Lung-derived innate cytokines: new epigenetic targets of allergen-specific sublingual immunotherapy.
OBJECTIVE
Sublingual allergen-specific immunotherapy is a safe and effective method for treatment of IgE-mediated respiratory allergies; however, the underlying mechanisms are not fully understood. This study was planned to test whether sublingual immunotherapy (SLIT) can exert epigenetic mechanisms through which the airway allergic responses can be extinguished.


METHODS
BALB/c mice were sensitized intraperitoneally and challenged intranasally. Then, they received sublingual treatment with recombinant Che a 2 (rChe a 2), a major allergen of Chenopodium album. After SLIT, allergen-specific antibodies in sera, cytokine profiles of spleen cell cultures, mRNA and protein expression of lung-derived IL-33, IL-25, and TSLP (thymic stromal lymphopoietin), and histone modifications of these three genes were assessed.


RESULTS
Following Immunotherapy, systemic immune responses shifted from Th2 to Th1 profile as demonstrated by significant decrease in IgE and IL-4 and substantial increase in IgG2a and IFN-γ. At local site, mRNA and protein levels of lung-derived pro-inflammatory cytokines IL-33 and TSLP were markedly down-regulated following SLIT that was associated with marked enrichment of trimethylated lysine 27 of histone H3 at promoter regions of these two cytokines.


CONCLUSIONS
In our study, sublingual immunotherapy with recombinant allergen effectively attenuated allergic immune responses, at least partly, by induction of distinct histone modifications at specific loci. Additionally, the lung-derived pro-allergic cytokines IL-33 and TSLP could be promising mucosal candidates for either monitoring allergic conditions or therapeutic approaches.
School of Medicine, Zabol University of Medical Sciences, Zabol, Iran; Student Research Committee, Immunology Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran.
Abbas
A
Pishdadian
Allergy Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran.
Abdolreza
A
Varasteh
Division of Human Genetics, Immunology Research Center, Avicenna Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
Mehran
M
Gholamin
Department of Food Science, Nour Branch, Islamic Azad University, Nour, Iran.
Leila Roozbeh
LR
Nasiraie
Immunology Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran.
Mitra
M
Hosseinpour
Immunology Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran.
Malihe
M
Moghadam
Immunology Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran.
Mojtaba
M
Sankian
Chenopodium album Histone modifications; IL-25; IL-33; Sublingual mmunotherapy; TSLP