Depigmented-polymerised allergoids favour regulatory over effector T cells: enhancement by 1α, 25-dihydroxyvitamin D3

Abstract

BackgroundAllergen immunotherapy (SIT) is the only treatment for allergic disease capable of modifying disease long term. To reduce the risk of anaphylaxis from SIT, allergen-extracts have been modified by polymerisation with glutaraldehyde to reduce IgE binding. It is suggested that these allergoid extracts also have reduced T cell activity, which could compromise clinical efficacy. Effective SIT is thought to act through regulatory T cells (Tregs) rather than activation of effector T cells. There is no published data on the activity of modified extracts on Tregs.ResultsWe compared the capacity of modified (depigmented-polymerised) versus unmodified (native) allergen extracts of grass pollen and house dust mite to stimulate proliferation/cytokine production and to modulate Treg/effector T cell frequency in cultures of peripheral blood mononuclear cells (PBMC), from volunteers sensitised to both allergens in vitro. Depigmented-polymerised allergen extracts stimulated less proliferation of PBMC, and reduced effector cell numbers after 7 days in culture than did native extracts. However, the frequency of Foxp3+ Tregs in cultures were similar to those seen with native extract so that ratios of regulatory to effector T cells were significantly increased in cultures stimulated with depigmented-polymerised extracts. Addition of 1α, 25-dihydroxyvitamin D3 further favoured Treg, and reduced effector cytokine production, but not interleukin-10.ConclusionsDepigmented-polymerised allergen extracts appear to favour Treg expansion over activation of effector T cells and this may relate to their demonstrated efficacy and safety in SIT. 1α, 25-dihydroxyvitamin D3 further reduces effector T cell activation by allergen extracts and may be a useful adjuvant for SIT.

Preclinical safety and immunological efficacy of Alternaria alternata polymerized extracts

“…TNF‐α and IFN‐γ presented a higher induction with NE than with ADP, which suggests a T cell shift to effector cells. Previous studies have also shown higher IFN‐γ titers in PBMCs from grass pollen and house dust mite atopic donors after stimulation with NE than after stimulation with depigmented‐polymerized extracts , manufactured in a similar way to ADP.…”

“…NE may favor CD4+ T cell shift to Th1 (higher IFN‐γ and TNF‐α), while ADP to Treg (IL‐10). Previous works also suggest that depigmented‐polymerized extracts induce a lower proliferation of effector T cells, which may contribute to side effects, than NE .…”

The Environment of Regulatory T Cell Biology: Cytokines, Metabolites, and the Microbiome

“…Furthermore, calcidiol (25-hydroxy vitamin D 3 ), a vitamin D metabolite similar to calcitriol, has been shown to prime mucosal DCs to induce suppressive IL-10 and IFN-γ producing Tr1 cells ( 127 ). A recent study has suggested that calcitriol could be a useful adjunct therapy with allergens in sublingual immunotherapy as it specifically enhanced Treg responses to allergens in vitro ( 137 ). It is interesting to note that, following treatment with UVB, MS patients had enhanced levels of serum calcitriol, which correlated with increased levels of circulating pTregs ( 138 ).…”

Indoor Allergens and Allergic Respiratory Disease

“…Hypoallergenic chemically modified extracts (allergoids) are successfully used in Europe for rhinitis, asthma, and atopic dermatitis. These include carbamylated allergoids and depigmented-polymerized extracts [115–117]. However, the Federal Drug Administration has not approved their use in the USA, because these preparations lack structurally well-defined molecules and are difficult to standardize.…”