Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease John Croese, MD, Paul Giacomin, PhD, Severine Navarro,

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Presentation transcript:

Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease John Croese, MD, Paul Giacomin, PhD, Severine Navarro, PhD, Andrew Clouston, MD, Leisa McCann, RN, Annette Dougall, PhD, Ivana Ferreira, BSc, Atik Susianto, MD, Peter O'Rourke, PhD, Mariko Howlett, MD, James McCarthy, MD, Christian Engwerda, PhD, Dianne Jones, BHSc, Alex Loukas, PhD Journal of Allergy and Clinical Immunology Volume 135, Issue 2, Pages 508-516.e5 (February 2015) DOI: 10.1016/j.jaci.2014.07.022 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Trial CONSORT diagram and participants. CONSORT chart showing flow of patients through the clinical trial (A). Table of patient identification (ID) numbers (B), displaying age, sex, clinical diagnosis and diet-management details, and whether patient was part of Group 1 (full trial, with anthelmintic drug treatment) or Group 2 (abbreviated trial, no anthelmintic drugs). Journal of Allergy and Clinical Immunology 2015 135, 508-516.e5DOI: (10.1016/j.jaci.2014.07.022) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Trial design and successful establishment of NA infection. Trial timeline (A). Quantitative PCR determination of mean NA eggs per gram of feces ± SEM throughout the trial (B). Blood eosinophil counts (C) and hemoglobin concentration (D) in Group 1 subjects. *P < .05 and **P < .001. Journal of Allergy and Clinical Immunology 2015 135, 508-516.e5DOI: (10.1016/j.jaci.2014.07.022) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 A, Primary trial outcomes did not display changes consistent with increased CeD severity following escalating gluten challenges. Vh:Cd values for each individual's duodenal biopsy specimen. B, Predicted median Vh:Cd ratio ± 95% CI following a 12-week challenge with 50 mg of gluten/day (historical data from Catassi et al19) and the results for the 10 subjects who completed the current GC-1g trial. C, Table depicting raw IgA-tTG titers from trial participants. D, Predicted mean IgA-tTG titers ± 95% CI following a 2-week challenge with 3 g or 7.5 g of gluten/day (historical data from Leffler et al20) and the results from the current GC-1g and GC-3g trials. *Significant (P < .05) reductions in Vh:Cd and increases in IgA-tTG were observed in historical control data sets and were used as predicted outcomes for the current trial. ˆ This was an exit biopsy done for clinical reasons 12 weeks after recommencing a GFD. #Pre-trial reference from 2008 to 2010 while subject was on a GFD. ND, Not determined. Journal of Allergy and Clinical Immunology 2015 135, 508-516.e5DOI: (10.1016/j.jaci.2014.07.022) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Questionnaire-based assessments of CeD severity remained unaltered or imporved following gluten challenges. A, Monthly or weekly CSI values for the 12 subjects and corresponding identification (ID) numbers. B, Mean CSI values ± SEM for the 8 to 12 trial subjects, grouped by the nature of the weekly intervention. C, QOL score for the 10 subjects who completed GC-1g, in which a lower value indicates greater CeD-related life quality. *P = .05. Journal of Allergy and Clinical Immunology 2015 135, 508-516.e5DOI: (10.1016/j.jaci.2014.07.022) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 A, Intestinal histopathology remained normal during GC-1g. Heat map displaying individual Marsh scores. B, Table displaying IEL counts/100 enterocytes for each individual's biopsy specimen. C, Median IEL % values ± 95% CI for the 10 subjects who completed the trial. # Pre-trial reference from 2008 to 2010 while subject was on a gluten-free diet. ˆ This was an exit biopsy done for clinical reasons 12 weeks after recommencing a GFD. ND, Not determined. Journal of Allergy and Clinical Immunology 2015 135, 508-516.e5DOI: (10.1016/j.jaci.2014.07.022) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 NA infection and gluten microchallenge alter intestinal proinflammatory and regulatory T cell subsets. A, Representative flow cytometric plots demonstrating gating strategy for identifying CD45+ CD3+ T cells; data from duodenal IEL tissue is shown. B, Representative plots showing IFNγ expression in gated CD3+ CD45+ cell population from part A. C, Mean frequencies of IFNγ+ T cells ± SEM in IEL, LPL, and blood. D, Mean frequencies of IL-17A+ T cells ± SEM. E, Representative flow cytometric plots showing frequency of CD4+ and Foxp3+ cells, gated on CD45+ CD3+ cells from the IEL. F, Mean frequencies of CD4+ Foxp3+ T cells ± SEM in each tissue. *P < .05 and **P < .005. Journal of Allergy and Clinical Immunology 2015 135, 508-516.e5DOI: (10.1016/j.jaci.2014.07.022) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Representative duodenal histology image and description of histological grading methods. Mid-duodenal mucosal biopsy scored Vh:Cd 3.1 and Marsh 0. Good orientation of the mucosal sample is essential to accurately grade celiac disease pathology. The orientation of this section was typical for Vh:Cd and Marsh grading: the long axes of villi were easily identified, and most crypts were sectioned along a longitudinal axis. To the right of this section, crypts sectioned across the longitudinal axis are evident, which creates uncertainty, with a tendency to falsely underscore the Vh:Cd. In clinical practice, it is recommended that 4 samples be provided so as to improve the likelihood of an acceptable section. In our study, 2 biopsies were provided for histology, a decision based on a need to share a limited resource for immunological evaluations. To avoid creating 2 primary outcomes, sampling from the proximal duodenum—as is often suggested in clinical practice to avoid missing localized pathology—was not done. Journal of Allergy and Clinical Immunology 2015 135, 508-516.e5DOI: (10.1016/j.jaci.2014.07.022) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Establishment of NA infection in Group 2 subjects. Quantitative PCR determination of mean NA eggs per gram of feces ± SEM throughout the trial in Group 2 subjects (n = 4). Journal of Allergy and Clinical Immunology 2015 135, 508-516.e5DOI: (10.1016/j.jaci.2014.07.022) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 IgG-DG titers remained stable in the 8 subjects who completed both GC-1g and GC-3g trials, aside from 1 subject (ID9). Journal of Allergy and Clinical Immunology 2015 135, 508-516.e5DOI: (10.1016/j.jaci.2014.07.022) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Foxp3+ Treg cells co-express the immunoregulatory molecule CTLA-4. Gated CD3+ CD45+ Foxp3+ cells from duodenal IEL, duodenal LPL, and blood were analyzed for the expression of the Treg marker CTLA-4 (grey histograms). CD8+ CD3+ cells were used as negative controls for CTLA-4 staining (white histograms). Representative data from samples derived post-GC-1g are displayed. Journal of Allergy and Clinical Immunology 2015 135, 508-516.e5DOI: (10.1016/j.jaci.2014.07.022) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions