Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease - 05/02/15
, Paul Giacomin, PhD b, ∗, Severine Navarro, PhD b, Andrew Clouston, MD c, Leisa McCann, RN b, Annette Dougall, PhD b, Ivana Ferreira, BSc b, Atik Susianto, MD b, Peter O'Rourke, PhD d, Mariko Howlett, MD e, James McCarthy, MD d, e, Christian Engwerda, PhD d, Dianne Jones, BHSc f, Alex Loukas, PhD b, ⁎ Abstract |
Background |
Celiac disease (CeD) is a common gluten-sensitive autoimmune enteropathy. A gluten-free diet is an effective treatment, but compliance is demanding; hence, new treatment strategies for CeD are required.
Objective |
Parasitic helminths hold promise for treating inflammatory disorders, so we examined the influence of experimental hookworm infection on the predicted outcomes of escalating gluten challenges in CeD subjects.
Methods |
A 52-week study was conducted involving 12 adults with diet-managed CeD. Subjects were inoculated with 20 Necator americanus larvae, and escalating gluten challenges consumed as pasta were subsequently administered: (1) 10 to 50 mg for 12 weeks (microchallenge); (2) 25 mg daily + 1 g twice weekly for 12 weeks (GC-1g); and (3) 3 g daily (60-75 straws of spaghetti) for 2 weeks (GC-3g). Symptomatic, serologic, and histological outcomes evaluated gluten toxicity. Regulatory and inflammatory T cell populations in blood and mucosa were examined.
Results |
Two gluten-intolerant subjects were withdrawn after microchallenge. Ten completed GC-1g, 8 of whom enrolled in and completed GC-3g. Primary outcomes: median villous height-to-crypt depth ratios (2.60-2.63; P = .98) did not decrease as predicted after GC-1g, and the mean IgA-tissue transglutaminase titers declined, contrary to the predicted rise after GC-3g. Secondary outcomes: quality of life scores improved (46.3-40.6; P = .05); celiac symptom indices (24.3-24.3; P = .53), intra-epithelial lymphocyte percentages (32.5-35.0; P = .47), and Marsh scores were unchanged by gluten challenge. Intestinal T cells expressing IFNγ were reduced following hookworm infection (23.9%-11.5%; P = .04), with corresponding increases in CD4+ Foxp3+ regulatory T cells (0.19%-1.12%; P = .001).
Conclusions |
Necator americanus and gluten microchallenge promoted tolerance and stabilized or improved all tested indices of gluten toxicity in CeD subjects.
Le texte complet de cet article est disponible en PDF.Key words : Celiac disease, gluten, hookworm, autoimmunity, helminth therapy, desensitization, mucosal immunology, regulatory T cells, intra-epithelial lymphocytes
Abbreviations used : CeD, CSI, DG, GC, GFD, IEL, LPL, NA, Treg, QOL, tTG, Vh:Cd
Plan
| The work was funded by an Australian National Health and Medical Research Council (NHMRC) Program Grant (1037304 to A.L., C.E., and J.M.), NHMRC Overseas Biomedical Fellowship 613718 (to P.G.), NHMRC Principal Research Fellowship (1020114 to A.L.), NHMRC Senior Research Fellowship (1058685 to C.E.), NHMRC Practitioner Fellowship and Government of Queensland Health Research Fellowship (1041802 to J.M.) and a Far North Queensland Hospital Foundation Small Research Grant (P.G. and S.N.). |
|
| Disclosure of potential conflict of interest: This work was funded by an Australian National Health and Medical Research Council Program Grant (1037304). The authors declare that they have no other relevant conflicts of interest. |
Vol 135 - N° 2
P. 508 - février 2015 Retour au numéro
Article précédent
- Intravenous anti–IL-13 mAb QAX576 for the treatment of eosinophilic esophagitis
- Marc E. Rothenberg, Ting Wen, Allison Greenberg, Oral Alpan, Benjamin Enav, Ikuo Hirano, Kari Nadeau, Sergio Kaiser, Thomas Peters, Antonio Perez, Ieuan Jones, Jonathan P. Arm, Robert M. Strieter, Ronald Sabo, Kulasiri A. Gunawardena
- Pioglitazone restores phagocyte mitochondrial oxidants and bactericidal capacity in chronic granulomatous disease
- Ruby F. Fernandez-Boyanapalli, S. Courtney Frasch, Stacey M. Thomas, Kenneth C. Malcolm, Michael Nicks, Ronald J. Harbeck, Claudia V. Jakubzick, Raphael Nemenoff, Peter M. Henson, Steven M. Holland, Donna L. Bratton
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?