title: Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease.
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  Two gluten-intolerant subjects were withdrawn after microchallenge.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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Croese
authors.affiliation: Center for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Giacomin
authors.affiliation: Center for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
authors.forename: Severine
authors.initials: S
authors.lastname: Navarro
authors.affiliation: Envoi Specialist Pathologists, Brisbane, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Clouston
authors.affiliation: Center for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
authors.forename: Leisa
authors.initials: L
authors.lastname: McCann
authors.affiliation: Center for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
authors.forename: Annette
authors.initials: A
authors.lastname: Dougall
authors.affiliation: Center for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
authors.forename: Ivana
authors.initials: I
authors.lastname: Ferreira
authors.affiliation: Center for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia.
authors.forename: Atik
authors.initials: A
authors.lastname: Susianto
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: O'Rourke
authors.affiliation: Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: Mariko
authors.initials: M
authors.lastname: Howlett
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia; Royal Brisbane and Women's Hospital, Brisbane, Australia.
authors.forename: James
authors.initials: J
authors.lastname: McCarthy
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Christian
authors.initials: C
authors.lastname: Engwerda
authors.affiliation: Logan Hospital, Brisbane, Australia.
authors.forename: Dianne
authors.initials: D
authors.lastname: Jones
authors.affiliation: 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.
authors.forename: Alex
authors.initials: A
authors.lastname: Loukas
mesh_terms: D000328:Adult; D000368:Aged; D000723:Ancylostomatoidea / Q000276:immunology*; D000818:Animals; D002446:Celiac Disease / Q000150:complications / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy; D004386:Duodenum / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D005260:Female; D005983:Glutens / Q000008:administration & dosage / Q000276:immunology*; D006725:Hookworm Infections / Q000150:complications / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D017221:Necator americanus / Q000276:immunology; D063868:Patient Outcome Assessment; D011795:Surveys and Questionnaires; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D005983:Glutens
keywords: Celiac disease; autoimmunity; desensitization; gluten; helminth therapy; hookworm; intra-epithelial lymphocytes; mucosal immunology; regulatory T cells