A novel allergen-specific therapy for allergy using CD40-silenced dendritic cells Motohiko Suzuki, MD, PhD, Xiufen Zheng, PhD, Xusheng Zhang, MD, PhD,

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Presentation transcript:

A novel allergen-specific therapy for allergy using CD40-silenced dendritic cells Motohiko Suzuki, MD, PhD, Xiufen Zheng, PhD, Xusheng Zhang, MD, PhD, Zhu-Xu Zhang, PhD, Thomas E. Ichim, PhD, Hongtao Sun, PhD, Yoshihisa Nakamura, MD, PhD, Akira Inagaki, MD, PhD, Marianne Beduhn, BS, Aminah Shunnar, BS, Bertha Garcia, PhD, Wei- Ping Min, MD, PhD Journal of Allergy and Clinical Immunology Volume 125, Issue 3, Pages 737-743.e6 (March 2010) DOI: 10.1016/j.jaci.2009.11.042 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Allergic nasal symptoms and IgE levels in sera by administration of CD40-silenced OVA DCs before sensitization. A and B, The number of sneezing (Fig 1, A) and nasal rubbing (Fig 1, B) after nasal OVA challenge. C and D, The number of sneezing (Fig 1, C) and nasal rubbing (Fig 1, D) movements after nasal KLH challenge. E and F, OVA-specific IgE (Fig 1, E) and KLH-specific IgE (Fig 1, F) levels. n = 5 per group. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2010 125, 737-743.e6DOI: (10.1016/j.jaci.2009.11.042) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 CD40-silenced OVA DCs facilitated OVA-specific Treg cells. A, CD4+ T cells were analyzed by means of flow cytometry. B, Foxp3 expression was determined by means of real-time PCR. C, CD4+CD25+ T cells as inhibitors, isolated from mice injected with CD40-silenced OVA DCs, were added to OVA-specific T-cell response. D, CD4+CD25+ T cells were added to KLH-specific T-cell response. n = 5 per group. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2010 125, 737-743.e6DOI: (10.1016/j.jaci.2009.11.042) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Reduction of allergic symptoms and responses by administration of CD40-silenced DCs in mice with established allergic rhinitis. A-C, The number of sneezing movements (Fig 3, A), nasal rubbing movements (Fig 3, B), and eosinophils in the nasal septum (Fig 3, C). D, OVA-specific IgE in sera. E, IL-4 production from splenocytes stimulated with OVA. F, Foxp3 expression determined by using real-time PCR. n = 5 per group. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2010 125, 737-743.e6DOI: (10.1016/j.jaci.2009.11.042) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Effect of CD40-silenced OVA DCs on effector T cells. OVA-specific T-cell responses were performed. Splenocytes isolated from allergic mice that were injected with OVA and alum were seeded in 96-well plates and cocultured with OVA. CD4+CD25− effector T cells were isolated from mice with allergic rhinitis treated with PBS, control OVA DCs, or CD40-silenced OVA DCs. A, Modulation of OVA-specific T-cell responses by CD4+CD25− effector T cells. Purified CD4+CD25− effector T cells were added to ongoing OVA-specific T-cell response. B and C, The levels of IL-4 (Fig 4, B) and IL-5 (Fig 4, C) produced by splenocytes cocultured with OVA and purified CD4+CD25− effector T cells. n = 5 per group. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2010 125, 737-743.e6DOI: (10.1016/j.jaci.2009.11.042) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 The effect of CD4+CD25+ Treg cells on allergic responses. Five mice with established allergic rhinitis were treated with PBS alone or Treg cells from mice that received CD40-silenced OVA DCs. The number of sneezing (A) and nasal rubbing (B) movements were counted after the last nasal challenge. C, The number of eosinophils in nasal septum. D, Level of OVA-specific IgE in sera. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2010 125, 737-743.e6DOI: (10.1016/j.jaci.2009.11.042) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

CD40-silencing DCs with CD40 siRNA CD40-silencing DCs with CD40 siRNA. Bone marrow–derived DCs were transfected with no siRNA, control siRNA, or CD40 siRNA. Total RNAs were extracted from DCs. A, CD40 expression determined by means of RT-PCR in vitro. RT-PCR was performed by using primers specific to CD40 and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). B, CD40 expression was determined by means of real-time PCR. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2010 125, 737-743.e6DOI: (10.1016/j.jaci.2009.11.042) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

OVA -specific and KLH-specific IgG2a levels in sera by administration of CD40-silenced OVA DCs before immunization. Five mice were sensitized and challenged with OVA and KLH after treatment with PBS, control OVA DCs, or CD40-silenced OVA DCs. A, OVA-specific IgG2a in sera. B, KLH-specific IgG2a in sera. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2010 125, 737-743.e6DOI: (10.1016/j.jaci.2009.11.042) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Administration of CD40-silenced OVA DCs before sensitization modulates the OVA-specific T-cell response. A, OVA-specific recall responses. B, KLH-specific recall responses. C and D, The levels of IL-4 (Fig E3, C) and IL-5 (Fig E3, D) by splenocytes stimulated with OVA. E and F, The levels of IL-4 (Fig E3, E) and IL-5 (Fig E3, F) by splenocytes stimulated with KLH. n = 5 per group. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2010 125, 737-743.e6DOI: (10.1016/j.jaci.2009.11.042) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Prime responses by CD40-silenced OVA DCs Prime responses by CD40-silenced OVA DCs. Five mice were injected with control OVA DCs or CD40-silenced OVA DCs. A, OVA-specific T-cell response of splenic cells. B and C, The level of IL-4 (Fig E4, B) and IL-5 (Fig E4, C) productions from splenocytes stimulated by OVA. D and E, The level of OVA-specific IgE (Fig E4, D) and IgG1 (Fig E4, E) in sera. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2010 125, 737-743.e6DOI: (10.1016/j.jaci.2009.11.042) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Long -term effect of CD40-silenced DCs Long -term effect of CD40-silenced DCs. Five mice were treated with PBS alone or CD40-silenced OVA DCs after establishment of allergic rhinitis. The number of sneezing (A) and nasal rubbing (B) was counted after nasal challenge 8 weeks after treatment. C, The number of eosinophil in nasal mucosa 8 weeks after treatment. D, Level of OVA-specific IgE in sera 8 weeks after treatment. E, Foxp3 gene expression in 8 weeks after treatment was determined by means of real-time PCR. ∗∗P < .01. Journal of Allergy and Clinical Immunology 2010 125, 737-743.e6DOI: (10.1016/j.jaci.2009.11.042) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions