Notch signaling contributes to the establishment of sustained unresponsiveness to food allergens by oral immunotherapy - 04/03/21
, Mutsuko Hara, PhD b, Hiromichi Yamada, MD a, Kumi Izawa, MD, PhD b, Koichiro Uchida, MD, PhD c, Ayako Kaitani, PhD b, Tomoaki Ando, MD, PhD b, Jiro Kitaura, MD, PhD b, Yoshikazu Ohtsuka, MD, PhD a, Hideoki Ogawa, MD, PhD b, Ko Okumura, MD, PhD b, Toshiaki Shimizu, MD, PhD aAbstract |
Background |
Oral immunotherapy (OIT) aims to establish desensitization and sustained unresponsiveness (SU) in patients with food allergy by ingestion of gradually increasing doses of specific food allergens. However, little is known about the mechanisms by which OIT induces SU to specific allergens.
Objectives |
We investigated the role of Notch signaling, which controls cell fate decisions in many types of immune cells in the induction of SU by OIT treatment.
Methods |
Two types of mouse models, ovalbumin-induced food allergy and OIT, were generated. To elucidate the role of Notch signaling in OIT-induced SU, mice were intraperitoneally injected with the Notch signaling inhibitor N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenylglycine-1,1-dimethylethyl ester during the OIT treatment period.
Results |
Ovalbumin-sensitized mice were desensitized and also had SU induced by OIT treatment, whereas repeated challenges with ovalbumin caused the development of severe allergic reactions in ovalbumin-sensitized mice. Administration of N-[(3,5-difluorophenyl)acetyl]-l-alanyl-2-phenylglycine-1,1-dimethylethyl ester to mice during the OIT treatment period inhibited the establishment of SU to ovalbumin but did not affect the induction of desensitization. OIT induced a systemic expansion of IL-10–producing CD4+ T cells, including TH2 cells, and myeloid-derived suppressor cells (MDSCs), particularly the monocytic MDSC subpopulation. Inhibition of Notch signaling prevented the OIT-induced expansion of those cells. In vitro cultures of bone marrow cells showed that Notch signaling directly promoted the generation of monocytic MDSCs. In addition, the contribution of MDSCs to OIT-induced SU was confirmed by MDSC depletion with the anti-Gr1 antibody.
Conclusion |
Notch signaling contributes to the establishment of SU induced by OIT through systemic expansion of immunosuppressive cells, such as IL-10–producing CD4+ T cells and MDSCs.
Il testo completo di questo articolo è disponibile in PDF.Graphical abstract |
Key words : Food allergy, oral immunotherapy, sustained unresponsiveness, Notch signaling, myeloid-derived suppressor cell
Abbreviations used : DAPT, DLL1, iNOS, LP, MDSC, Mo-MDSC, OFC, OIT, PMN-MDSC, SU, Treg
Mappa
| Supported in part by the Ministry of Education, Culture, Sports, Science and Technology Grants-in-Aid for Scientific Research program (grant 18K08416) and Research Grant 2018 from the Foundation for Dietary Scientific Research. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 3
P. 1063 - Marzo 2021 Ritorno al numero
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