Induction of anergic allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites

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Induction of anergic allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites Valentina Pacciani, PhD, Silvia Gregori, PhD, Loredana Chini, MD, Stefania Corrente, MD, Marco Chianca, MD, Viviana Moschese, MD, Paolo Rossi, MD, PhD, Maria Grazia Roncarolo, MD, Federica Angelini, MD, PhD Journal of Allergy and Clinical Immunology Volume 125, Issue 3, Pages 727-736 (March 2010) DOI: 10.1016/j.jaci.2009.12.004 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Der p 2 induces partial maturation of DCs, and Der p 2–pulsed DCs promote allergen-specific T-cell proliferation. A, CD14– cells from patients with HDM allergy were stimulated with autologous iDCs, DCs pulsed with Der p 2 (1 μg/mL; Dp2-DCs), DCs matured with LPS (1 μg/mL; LPS-DCs), or DCs pulsed with Der p 2 and matured with LPS (LPS-Dp2-DCs) at a ratio of 10:1. Proliferative responses were evaluated after 5 days of culture. One representative patient of the 3 analyzed is shown. B, CD86 expression on iDCs, Dp2-DCs, or LPS-Dp2-DCs was evaluated by flow cytometry analysis. Numbers represent the percentages of positive cells and the MFI. Data from 1 representative patient of 8 patients tested are presented. Journal of Allergy and Clinical Immunology 2010 125, 727-736DOI: (10.1016/j.jaci.2009.12.004) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Dp2-DCs induce a TH2-cell response in patients who are allergic to HDM (HDM patients) but not in healthy controls. A, CD14– cells from HDM patients and controls were stimulated with autologous Dp2-DCs at a ratio of 10:1. Results are expressed as SI. The horizontal bars indicate the means. A responder was defined any patient displaying a SI greater than or equal to the mean SI + 2 SDs, obtained by stimulating T cells of healthy controls with autologous Dp2-DCs. The cutoff value was set at 1.4. B, Production of IL-5 (n = 20), IL-13 (n = 18), and IFN-γ (n = 7; means ± SEMs) by T(iDC) and T(Dp2-DC) cells. Culture supernatants were collected after 5 days, and cytokine production was determined by the Bioplex Protein Array system. Journal of Allergy and Clinical Immunology 2010 125, 727-736DOI: (10.1016/j.jaci.2009.12.004) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 IL-10–DCs and DC-10s are phenotypically and functionally different. A, Monocyte-derived DCs were differentiated by incubation with IL-4 and GM-CSF for 5 days and then incubated with IL-10 (40 ng/mL) for an additional 2 days (IL-10–DCs), or with IL-4 and GM-CSF in the presence of IL-10 for 7 days (10 ng/mL; DC-10s). As a control, DCs were cultured for an additional 2 days with (mDCs) or without LPS (iDCs). Expression levels of CD14, CD1a, HLA DR, CD80, CD83 and CD86 were evaluated by flow cytometry. Data from 1 representative donor of 4 tested are presented. B, iDCs, IL-10–DCs, DC-10s, and mDCs were cultured alone or activated with IFN-γ (50 ng/mL) and LPS (1 μg/mL). Culture supernatants were collected after 48 hours, and cytokine levels were determined by ELISA in 4 independent experiments. C, Naive CD4+ T cells were stimulated with allogenic iDCs, DC-10s, IL-10–DCs, and mDCs at a ratio of 10:1. Proliferative responses were evaluated 4 days after culture. Numbers represent the percentage of inhibition of proliferation of T cells primed with IL-10–DCs or DC-10s compared with proliferation of T cells stimulated with mDCs. Results from 1 representative donor of 6 tested are shown. Journal of Allergy and Clinical Immunology 2010 125, 727-736DOI: (10.1016/j.jaci.2009.12.004) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Dp2–IL-10–DCs and Dp2–DC-10s inhibit Der p 2–specific T-cell responses. T cells from HDM patients were stimulated with autologous Dp2-DCs (T[Dp2-DCs]), IL-10–Dp2–DCs (T[Dp2–IL-10–DCs]), or Dp2–DC-10s (T[Dp2–DC-10s]) at a ratio of 10:1. A, Proliferative responses were evaluated after 5 days of culture. Dots represent each individual patient, and bars represent the means of cpm. B, Cytokine production was determined in T-DC cell culture supernatants by the Bioplex Protein Array system. Results relative to T(Dp2–IL-10–DCs) and T(Dp2–DC-10s) are shown in the left and right panels, respectively, for each patient. Horizontal bars represent the mean cytokine production values. IL-5 production by T(Dp2–IL-10–DCs) versus T(Dp2-DCs), P = .04; by T(Dp2–DC-10s) versus T(Dp2-DCs), P = .015. IL-13 production, P = NS. Journal of Allergy and Clinical Immunology 2010 125, 727-736DOI: (10.1016/j.jaci.2009.12.004) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Dp2–DC-10s induce allergen-specific T-cell anergy. A, CD14– cells from HDM patients were stimulated with autologous Dp2-DCs (T[Dp2-DCs]) or Dp2–DC-10s (T[Dp2–DC-10s]) for 14 days. After stimulation, T-cell lines were collected and tested for their ability to proliferate in response to autologous CD14+ cells pulsed with Der p 2 (1 μg/mL) at a ratio of 1:1. Two days later, proliferation was evaluated. Proliferative responses of 16 HDM experiments are shown. Means of triplicates ± SDs and percentages of anergic cells are presented for each patient; n.i., anergy not induced. Average allergen-induced proliferation of T(Dp2–DC-10s) versus T(Dp2-DCs), P = .0026 (n = 16). B, Levels of IL-5, IL-13, IFN-γ, and TNF-α in culture supernatants were determined by the Bioplex Protein Array system. The cytokine profile of each patient is shown, and the horizontal bars represent the mean values. T(Dp2–DC-10s) versus T(Dp2-DCs), IL-5 production, P = .05; IL-13 production, P = .003; IFN-γ production, P = NS; and TNF-α production, P = NS; n = 15. C, Induction of T-cell anergy by Dp2-DCs is allergen-specific. The proliferative responses of cells from 3 patients, in which anergy was induced, are shown on restimulation of T(Dp2–DC-10s) with either Der p 2 (1 μg/mL) or HSV1 (0.5 μg/mL) in the presence of autologous monocytes. Journal of Allergy and Clinical Immunology 2010 125, 727-736DOI: (10.1016/j.jaci.2009.12.004) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Dp2–DC-10s induce allergen-specific Tr1 cells. CD14– cells from HDM patients were stimulated with autologous Dp2-DCs (T[Dp2-DCs]) or Dp2–DC-10s (T[Dp2–DC-10s]) for 14 days. T(Dp2-DC)–cell lines were cultured with autologous CD14+ pulsed with Der p 2 (1 μg/mL) in the presence or absence of autologous T(Dp2–DC-10) cell lines at a ratio of 1:1. A, Culture supernatants were collected after 3 days of culture; levels of IL-5 and IL-13 were measured by using the Bioplex Protein Array system. Numbers represent the percentage suppression of cytokine production in T(Dp2-DCs) cocultured in the presence of T(Dp2–DC-10s) compared with T(Dp2-DCs) alone (IL-5, P = .08; IL-13, P = .02; n = 5). B, T(Dp2–DC-10) cells suppress cytokine production of T(Dp2-DC) cells partially via IL-10 and TGF-β. T(Dp2–DC-10) cell lines were tested for their ability to suppress cytokine production by allergen-specific T cells in response to autologous CD14+ cells pulsed with Der p 2 (1 μg/mL) in the absence or presence of mAbs against IL-10R (30 μg/mL) and TGF-β (50 μg/mL). Levels of IL-5 and IL-13 were measured in culture supernatants after 3 days of culture. Numbers represent the suppression rate of cytokine production in T(Dp2-DC) cells cocultured with T(Dp2–DC-10) cells, with or without mAbs against IL-10R and TGF-β, compared with T(Dp2-DC) cells alone (reversion of IL-5, P = NS; reversion of IL-13, P = .05; n = 3). Journal of Allergy and Clinical Immunology 2010 125, 727-736DOI: (10.1016/j.jaci.2009.12.004) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions