Alex KleinJan, PhD, Monique Willart, BSc, Leonie S

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Presentation transcript:

An essential role for dendritic cells in human and experimental allergic rhinitis Alex KleinJan, PhD, Monique Willart, BSc, Leonie S. van Rijt, PhD, Gert-Jan Braunstahl, MD, PhD, Karolina Leman, BSc, Steffen Jung, PhD, Henk C. Hoogsteden, MD, PhD, Bart N. Lambrecht, MD, PhD Journal of Allergy and Clinical Immunology Volume 118, Issue 5, Pages 1117-1125 (November 2006) DOI: 10.1016/j.jaci.2006.05.030 Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 1 Presence of mDCs in the nasal mucosa of patients with AR and healthy control subjects. When nasal tissues were stained with MHCII, a DC network was seen in the upper epithelial layer (A, Nomarski microscopy). Double staining revealed that these DCs were CD11c+ (blue) and MHCII+ (red; B). More DCs positive for CD1a (C) and CD11c+ (D) cells were observed in the epithelium and in the lamina propria in the nasal mucosa of patients with AR compared with those seen in healthy control subjects. Some cells were positive for the plasmacytoid marker CD123 (blue) and weakly expressed CD11c (red), identifying them as pDCs (E). CD11c+ (red) cells expressing CD86 (blue) cells were observed in the epithelium and in the lamina propria of nasal mucosal biopsy specimens (F). A higher proportion of CD86+ DCs (total CD11c+ cells) was observed in the lamina propria of patients with AR compared with that seen in healthy control subjects (G). Clusters of CD3+ T cells (blue) and CD11c+ DCs (red) were observed in the epithelium and in the lamina propria of the nasal mucosa in both patients with AR (H) and healthy control subjects (not shown). ∗P < .05; ∗∗P < .01 (bars represent the median value). Journal of Allergy and Clinical Immunology 2006 118, 1117-1125DOI: (10.1016/j.jaci.2006.05.030) Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 2 A model of AR in OVA-sensitized mice. Nasal mucosal sections were stained for murine MBPa specific marker for eosinophils (A; lp, lamina propria; epi, epithelium) and quantified (B; PBS are control mice and OVA are mice with AR). Murine eosinophils have a ring-shaped or a bilobular nucleus. IgE- and OVA-specific IgE (C) cytokine levels (D) after OVA restimulation of CLN cells are also shown (∗P < .05). Journal of Allergy and Clinical Immunology 2006 118, 1117-1125DOI: (10.1016/j.jaci.2006.05.030) Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 3 Increased number of mDCs can be found in the nasal mucosa of mice with AR. Only few CD11c+ cells were observed in the control mice compared with those seen in the mice with AR in the epithelium (epi) and the lamina propria (lp; dotted line indicates the position of the basal membrane; A, red) of the nose. The number of CD11c+ cells (nucleus and red staining) was counted in the entire epithelium, in the submucosa 100 μm deep in the lamina propria, and along the basal membrane (B). Data are presented as the mean ± SEM. Double staining for DCs (CD11c, red) and T cells (CD4, blue) revealed intense clustering in inflammatory sites (C) of the nasal mucosa in mice with AR. This was not seen in control mice (not shown). ∗P < .05. Journal of Allergy and Clinical Immunology 2006 118, 1117-1125DOI: (10.1016/j.jaci.2006.05.030) Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 4 Administration of OVA-pulsed DCs enhances AR. Mice were first immunized to OVA in alum. Ten days later, they received an intranasal application of PBS, PBS-pulsed DCs, or OVA-pulsed DCs. Another 10 days later, they received 3 OVA nasal challenges while one group received PBS challenge. Groups are coded as priming/treatment/challenge. Significantly more eosinophils were observed in the OVA/OVA-DC/OVA group compared with in the OVA/PBS/PBS group or the OVA/PBS/OVA group (A; P = .02 and P = .04, respectively, for epithelium and P = .01 and P = .04, respectively, for the lamina propria). B, Cytokine levels of CLN cells restimulated in vitro. Levels of the TH2 cytokines IL-5, IL-10, and IL-13 were increased in all mice exposed to OVA challenge compared with in those exposed to PBS challenge. Overall, in the OVA/OVA-DC/OVA group the TH2 cytokine levels were highest and reached a significantly higher (P = .05) level for IL-13 compared with in the OVA/PBS/OVA group not receiving any DCs. Journal of Allergy and Clinical Immunology 2006 118, 1117-1125DOI: (10.1016/j.jaci.2006.05.030) Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 5 Depletion of CD11c DCs reduces the characteristics of AR. On day 20 of the protocol, OVA/alum-sensitized and OVA-challenged CD11c-DTR transgenic mice were randomized to receive either DT to deplete DCs, generating transgenic DC− mice, or PBS, generating transgenic DC+ mice. One additional control group of nontransgenic littermate control animals received DT, generating nontransgenic DC+ mice. Subsequently, mice were challenged an additional 4 times with intranasal OVA twice a day in the presence or absence of DCs. A, Significantly fewer eosinophils were observed in the epithelium of the transgenic DC−/OVA mice compared with those seen in the transgenic DC+/OVA or nontransgenic DC+/OVA mice. In the lamina propria eosinophils were lower in DC-depleted mice, but this failed to reach statistical significance. B, The levels of serum OVA-specific IgE were significantly lower in mice in which DCs were depleted (transgenic DC−/OVA group) compared with in mice in which DCs were normal (transgenic DC+/OVA or nontransgenic DC+/OVA). C, In mice in which DCs were depleted (transgenic DC−/OVA), significantly less TH2 cytokines were produced by CLN cells compared with those seen in mice with normal DCs (P < .05). Journal of Allergy and Clinical Immunology 2006 118, 1117-1125DOI: (10.1016/j.jaci.2006.05.030) Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions