Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency Fleur Bossi, PhD, Fabio Fischetti, MD, Domenico.

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Presentation transcript:

Novel pathogenic mechanism and therapeutic approaches to angioedema associated with C1 inhibitor deficiency Fleur Bossi, PhD, Fabio Fischetti, MD, Domenico Regoli, MD, Paolo Durigutto, BSc, Barbara Frossi, PhD, Fernand Gobeil, PhD, Berhane Ghebrehiwet, DVM/DSc, Ellinor I. Peerschke, PhD, Marco Cicardi, MD, Francesco Tedesco, MD Journal of Allergy and Clinical Immunology Volume 124, Issue 6, Pages 1303-1310.e4 (December 2009) DOI: 10.1016/j.jaci.2009.08.007 Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A, HUVEC permeability induced by APL (white bars) or RPL (black bars) from a patient with HAE (1) or AAE (2), 2 blood donors (A, B; gray bars), and bradykinin (BK; 10−6 M). B, ADMEC permeability induced by RPL or APL from 15 patients and by plasma samples from 15 blood donors. Horizontal bars indicate geometric means.∗P < .001 vs CPL; #P < .01 vs RPL; §P < .01 vs CPL. Journal of Allergy and Clinical Immunology 2009 124, 1303-1310.e4DOI: (10.1016/j.jaci.2009.08.007) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 In vivo analysis of plasma-induced vascular leakage. Rat ileal mesentery was superfused with 200 μL APL, RPL, or bradykinin (BK; 10−7 M), and the extravasated FITC-BSA was monitored for 30 minutes. A, Images from 1 representative experiment. B, Means ± SDs of albumin leakage index. ∗P < .01 vs time=0; §P < .01 vs RPL; #P < .01 vs APL. Journal of Allergy and Clinical Immunology 2009 124, 1303-1310.e4DOI: (10.1016/j.jaci.2009.08.007) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 A, Permeability of ADMECs incubated with mAb 60.11 or 74.5.2 anti-gC1qR (20 μg/mL) for 10 minutes before addition of APL from 3 patients for further 30 minutes. ∗P < .01 vs APL. B, Effect of HOE 140 (10-5 M), R715 (10-5 M) or R954 (10-5 M) on ADMECs evaluated as in A. Patients with HAE, open symbols; patients with AAE, solid symbols. ∗P < .05; ∗∗P < .01 vs APL. Journal of Allergy and Clinical Immunology 2009 124, 1303-1310.e4DOI: (10.1016/j.jaci.2009.08.007) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Modulation of B1R expression by IL-1β and brefeldin A (BA). A, ADMEC monolayer, stimulated with IL-1β (0.1 ng/mL) for 60 minutes at 37°C, was exposed to 10% APL or RPL from 1 representative patient, or Lys-des-Arg9-bradykinin (BK; 10−6 M). B, ADMEC monolayer, treated for 1 hour with brefeldin A (0.5 μM) and then with APL (10%) from 2 representative patients for 30 minutes. ∗P < .01. Journal of Allergy and Clinical Immunology 2009 124, 1303-1310.e4DOI: (10.1016/j.jaci.2009.08.007) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 In vivo effect of kinin receptor antagonists. Rat ileal mesentery was superfused with HOE 140 (10−5 M), R954 (10−5 M), or both before the addition of APL (50 μL). A, Images from 1 representative experiment. B, Means ± SDs of albumin leakage. ∗P < .01 vs time=0; §P < .01 vs HOE 140 and/or R954; #P < .05 vs R954 and HOE 140+ R954. Journal of Allergy and Clinical Immunology 2009 124, 1303-1310.e4DOI: (10.1016/j.jaci.2009.08.007) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Endothelial leakageis induced by the stimulation on luminal or abluminal side of the monolayer. ADMEC monolayer was incubated with 10% CPL, APL, or RPL obtained from 1 representative patient, or bradykinin (BK; 10−6 mol/L) as a positive control into the lower chamber (abluminal side) or the upper chamber (luminal side) of the transwell system for 30 minutes at 37°C, and the FITC-BSA leakage was quantified by Infinite 200 (Tecan, Switzerland). Values are expressed as means ± SDs of duplicate determinations of 3 different experiments. ∗P < .01; ∗∗P < .05 vs CPL; #P < .05 vs RPL. Journal of Allergy and Clinical Immunology 2009 124, 1303-1310.e4DOI: (10.1016/j.jaci.2009.08.007) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Permeabilizing factors promoting vascular leakage in vivo do not stimulate rat mast cells. RBL cells 5×105 were treated for 30 minutes with 2 μL plasma collected from 2 patients during the attack or remission phase diluted 1:2 in PBS, with 2 μL PBS as a negative control or phorbol 12-myristate 13-acetate and ionomycin (PMA/IONO), respectively, at 10 ng/mL and 400 ng/mL final concentration, as a positive control. The percentage of β-hexosaminidase release, indicating the positive response of RBL, was calculated. Values are expressed as means ± SDs of duplicate determinations of 3 different experiments. ∗P < .05 vs control. Journal of Allergy and Clinical Immunology 2009 124, 1303-1310.e4DOI: (10.1016/j.jaci.2009.08.007) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Removal of IL-1β may inhibit APL- induced leakage Removal of IL-1β may inhibit APL- induced leakage. 10% APL was incubated in a 96-well plate coated with goat polyclonal anti–IL-1β (1:30) for 45 minutes at room temperature before adding to the Traswell system (Corning, NY). The leakage was then monitored as previously described. Values are means ± SDs of duplicate determinations of 3 different experiments. ∗P < .01 vs APL. Journal of Allergy and Clinical Immunology 2009 124, 1303-1310.e4DOI: (10.1016/j.jaci.2009.08.007) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Model of kinin release during angioedema attack and contribution of B1R and gC1qR. BK, Bradykinin; CP M, carboxypeptidase M; PRCP, prolylcarboxypeptidase; uPAR, receptor for urokinase plasminogen activator; CK-1, cytokeratin 1. Journal of Allergy and Clinical Immunology 2009 124, 1303-1310.e4DOI: (10.1016/j.jaci.2009.08.007) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions