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J Allergy Clin Immunol. 2015 Feb;135(2):508-16. doi: 10.1016/j.jaci.2014.07.022. Epub 2014 Sep 20.

Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease.

Author information

1
Department of Gastroenterology and Hepatology, The Prince Charles Hospital, Brisbane, Australia; Center for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia. Electronic address: mcroese@bigpond.net.au.
2
Center for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
3
Envoi Specialist Pathologists, Brisbane, Australia.
4
QIMR Berghofer Medical Research Institute, Brisbane, Australia.
5
Royal Brisbane and Women's Hospital, Brisbane, Australia.
6
QIMR Berghofer Medical Research Institute, Brisbane, Australia; Royal Brisbane and Women's Hospital, Brisbane, Australia.
7
Logan Hospital, Brisbane, Australia.
8
Center for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia. Electronic address: alex.loukas@jcu.edu.au.

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Two gluten-intolerant subjects were withdrawn after microchallenge.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.

KEYWORDS:

Celiac disease; autoimmunity; desensitization; gluten; helminth therapy; hookworm; intra-epithelial lymphocytes; mucosal immunology; regulatory T cells

PMID:
25248819
DOI:
10.1016/j.jaci.2014.07.022
[Indexed for MEDLINE]

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