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Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand  Junyan Han, PhD, Azzeddine.

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Presentation on theme: "Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand  Junyan Han, PhD, Azzeddine."— Presentation transcript:

1 Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand  Junyan Han, PhD, Azzeddine Dakhama, PhD, Yi Jia, PhD, Meiqin Wang, MD, PhD, Wanjiang Zeng, MD, PhD, Katsuyuki Takeda, MD, PhD, Yoshiki Shiraishi, PhD, Masakazu Okamoto, MD, PhD, Steven F. Ziegler, PhD, Erwin W. Gelfand, MD  Journal of Allergy and Clinical Immunology  Volume 130, Issue 5, Pages e9 (November 2012) DOI: /j.jaci Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 RSV infection induces OX40L expression on lung DCs. Mice were infected as neonates or at 5 weeks of age. Age-matched control mice were inoculated with PBS. One day after RSV infection, lung single-cell suspensions were prepared, and lung DC subsets were identified following the gating strategy described in Fig E1. The percentage of OX40L+ cells among CD11c+CD11b+CD103− DCs (A) and the percentage of IL-12+ cells among CD11c+ cells (B) was analyzed by using flow cytometry, as described in the Methods section. Results are from 3 independent experiments (n = 12). **P < .01. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Effect of anti-OX40L on airway responsiveness to primary RSV infection in adult mice. Mice were infected on day 0 at 5 weeks of age. Anti-OX40L (RM134L) or control antibody was administered intraperitoneally at 15 mg/kg on days −1, +1, and +2. Airway responsiveness to inhaled MCh (A), BAL cellularity (B), and BAL fluid IFN-γ levels (C) were assessed on day 7 after infection. Results are from 3 independent experiments (n = 12). Data are expressed as means ± SEMs. *P < .05 and **P < .01. Ab, Antibody; Eos, eosinophil; Lym, lymphocyte; Mac, macrophage; Neu, neutrophil; RL, lung resistance. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Effect of anti-OX40L administered during primary infection on secondary RSV infection in adult mice. Mice were initially infected with RSV at 5 weeks of age and reinfected with RSV 5 weeks later. Anti-OX40L or control antibody was administered during primary RSV infection. Airway responsiveness to inhaled MCh (A), BAL cellularity (B), and BAL fluid IFN-γ levels (C) were assessed on day 7 after reinfection. Results are from 3 independent experiments (n = 12). Data are expressed as means ± SEMs. *P < .05 and **P < .01. Ab, Antibody; Eos, eosinophil; Lym, lymphocyte; Mac, macrophage; Neu, neutrophil; RL, lung resistance. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Effect of anti-OX40L administered during neonatal primary infection on the response to RSV reinfection. Newborn mice were infected with RSV on day 0. Anti-OX40L or control antibody was administered on days −1, +1, and +2. Five weeks later, mice were reinfected with RSV. Airway responsiveness to inhaled MCh (A), BAL cellularity (B), and BAL fluid cytokine levels (C) were assessed on day 7 after secondary RSV infection. Results are from 3 independent experiments (n = 12). Data are expressed as means ± SEMs. *P < .05 and **P < .01. Ab, Antibody; Eos, eosinophil; Lym, lymphocyte; Mac, macrophage; Neu, neutrophil; RL, lung resistance. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Administration of anti-OX40L during neonatal infection affects cytokine responses in PBLNs. Newborn mice were infected with RSV and reinfected with RSV 5 weeks later. Anti-OX40L or control antibody was administered either during primary RSV (A) or secondary RSV (B) infection. Seven days after reinfection, PBLN cells were collected and seeded in 96-well plates and stimulated with UV-RSV. IL-4, IL-5, IL-6, IL-13, and IFN-γ levels in the supernatants were measured 3 days after culture. Results are from 3 independent experiments (n = 12). Data are expressed as means ± SEMs. *P < .05 and **P < .01. Ab, Antibody. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 RSV induces TSLP expression in the lung and neutralization of TSLP before primary infection affects the responses to RSV reinfection. A, Lung mRNA was isolated 1 day after primary infection of neonates or adult mice and TSLP mRNA levels were measured by quantitative RT-PCR. Increases in expression levels were compared with those in adult noninfected control animals. B-D, Newborn mice were infected with RSV and reinfected with RSV 5 weeks later. Anti-TSLP or control antibody was administered 1 day before neonatal infection. Seven days after reinfection, airway responsiveness to inhaled MCh (Fig 6, B), BAL cellularity (Fig 6, C), and BAL fluid cytokine levels (Fig 6, D) were assessed. E-G, Mice were infected with RSV as neonates. Anti-TSLP or control antibody was administered 1 day before infection. Lung single-cell suspensions were prepared 1 day after infection, and OX40L expression was analyzed by flow cytometry. Fig 6, E, Percentage of OX40L+ cells among lung CD11c+CD11b+ DCs. Fig 6, F, Total number of OX40L+CD11c+ cells in the lung. Fig 6, G, OX40L MFI expression on CD11c+CD11b+ DCs. Representative histogram and combined MFI depicting expression of OX40L on CD11c+CD11b+ DCs; the isotype control is shown as a shaded line. Results are from 2 to 4 independent experiments (n = 6-12). Data are expressed as means ± SEMs. **P < .01. Ab, Antibody; Eos, eosinophil; Lym, lymphocyte; Mac, macrophage; Neu, neutrophil; RL, lung resistance. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 6 RSV induces TSLP expression in the lung and neutralization of TSLP before primary infection affects the responses to RSV reinfection. A, Lung mRNA was isolated 1 day after primary infection of neonates or adult mice and TSLP mRNA levels were measured by quantitative RT-PCR. Increases in expression levels were compared with those in adult noninfected control animals. B-D, Newborn mice were infected with RSV and reinfected with RSV 5 weeks later. Anti-TSLP or control antibody was administered 1 day before neonatal infection. Seven days after reinfection, airway responsiveness to inhaled MCh (Fig 6, B), BAL cellularity (Fig 6, C), and BAL fluid cytokine levels (Fig 6, D) were assessed. E-G, Mice were infected with RSV as neonates. Anti-TSLP or control antibody was administered 1 day before infection. Lung single-cell suspensions were prepared 1 day after infection, and OX40L expression was analyzed by flow cytometry. Fig 6, E, Percentage of OX40L+ cells among lung CD11c+CD11b+ DCs. Fig 6, F, Total number of OX40L+CD11c+ cells in the lung. Fig 6, G, OX40L MFI expression on CD11c+CD11b+ DCs. Representative histogram and combined MFI depicting expression of OX40L on CD11c+CD11b+ DCs; the isotype control is shown as a shaded line. Results are from 2 to 4 independent experiments (n = 6-12). Data are expressed as means ± SEMs. **P < .01. Ab, Antibody; Eos, eosinophil; Lym, lymphocyte; Mac, macrophage; Neu, neutrophil; RL, lung resistance. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig 6 RSV induces TSLP expression in the lung and neutralization of TSLP before primary infection affects the responses to RSV reinfection. A, Lung mRNA was isolated 1 day after primary infection of neonates or adult mice and TSLP mRNA levels were measured by quantitative RT-PCR. Increases in expression levels were compared with those in adult noninfected control animals. B-D, Newborn mice were infected with RSV and reinfected with RSV 5 weeks later. Anti-TSLP or control antibody was administered 1 day before neonatal infection. Seven days after reinfection, airway responsiveness to inhaled MCh (Fig 6, B), BAL cellularity (Fig 6, C), and BAL fluid cytokine levels (Fig 6, D) were assessed. E-G, Mice were infected with RSV as neonates. Anti-TSLP or control antibody was administered 1 day before infection. Lung single-cell suspensions were prepared 1 day after infection, and OX40L expression was analyzed by flow cytometry. Fig 6, E, Percentage of OX40L+ cells among lung CD11c+CD11b+ DCs. Fig 6, F, Total number of OX40L+CD11c+ cells in the lung. Fig 6, G, OX40L MFI expression on CD11c+CD11b+ DCs. Representative histogram and combined MFI depicting expression of OX40L on CD11c+CD11b+ DCs; the isotype control is shown as a shaded line. Results are from 2 to 4 independent experiments (n = 6-12). Data are expressed as means ± SEMs. **P < .01. Ab, Antibody; Eos, eosinophil; Lym, lymphocyte; Mac, macrophage; Neu, neutrophil; RL, lung resistance. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E1 Gating strategy to identify lung DC subsets. Lung single-cell suspensions from RSV-infected or control (PBS-inoculated) mice were evaluated for expression of CD11c, MHCII, CD11b, B220, and CD103. Gated live cells were first plotted as CD11c versus forward scatter (FSC) to identify lung DC subsets. The CD11c+ cells were then plotted as MHCII versus FSC or MHCII versus B220. The CD11c+MHCII+ cells were then plotted as CD103 versus CD11b. As shown in the representative flow plots, CD103+ DCs were identified as CD11c+MHCII+CD103+CD11blo cells, mDCs were identified as CD11c+MHCII+CD11b+CD103− cells, and pDCs were identified as CD11c+MHCII+B220+ cells. Numbers indicate the percentages of each gated DC subset among total CD11c+ cells. Representative plots from 3 independent experiments with 4 mice per group are shown. SSC, Side scatter. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E2 OX40L expression on mDCs and CD103+ DCs. Mice were infected as neonates or at 5 weeks of age. Age-matched control mice were inoculated with PBS. One day after RSV infection, lung single-cell suspensions were prepared, and CD103+ DCs and mDCs were identified as shown in Fig E1. The percentages of OX40L+ cells among mDCs (A) and CD103+ DCs (B) are shown. The gate for OX40L expression was set based on isotype staining. Representative plots from 3 independent experiments with 4 mice per group are shown. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 Fig E2 OX40L expression on mDCs and CD103+ DCs. Mice were infected as neonates or at 5 weeks of age. Age-matched control mice were inoculated with PBS. One day after RSV infection, lung single-cell suspensions were prepared, and CD103+ DCs and mDCs were identified as shown in Fig E1. The percentages of OX40L+ cells among mDCs (A) and CD103+ DCs (B) are shown. The gate for OX40L expression was set based on isotype staining. Representative plots from 3 independent experiments with 4 mice per group are shown. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 Fig E3 OX40L expression on pDCs. Mice were infected as neonates or at 5 weeks of age. Age-matched control mice were inoculated with PBS. One day after RSV infection, lung single-cell suspensions were prepared and evaluated for expression of OX40L on pDCs. A, The lung CD11c+ cells were plotted as MHCII versus B220. Numbers indicate the percentages of pDCs among CD11c+ cells. B, Percentage of OX40L-expressing pDCs. Representative plots from 3 independent experiments with 4 mice per group are shown. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

14 Fig E3 OX40L expression on pDCs. Mice were infected as neonates or at 5 weeks of age. Age-matched control mice were inoculated with PBS. One day after RSV infection, lung single-cell suspensions were prepared and evaluated for expression of OX40L on pDCs. A, The lung CD11c+ cells were plotted as MHCII versus B220. Numbers indicate the percentages of pDCs among CD11c+ cells. B, Percentage of OX40L-expressing pDCs. Representative plots from 3 independent experiments with 4 mice per group are shown. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

15 Fig E4 IL-12 expression on CD11c+ cells. Mice were infected as neonates or at 5 weeks of age. Age-matched control mice were inoculated with PBS. Twelve hours after RSV infection, lung single-cell suspensions were prepared and evaluated for intracellular expression of IL-12 on CD11c+ cells. Numbers indicate the percentages of IL-12+ cells among CD11c+ cells. The gate for IL-12 expression was set based on isotype staining. Representative plots from one of 3 independent experiments with 4 mice per group are shown. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

16 Fig E5 Effect of anti-OX40L during secondary infection on the response to reinfection in newborn mice. Newborn mice were infected with RSV and reinfected with RSV 5 weeks later. Anti-OX40L or control antibody was administered during secondary RSV infection. Airway responsiveness to inhaled MCh (A), BAL cellularity (B), and BAL fluid cytokine levels (C) were assessed on day 7 after secondary RSV infection. Results are from 3 independent experiments (n = 12). Data are expressed as means ± SEMs. Ab, Antibody; Eos, eosinophil; Lym, lymphocyte; Mac, macrophage; Neu, neutrophil; NS, nonsignificant; RL, lung resistance. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

17 Fig E5 Effect of anti-OX40L during secondary infection on the response to reinfection in newborn mice. Newborn mice were infected with RSV and reinfected with RSV 5 weeks later. Anti-OX40L or control antibody was administered during secondary RSV infection. Airway responsiveness to inhaled MCh (A), BAL cellularity (B), and BAL fluid cytokine levels (C) were assessed on day 7 after secondary RSV infection. Results are from 3 independent experiments (n = 12). Data are expressed as means ± SEMs. Ab, Antibody; Eos, eosinophil; Lym, lymphocyte; Mac, macrophage; Neu, neutrophil; NS, nonsignificant; RL, lung resistance. Journal of Allergy and Clinical Immunology  , e9DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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