Successful Milk Oral Immunotherapy Promotes Generation of Casein-Specific CD137+ FOXP3+ Regulatory T Cells Detectable in Peripheral Blood
BackgroundOral immunotherapy (OIT) is an emerging treatment for cow’s milk protein (CMP) allergy in children. The mechanisms driving tolerance following OIT are not well understood. Regulatory T cells (TREG) cells are key inhibitors of allergic responses and promoters of allergen-specific tolerance....
Guardado en:
| Autores principales: | , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Frontiers Media S.A.
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/f9b863f16fe24acabcc832c2ecdfd742 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:f9b863f16fe24acabcc832c2ecdfd742 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:f9b863f16fe24acabcc832c2ecdfd7422021-11-30T14:07:24ZSuccessful Milk Oral Immunotherapy Promotes Generation of Casein-Specific CD137+ FOXP3+ Regulatory T Cells Detectable in Peripheral Blood1664-322410.3389/fimmu.2021.705615https://doaj.org/article/f9b863f16fe24acabcc832c2ecdfd7422021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.705615/fullhttps://doaj.org/toc/1664-3224BackgroundOral immunotherapy (OIT) is an emerging treatment for cow’s milk protein (CMP) allergy in children. The mechanisms driving tolerance following OIT are not well understood. Regulatory T cells (TREG) cells are key inhibitors of allergic responses and promoters of allergen-specific tolerance. In an exploratory study, we sought to detect induction of allergen-specific TREG in a cohort of subjects undergoing OIT.MethodsPediatric patients with a history of allergic reaction to cow’s milk and a positive Skin Pick Test (SPT) and/or CMP-specific IgE >0.35 kU, as well as a positive oral challenge to CMP underwent OIT with escalating doses of milk and were followed for up to 6 months. At specific milestones during the dose escalation and maintenance phases, casein-specific CD4+ T cells were expanded from patient blood by culturing unfractionated PBMCs with casein in vitro. The CD4+ T cell phenotypes were quantified by flow cytometry.ResultsOur culture system induced activated casein-specific FOXP3+Helios+ TREG cells and FOXP3- TEFF cells, discriminated by expression of CD137 (4-1BB) and CD154 (CD40L) respectively. The frequency of casein-specific TREG cells increased significantly with escalating doses of milk during OIT while casein-specific TEFF cell frequencies remained constant. Moreover, expanded casein-specific TREG cells expressed higher levels of FOXP3 compared to polyclonal TREG cells, suggesting a more robust TREG phenotype. The induction of casein-specific TREG cells increased with successful CMP desensitization and correlated with increased frequencies of casein-specific Th1 cells among OIT subjects. The level of casein-specific TREG cells negatively correlated with the time required to reach the maintenance phase of desensitization.ConclusionsOverall, effective CMP-OIT successfully promoted the expansion of casein-specific, functionally-stable FOXP3+ TREG cells while mitigating Th2 responses in children receiving OIT. Our exploratory study proposes that an in vitro TREG response to casein may correlate with the time to reach maintenance in CMP-OIT.Yi ZhangLei LiGeneviève GenestWei ZhaoDan KeSabrina BartolucciSabrina BartolucciSabrina BartolucciNils PaveyNils PaveyNils PaveyTho-Alfakar Al-AubodahTho-Alfakar Al-AubodahTho-Alfakar Al-AubodahDuncan LejtenyiBahar TorabiBahar TorabiMoshe Ben-ShoshanBruce MazerBruce MazerBruce MazerCiriaco A. PiccirilloCiriaco A. PiccirilloCiriaco A. PiccirilloFrontiers Media S.A.articleallergymilk immunotherapyregulatory T cellsclinical trialtolerancedesensitizationImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
allergy milk immunotherapy regulatory T cells clinical trial tolerance desensitization Immunologic diseases. Allergy RC581-607 |
| spellingShingle |
allergy milk immunotherapy regulatory T cells clinical trial tolerance desensitization Immunologic diseases. Allergy RC581-607 Yi Zhang Lei Li Geneviève Genest Wei Zhao Dan Ke Sabrina Bartolucci Sabrina Bartolucci Sabrina Bartolucci Nils Pavey Nils Pavey Nils Pavey Tho-Alfakar Al-Aubodah Tho-Alfakar Al-Aubodah Tho-Alfakar Al-Aubodah Duncan Lejtenyi Bahar Torabi Bahar Torabi Moshe Ben-Shoshan Bruce Mazer Bruce Mazer Bruce Mazer Ciriaco A. Piccirillo Ciriaco A. Piccirillo Ciriaco A. Piccirillo Successful Milk Oral Immunotherapy Promotes Generation of Casein-Specific CD137+ FOXP3+ Regulatory T Cells Detectable in Peripheral Blood |
| description |
BackgroundOral immunotherapy (OIT) is an emerging treatment for cow’s milk protein (CMP) allergy in children. The mechanisms driving tolerance following OIT are not well understood. Regulatory T cells (TREG) cells are key inhibitors of allergic responses and promoters of allergen-specific tolerance. In an exploratory study, we sought to detect induction of allergen-specific TREG in a cohort of subjects undergoing OIT.MethodsPediatric patients with a history of allergic reaction to cow’s milk and a positive Skin Pick Test (SPT) and/or CMP-specific IgE >0.35 kU, as well as a positive oral challenge to CMP underwent OIT with escalating doses of milk and were followed for up to 6 months. At specific milestones during the dose escalation and maintenance phases, casein-specific CD4+ T cells were expanded from patient blood by culturing unfractionated PBMCs with casein in vitro. The CD4+ T cell phenotypes were quantified by flow cytometry.ResultsOur culture system induced activated casein-specific FOXP3+Helios+ TREG cells and FOXP3- TEFF cells, discriminated by expression of CD137 (4-1BB) and CD154 (CD40L) respectively. The frequency of casein-specific TREG cells increased significantly with escalating doses of milk during OIT while casein-specific TEFF cell frequencies remained constant. Moreover, expanded casein-specific TREG cells expressed higher levels of FOXP3 compared to polyclonal TREG cells, suggesting a more robust TREG phenotype. The induction of casein-specific TREG cells increased with successful CMP desensitization and correlated with increased frequencies of casein-specific Th1 cells among OIT subjects. The level of casein-specific TREG cells negatively correlated with the time required to reach the maintenance phase of desensitization.ConclusionsOverall, effective CMP-OIT successfully promoted the expansion of casein-specific, functionally-stable FOXP3+ TREG cells while mitigating Th2 responses in children receiving OIT. Our exploratory study proposes that an in vitro TREG response to casein may correlate with the time to reach maintenance in CMP-OIT. |
| format |
article |
| author |
Yi Zhang Lei Li Geneviève Genest Wei Zhao Dan Ke Sabrina Bartolucci Sabrina Bartolucci Sabrina Bartolucci Nils Pavey Nils Pavey Nils Pavey Tho-Alfakar Al-Aubodah Tho-Alfakar Al-Aubodah Tho-Alfakar Al-Aubodah Duncan Lejtenyi Bahar Torabi Bahar Torabi Moshe Ben-Shoshan Bruce Mazer Bruce Mazer Bruce Mazer Ciriaco A. Piccirillo Ciriaco A. Piccirillo Ciriaco A. Piccirillo |
| author_facet |
Yi Zhang Lei Li Geneviève Genest Wei Zhao Dan Ke Sabrina Bartolucci Sabrina Bartolucci Sabrina Bartolucci Nils Pavey Nils Pavey Nils Pavey Tho-Alfakar Al-Aubodah Tho-Alfakar Al-Aubodah Tho-Alfakar Al-Aubodah Duncan Lejtenyi Bahar Torabi Bahar Torabi Moshe Ben-Shoshan Bruce Mazer Bruce Mazer Bruce Mazer Ciriaco A. Piccirillo Ciriaco A. Piccirillo Ciriaco A. Piccirillo |
| author_sort |
Yi Zhang |
| title |
Successful Milk Oral Immunotherapy Promotes Generation of Casein-Specific CD137+ FOXP3+ Regulatory T Cells Detectable in Peripheral Blood |
| title_short |
Successful Milk Oral Immunotherapy Promotes Generation of Casein-Specific CD137+ FOXP3+ Regulatory T Cells Detectable in Peripheral Blood |
| title_full |
Successful Milk Oral Immunotherapy Promotes Generation of Casein-Specific CD137+ FOXP3+ Regulatory T Cells Detectable in Peripheral Blood |
| title_fullStr |
Successful Milk Oral Immunotherapy Promotes Generation of Casein-Specific CD137+ FOXP3+ Regulatory T Cells Detectable in Peripheral Blood |
| title_full_unstemmed |
Successful Milk Oral Immunotherapy Promotes Generation of Casein-Specific CD137+ FOXP3+ Regulatory T Cells Detectable in Peripheral Blood |
| title_sort |
successful milk oral immunotherapy promotes generation of casein-specific cd137+ foxp3+ regulatory t cells detectable in peripheral blood |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/f9b863f16fe24acabcc832c2ecdfd742 |
| work_keys_str_mv |
AT yizhang successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT leili successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT genevievegenest successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT weizhao successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT danke successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT sabrinabartolucci successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT sabrinabartolucci successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT sabrinabartolucci successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT nilspavey successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT nilspavey successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT nilspavey successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT thoalfakaralaubodah successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT thoalfakaralaubodah successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT thoalfakaralaubodah successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT duncanlejtenyi successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT bahartorabi successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT bahartorabi successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT moshebenshoshan successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT brucemazer successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT brucemazer successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT brucemazer successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT ciriacoapiccirillo successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT ciriacoapiccirillo successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood AT ciriacoapiccirillo successfulmilkoralimmunotherapypromotesgenerationofcaseinspecificcd137foxp3regulatorytcellsdetectableinperipheralblood |
| _version_ |
1718406540981960704 |