were administered a commercially available immunotherapy sublingually (under the tongue) in four-month regimens over two or three consecutive years, avoiding the pollen season in Melbourne so they weren’t exposed to unpredictably high levels of additional pollen allergens during the season, and in line with the proven effective regimen for injection immunotherapy.

The study found that the therapy was effective in alleviating symptoms after only four months although three-year regimens are needed for sustained benefit.

“The clinical improvement was quite dramatic,” Dr McKenzie said. “When we asked the patients how severe the symptoms were out of 100, this dropped from 80 to 30 – that’s quite a significant drop,” he said. Exhaled nitric oxide levels also fell after the therapy; high levels of exhaled nitric oxide in the breath can mean the airways are inflamed.

Importantly, the thunderstorm asthma event in November 2016 occurred while these patients were on the therapy and none of them had an exacerbation of their allergic symptoms on the day, Dr McKenzie said. This was in stark contrast to large numbers of patients with allergic rhinitis who were not on treatment and presented with asthma symptoms in emergency care, suggesting the treatment could help protect against such an event, he said.

The study results show that the immunotherapy increased allergen-specific IgG2 and IgG4 serum levels, and proportions of IgG2- and IgG4-expressing memory B cells.

“The increase in IgG4 was consistent with what had been found before but not so IgG2 – that’s something new,” Associate Professor van Zelm said. “Most of the time it’s not included in analyses.”

The paper suggests that skewing the treatment toward the anti‐inflammatory IgG2 and IgG4 might be a way of suppressing IgE-mediated allergic responses. The immunotherapy, a readily available tablet, also increased proportions of the regulatory T cells specific to ryegrass pollen.

“What was also intriguing for us was that IgG4 goes up quickly, and that’s what’s been seen before, but IgG2 takes some time,” Associate Professor van Zelm said. “It was only after three years that there was a significant increase in IgG2 – and that’s exactly the minimal amount of treatment required for a long-term benefit.

“Maybe we could sharpen the focus on getting IgG2 up earlier and thereby optimise treatment,” he said.

However, Associate Professor van Zelm cautioned that the findings were correlative, not causative. “The findings are exciting but we will need to follow up formally to prove cause and effect first. Then maybe we could find ways to manipulate the response in cells.”

Professor O’Hehir added, “Although it is accepted widely that allergen immunotherapy is the only treatment to alter the natural course of allergic diseases, it is under-utilised. A better definition of the mechanisms and identification of biomarkers of efficacy will hopefully encourage greater uptake of this treatment modality.”

Heeringa JJ, McKenzie CI, Varese N, Hew M, Bakx ATCM, Aui PM, Rolland JM, O'Hehir RE, van Zelm MC. Induction of IgG2 and IgG4 B-cell memory following sublingual immunotherapy for ryegrass pollen allergy. Allergy. 2019 Oct 6. doi: 10.1111/all.14073. [Epub ahead of print]

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