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Intravenous immunoglobulin attenuates airway inflammation through induction of forkhead box protein 3–positive regulatory T cells  Amir H. Massoud, MSc,

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Presentation on theme: "Intravenous immunoglobulin attenuates airway inflammation through induction of forkhead box protein 3–positive regulatory T cells  Amir H. Massoud, MSc,"— Presentation transcript:

1 Intravenous immunoglobulin attenuates airway inflammation through induction of forkhead box protein 3–positive regulatory T cells  Amir H. Massoud, MSc, Julie Guay, BSc, Karim H. Shalaby, PhD, Eva Bjur, PhD, Aidan Ablona, BSc, Daniel Chan, BSc, Yasaman Nouhi, MSc, Christine T. McCusker, MD, M. Walid Mourad, PhD, Ciriaco A. Piccirillo, PhD, Bruce D. Mazer, MD  Journal of Allergy and Clinical Immunology  Volume 129, Issue 6, Pages e3 (June 2012) DOI: /j.jaci Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 IVIG induces de novo Treg cells from Foxp3− T cells. Representative flow cytometric analysis of endogenous host Treg cells stained with anti-Foxp3 antibodies conjugated to APC (Foxp3APC+GFP−) and induced donor Foxp3APC+GFP+ Treg cells within the lungs of mice with allergic airways disease is shown. A, Frequency of (host) Foxp3APC+GFP− Treg cells and (donor) Foxp3APC+GFP+ cells. OVA-IVIG-OVA treatment induced Treg cells from Foxp3GFP− precursors. Results are representative of 3 identical studies (n = 9 for each condition). B, Bar graphs demonstrating the fold increase of induced Foxp3GFP+ cells among all Treg cells within spleens, dLNs, and lungs. ∗P < .05. Results represent 3 identical experiments with 9 mice in each group. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 IVIG-induced Treg cells are greatly enriched in inflamed pulmonary tissues. Immunohistopathologic analysis of donor Foxp3GFP+ cells in lung sections by using anti-GFP antibody. A, Control (PBS-HSA-PBS) mice, B and C, OVA-IVIG-OVA mice (Fig 2, C) have decreased mononuclear cell infiltration compared with OVA-HSA-OVA mice (Fig 2, B). Within the mononuclear infiltrate, the frequency of induced GFP+ Treg cells in OVA-IVIG-OVA (Fig 2, C) mice is increased compared with that seen in the other groups. D, Histogram indicating the percentage of Treg cells within the mononuclear cell infiltrate (MNC) from each condition. Slides were prepared from 6 lungs for each experimental condition, representing 3 experiments. E, CD62 ligand (CD62L) expression was assessed on Treg cells from lungs and dLNs by using flow cytometry. IVIG-treated mice had diminished CD62 ligand expression on Treg cells in lungs compared with that seen in LNs. F, The expression of CCR4 was determined as above. Treg cell populations within the lungs of OVA-IVIG-OVA mice had significantly higher CCR4 expression than those in dLNs and compared with Treg cells in all other experimental conditions. ∗P < .05. Representative of 2 separate experiments with 6 mice in each group. Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 IVIG induces antigen-specific Treg cells. A and B, Representative flow cytometric plots of (donor) Foxp3GFP+APC+ and (host) Foxp3APC+GFP− Treg cells within the lungs of WT recipient mice. Before sensitization, all groups received 3 × 106 CD4+GFP− T cells from OT-II–Foxp3GFP reporter mice. Only OVA-IVIG-OVA mice demonstrate an increase in OVA-specific CD4+Foxp3+GFP+ cell numbers (Fig 3, A) among the total Treg cells induced by IVIG. Ragweed (RW)–IVIG–RW mice (Fig 3, B) demonstrate an increase in CD4+Foxp3+ cell numbers compared with other groups but no increase in Foxp3+GFP+ cell numbers. C and D, Fold increase of OVA-specific Foxp3GFP+ cell numbers among all Treg cells within the spleens, dLNs, and lungs compared with those seen in sham-treated PBS-HSA-PBS control mice. ∗P < .05. Data are from 2 experiments (n = 6 mice per group). Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Treg cells from IVIG-treated mice are highly suppressive. The ability of Treg cells from the experimental animals to suppress OVA-induced proliferation was evaluated by using an ex vivo suppression assay (see the Methods section) and monitored by means of CFSE dilution. Foxp3GFP+ cells from OVA-IVIG-OVA mice suppressed the proliferation of responder T cells (TResp) to OVA stimulation to a greater degree at all ratios from 1:1 to 1:16 compared with those seen in the other control groups. The left panel is a representative histogram plot for data obtained at a ratio of 1 Treg cells to 4 responder T cells. The proliferating cells fall to the left of the upper line, and the percentage of proliferating cells are indicated. The right panel demonstrates the survival graph of the percentage suppression by donor Treg cells from each experimental group at 1:1 to 1:16 (Treg cell/responder T cell) ratios. ∗P < .05. Results are representative of 2 experiments (n = 6 mice per group). Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 IVIG primes CD11c+ pulmonary DCs to induce Treg cells. A, DCs were purified from naive mice and pulsed with IVIG with and without OVA and then cocultured with CD4+ cells from OT-II–Foxp3GFP reporter mice. The induction of de novo Treg cells was assessed by measuring the percentage of Foxp3GFP+APC+ cells in the CD4+ population by means of flow cytometry. Only OVA-IVIG–pretreated DCs induced the expansion of Treg cells. B, Purified CD11c+ DCs or plasmacytoid CD11c− DCs from the lungs of OVA-IVIG-OVA and OVA-HSA-OVA mice were cocultured with CD4+GFP− T cells from OT-II–Foxp3 reporter mice. Only pulmonary CD11c+ DCs from OVA-IVIG-OVA mice induced expression of Foxp3. ∗P < .05 (n = 6 mice for each experimental condition). Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Adoptive transfer of pulmonary DCs from IVIG-treated mice recapitulates the protective effect of IVIG therapy by inducing Treg cells. Pulmonary DCs were purified from the lungs of mice from each experimental group after the completed challenge protocol. Recipient mice received adoptive transfer of purified DCs 1 day before challenge (day 28) in place of IVIG or HSA treatment. A and B, Representative flow cytometric plots (Fig 6, A) and quantification of CD4+CD25+Foxp3+ Treg cells (Fig 6, B) within the digested lung tissue of recipient mice after challenge. Adoptive transfer of pulmonary DCs from OVA-IVIG-OVA and PBS-IVIG-PBS mice to OVA-sensitized animals induced Treg cells comparably to IVIG treatment. ∗P < .05. Results are representative of 2 experiments (n = 6 mice for each experimental group). Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 Adoptive transfer of pulmonary DCs from IVIG-treated mice protects against increased AHR and pulmonary inflammation. Pulmonary DCs were purified from the lungs of mice from each experimental group after the completed challenge protocol. Recipient mice received adoptive transfer of purified DCs 1 day before challenge (day 28) in place of IVIG or HSA treatment. A-E, Histologic examination of hematoxylin and eosin–stained representative lung sections, demonstrating the protective effect of DCs adoptively transferred from IVIG-treated mice to OVA-HSA-OVA mice: untreated control mice (Fig 7, A), DCs from PBS-HSA-PBS mice (Fig 7, B), DCs from OVA-HSA-OVA mice (Fig 7, C), DCs from OVA-IVIG-OVA mice (Fig 7, D), and DCs from PBS-IVIG-PBS mice (Fig 7, E). F, AHR to methacholine (pulmonary resistance) was measured by using the flexiVent, as shown in the Methods section. DCs from IVIG-treated mice substantially attenuated methacholine-induced AHR. ∗P < .05. Results are representative of 2 experiments (n = 6 mice for each experimental group). Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E1 IVIG does not directly act on T cells to induce Treg cells. CD4+ T cells and CD11c+ DCs were purified from spleens of WT C57BL/6 mice, as shown in the Methods section. DCs were preincubated with OVA (1 mg/mL) with or without IVIG for 3 hours (10 mg/mL) and then washed before culturing with T cells for 5 days. Alternatively, T cells were preincubated with IVIG (10 mg/mL) for 3, 12, or 24 hours and then washed before coculturing with OVA-pulsed DCs. A, Representative dot plot indicating the numbers of Treg cells that costain for both CD25 and Foxp3 (right upper quadrant of dot plot). Only DCs preincubated with IVIG and OVA and then cocultured with T cells showed increased numbers of Treg cells compared with baseline values. Preincubating T cells with IVIG before coculture did not increase Treg cell numbers over baseline values. B, Summary of the above data indicating only DCs plus IVIG plus OVA is able to increase Treg cell percentages in vitro. ∗∗P < .05 (n = 3). C, Summary of activated T cells in coculture, as delineated by CD25+Foxp3− cells detected in right lower quadrant of Fig E1, A. Only DCs preincubated with IVIG and OVA decreased the numbers of activated T cells in culture, suggesting induction of highly suppressive Treg cells by IVIG. Preincubation of T cells with IVIG before washing did not decrease the number of activated T cells on exposure to OVA-pulsed DCs. ∗∗P < .05 (n = 3). Journal of Allergy and Clinical Immunology  , e3DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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