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. 2016 Aug 5:14:7.
doi: 10.1186/s12948-016-0044-1. eCollection 2016.

Vitamin D3 improves the effects of low dose Der p 2 allergoid treatment in Der p 2 sensitized BALB/c mice

Claudia Petrarca  1 , Emanuela Clemente  2 , Valentina Amato  1 , Alessia Gatta  2 , Sara Cortese  2 , Alessia Lamolinara  3 , Cosmo Rossi  4 , Stefania Zanotta  5 , Gianni Mistrello  5 , Roberto Paganelli  2 , Mario Di Gioacchino  6
Affiliations

Vitamin D3 improves the effects of low dose Der p 2 allergoid treatment in Der p 2 sensitized BALB/c mice

Claudia Petrarca et al. Clin Mol Allergy. .

Abstract

Background: Airborne allergens can induce an immunological chronic disease characterized by airway hyper responsiveness and inflammation, mediated by exaggerated Th2 immune response. Allergen-specific immunotherapy (AIT) is effective for treating this condition because it is able to modify its natural course by opposing the underlying pathogenic mechanisms and determining immune suppression, immune deviation and tolerance. The rational for the present study was to investigate the possibility of improving allergoid-based IT in terms of efficacy and safety. Recently, 1α,25-dihydroxyvitamin D3 (VD3), the active metabolite of vitamin D3, was described to be a potent inducer of T regulatory cells and to be a good adjuvant in AIT settings.

Methods: We investigated whether the co-administration of VD3 could potentiate the effect of AIT even when added to a low dose of chemically-modified monomeric allergoid of Der p 2 (d2-OID), in a Derp p 2 (d2)-sensitized BALB/c mice model. Control groups where treated with sham, VD3 alone or d2-OID only.

Results: The d2-OID alone was not fully successful, as expected for a low dose. VD3 administration was associated with some valuable, although limited, changes in the immunological parameters in the lung. On the contrary, the VD3 adjuvated allergoid vaccine induced the most prominent reduction of airway eosinophilia and Th2 cytokines and concomitant increase of T regulatory cells and IL-10 in the lung and Der p 2-specific IgG2a in the serum.

Conclusions: The addition of VD3 to a conventional AIT protocol would allow the reduction of allergoid dose needed and therefore, the production costs. Moreover, beneficial immunomodulatory effects have been achieved by the oral administration which might favour the management of the therapy by the patients and their adherence, possibly enhancing the efficacy of the treatment.

Keywords: Allergen immunotherapy; Allergoid; Allergy; Asthma; Der p 2; Eosinophils; IL-10; IgE; T regulatory cells; Vitamin D3.

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Figures

Fig. 1
Fig. 1
Evaluation of the allergic sensitization state in mice. Detection of total and anti-d2 specific serum IgE to evaluate the occurrence of allergic sensitization in mice. The mice were sensitized by 2 i.p. with 1 µg of recombinant d2, and the level of IgE in serum was measured 1 week after the last i.p. Significantly higher total IgE (a) and d2-specific IgE (b) levels are found in serum of sensitized mice compared with naïve mice. Values are expressed as mean ± SD (n = 4). **p < 0.01 compared with naive mice
Fig. 2
Fig. 2
Serum levels of d2-specific antibodies. Specific antibodies levels in serum were measured by ELISA 48 h after the last HDM aerosol challenge, to determine the effect of different treatments on the humoral response. d2-specific IgG2a level was most significantly increased in the d2-OID + VD3 group compared to sham- and d2-OID-treated mice (p < 0.01). Values are expressed as mean ± SD (n = 12). *p < 0.05; **p < 0.01
Fig. 3
Fig. 3
Treatment-induced modulation of cytokines’ levels in BALF. The levels of IL-4, IL-13, IL-10, INF-γ in BALF were measured by ELISA. The conventional low dose IT with d2-OID or the sole VD3 administration induced decrease of IL-4 (a) and increase in IL-10 (c) and no change in the level of IL-13 and IFN-γ. Only the association d2-OID + VD3 produced the highest modification of these cytokines, well-matched with the resolution of the allergic inflammation, induction of tolerance and immune deviation: in fact, IL-4 (a) and IL-13 (b), were significantly lower and IL-10 (c) and IFN-γ (d) were significantly higher, compared with all the other groups. Values are expressed as mean ± SD (n = 12). *p < 0.05, **p < 0.01, ***p < 0.001
Fig. 4
Fig. 4
Frequency of Tregs in spleen cells. Flow cytometry data showing the percentage of FoxP3+CD25+ cells on gated CD4+ cells of total spleen cells. The d2-OID treatment produced an increase of this subpopulation of regulatory cells (p < 0.05 vs sham) but not as high as for the other groups of treatment. Either VD3 or d2-OID administration induced the highest increase in FoxP3+CD25+ cells, compared with sham (p < 0.01, for both groups) or d2-OID (p < 0.05, for both groups). Values are expressed as mean ± SD (n = 12). *p < 0.05 and **p < 0.01
Fig. 5
Fig. 5
Abundance of T regulatory cells in lung tissue. A significant comparable increase in FoxP3+:CD3+ cells ratio was induced by d2-OID and VD3 treatments (p < 0.05 vs sham); the combination treatment d2-OID + VD3 was even more efficacious in inducing such an increase (p < 0.001 vs sham, p < 0.01 vs d2-OID and VD3 treatments) Values are expressed as mean ± SD (n = 7). ***p < 0.001 **p < 0.01. *p < 0.05
Fig. 6
Fig. 6
Eosinophils abundance in BALF. The frequency of eosinophils cells in total BALF cells showed a trend in diminution following d2-OID treatment, but it was significantly decreased only with the treatments VD3 (p = 0.02 vs sham and p = 0.05 vs d2-OID) and d2-OID + VD3 (p = 0.01 compared with sham and p = 0.02 vs d2-OID). The d2-OID + VD3 induced a further decrease in eosinophils at the limit of significance, compared to VD3 (p = 0.051). Values are expressed as mean ± SD (n = 7)
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