Role of IL-35 in sublingual allergen immunotherapy

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Presentation transcript:

Role of IL-35 in sublingual allergen immunotherapy Mohamed H. Shamji, PhD, FAAAAI, Janice A. Layhadi, PhD, Daniela Achkova, MSc, Lubna Kouser, PhD, Alan Perera-Webb, MSc, Natália C. Couto-Francisco, MSc, Rebecca V. Parkin, BSc, Tomokazu Matsuoka, MD, PhD, Guy Scadding, MD, Philip G. Ashton- Rickardt, PhD, Stephen R. Durham, MD, FRCP Journal of Allergy and Clinical Immunology Volume 143, Issue 3, Pages 1131-1142.e4 (March 2019) DOI: 10.1016/j.jaci.2018.06.041 Copyright © 2018 The Authors Terms and Conditions

Journal of Allergy and Clinical Immunology 2019 143, 1131-1142 Journal of Allergy and Clinical Immunology 2019 143, 1131-1142.e4DOI: (10.1016/j.jaci.2018.06.041) Copyright © 2018 The Authors Terms and Conditions

Fig 1 IL-35 suppresses proallergic cytokine (IL-5 and IL-13) production by ILC2s after IL-25 and IL-33 ex vivo stimulation. A and B, Proportions of Lin−CD127+CRTH2+ cells (ILC2s) were quantified in PBMCs obtained from patients with grass pollen allergy (SAR group, n = 12) and NACs (n = 12). C, IL-5+, IL-13+, and IL-5+IL-13+ ILC2s were also quantified in both groups. D-F, ILC2s were sorted by means of fluorescence-activated cell sorting and stimulated with IL-25 and IL-33 in the presence/absence of IL-35. IL-5 and IL-13 levels are shown. P values were determined by using the Mann-Whitney U test or Wilcoxon matched-pairs signed-rank test: *P < .05 and **P < .001. Journal of Allergy and Clinical Immunology 2019 143, 1131-1142.e4DOI: (10.1016/j.jaci.2018.06.041) Copyright © 2018 The Authors Terms and Conditions

Fig 2 IL-35 suppresses grass pollen allergen–driven TH2 effector cell proliferation and cytokine responses. A, CD4+CD25− T cells were cocultured with APCs and stimulated with P pratense allergen in the presence of IL-35. Proliferation was assessed by using tritiated thymidine incorporation. B and C, Effect of IL-35 on allergen-driven production of TH2 cytokines (Fig 2, B) and TH1 cytokines and IL-10 (Fig 2, C). D-F, Effects of IL-35 were also assessed on TH2 clone proliferation (Fig 2, D); IL5, IL13, and IFNG mRNA expression (Fig 2, E), and GATA3 expression (Fig 2, F). G-I, Effects of IL-35 on TH1 clone proliferation (Fig 2, G), cytokine production (Fig 2, H), and T-bet mRNA expression (Fig 2, I) were assessed. P values were determined by using the Wilcoxon matched-pairs signed-rank test: *P < .05, **P < .001, and ***P < .0001. Journal of Allergy and Clinical Immunology 2019 143, 1131-1142.e4DOI: (10.1016/j.jaci.2018.06.041) Copyright © 2018 The Authors Terms and Conditions

Fig 3 IL-35–treated Teff cells inhibit grass pollen–driven TH2 effector cell responses, and this is reversed by neutralizing anti–IL-35. CD4+CD25− T cells were enriched from PBMCs obtained from patients with grass pollen allergy (n = 12) and treated with IL-35 or control for 9 days. IL-35− or control-treated T cells were cocultured with autologous CD4+CD25− T cells or APCs in the presence of P pratense allergen supplemented with neutralizing anti–IL-35 antibody. Allergen-driven TH2 cell proliferation (A) and IL-4, IL-5, IL-13, and IL-17 responses (B) were measured. P values were determined by using the Wilcoxon matched-pairs signed-rank test: *P < .05, **P < .001, and ***P < .0001. Journal of Allergy and Clinical Immunology 2019 143, 1131-1142.e4DOI: (10.1016/j.jaci.2018.06.041) Copyright © 2018 The Authors Terms and Conditions

Fig 4 IL-35 polarizes naive T cells into the iTR35 phenotype. A, Naive and memory T cells were enriched from PBMCs of patients with grass pollen allergy (n = 12). Naive T cells were stimulated with CD3/CD28 and treated with IL-35 to allow generation of iTR35 cells. mRNA expression of IL12A and EBI3 were confirmed in iTR35 and control cells. B, IL-35 protein levels were quantified in iTR35 and control cells. C, Allergen-driven memory TH2 cell proliferation was assessed. D, Relationship between suppression of proliferation and IL-35 levels. E, Effects of iTR35 and control cells on memory TH2 cytokine responses. F, IL-35 exerts its action on Teff cells through STAT1 and STAT4 signaling. P values were determined by using the Wilcoxon matched-pairs signed-rank test: *P < .05, **P < .001, and ***P < .0001. Journal of Allergy and Clinical Immunology 2019 143, 1131-1142.e4DOI: (10.1016/j.jaci.2018.06.041) Copyright © 2018 The Authors Terms and Conditions

Fig 5 IL-35 suppresses CD40L/IL-4/IL-21–driven IgE production in PBMCs from patients with grass pollen allergy. A, Total IgE production from B cells in the presence or absence of IL-4, CD40L, and IL-21 was measured in cell-culture supernatants. B, Total IgE production by B cells with or without IL-4, CD40L, and IL-21. C, Effect of CD40L, IL-4, and IL-21 on IgE production in the presence of IL-35–neutralizing antibodies. P values were determined by using the Wilcoxon matched-pairs signed-rank test: *P < .05 and **P < .001. nAb, Neutralizing antibody; TCM, tissue culture medium. Journal of Allergy and Clinical Immunology 2019 143, 1131-1142.e4DOI: (10.1016/j.jaci.2018.06.041) Copyright © 2018 The Authors Terms and Conditions

Fig 6 Effect of IL-35 on proliferation and cytokine production. DCs and naive T cells were obtained from PBMCs of patients with allergic rhinitis. A, TSLP-, IL-25–, and IL-33–primed DCs were challenged with or without allergen to determine T-cell proliferation. B and C, Allergen-driven IL-5 (Fig 6, B) and IL-13 (Fig 6, C) secretion was measured in the presence or absence of TSLP. D-F, Suppressive effect of IL-35 on naive T-cell proliferation (Fig 6, D) and TH2-driven cytokine production of IL-5 (Fig 6, E) and IL-13 (Fig 6, F). P values were determined by using the Wilcoxon matched-pairs signed-rank test: *P < .05, **P < .001, and ***P < .0001. TCM, Tissue culture medium. Journal of Allergy and Clinical Immunology 2019 143, 1131-1142.e4DOI: (10.1016/j.jaci.2018.06.041) Copyright © 2018 The Authors Terms and Conditions

Fig 7 IL-35 levels and iTR35 cell counts were increased in the SLIT-treated group and NACs but not the SAR group. A, RTSSs were evaluated in the SLIT (n = 16), SAR (n = 16), and NAC (n = 16) groups. B and C, iTR35 cells (IL-35+CD4+CD25+) were quantified in PBMCs obtained from each group by using flow cytometry. D, IL-35 levels were measured in supernatants of CD4+ T cells cocultured with APCs and P pratense. E, Correlation between IL-35 levels and iTR35 cell counts. F and G, RTSSs correlated with IL-35 levels and iTR35 counts. P values were determined by using the Mann-Whitney U test: ***P < .0001. Symbols represent individual patients, and horizontal bars represent means. Correlation was determined by using the Spearman rank method. Journal of Allergy and Clinical Immunology 2019 143, 1131-1142.e4DOI: (10.1016/j.jaci.2018.06.041) Copyright © 2018 The Authors Terms and Conditions

Fig E1 Patient recruitment flow chart. Sixteen NACs, 16 patients with SAR, and 16 SLIT-treated patients were recruited for this study. Blood samples were collected during the grass pollen season (May-July). Averages of RTSSs and T-cell responses are presented as means ± SEMs. Journal of Allergy and Clinical Immunology 2019 143, 1131-1142.e4DOI: (10.1016/j.jaci.2018.06.041) Copyright © 2018 The Authors Terms and Conditions

Fig E2 Recombinant IL-35 but not the C-peptide linker used for its expression (control) suppresses grass pollen allergen–driven TH2 effector cell proliferation and cytokine responses. A, CD4+CD25− Teff cells were cocultured with irradiated APCs and stimulated with P pratense allergen in the presence of IL-35 or control. Proliferation was assessed. B and C, TH2 (Fig E2, B) and TH1 and IL-10 (Fig E2, C). P values were determined by using the Mann-Whitney U test: *P < .05, **P < .001, and ***P < .0001. Journal of Allergy and Clinical Immunology 2019 143, 1131-1142.e4DOI: (10.1016/j.jaci.2018.06.041) Copyright © 2018 The Authors Terms and Conditions