Effect of Hookworm Infection on Wheat Challenge in Celiac Disease – A Randomised Double-Blinded Placebo Controlled Trial

Abstract

Background and AimsThe association between hygiene and prevalence of autoimmune disease has been attributed in part to enteric helminth infection. A pilot study of experimental infection with the hookworm Necator americanus was undertaken among a group of otherwise healthy people with celiac disease to test the potential of the helminth to suppress the immunopathology induced by gluten.MethodsIn a 21-week, double-blinded, placebo-controlled study, we explored the effects of N. americanus infection in 20 healthy, helminth-naïve adults with celiac disease well controlled by diet. Staged cutaneous inoculations with 10 and 5 infective 3rd stage hookworm larvae or placebo were performed at week-0 and -12 respectively. At week-20, a five day oral wheat challenge equivalent to 16 grams of gluten per day was undertaken. Primary outcomes included duodenal Marsh score and quantification of the immunodominant α-gliadin peptide (QE65)-specific systemic interferon-γ-producing cells by ELISpot pre- and post-wheat challenge.ResultsEnteric colonisation with hookworm established in all 10 cases, resulting in transiently painful enteritis in 5. Chronic infection was asymptomatic, with no effect on hemoglobin levels. Although some duodenal eosinophilia was apparent, hookworm-infected mucosa retained a healthy appearance. In both groups, wheat challenge caused deterioration in both primary and several secondary outcomes.ConclusionsExperimental N. americanus infection proved to be safe and enabled testing its effect on a range of measures of the human autoimmune response. Infection imposed no obvious benefit on pathology.Trial RegistrationClinicalTrials.gov NCT00671138

Celiac Disease: A Challenging Disease for Pharmaceutical Scientists

“…CD patients were cutaneously inoculated twice with larvae of the hookworm Necator americanus in a phase Ib/IIa trial (NCT00671138), and subsequently underwent a wheat challenge for 5 days (16 g of gluten/day). No significant differences between infected and non-infected patients were seen with respect to histological, clinical, or inflammation-related parameters (34). Further analysis of the biopsy specimens, however, indicated that hookworm-infection lowered the production of proinflammatory cytokines (IL-17A, IFNγ) but did not influence the response of duodenal memory T cells towards a gliadin peptide (35).…”

“…Further challenges are a potential immune system activation with a disease flare in response to the vaccine (31), and the restriction to patients with HLA-DQ2. Another investigated means of desensitizing patients is hookworm-infection (34). CD patients were cutaneously inoculated twice with larvae of the hookworm Necator americanus in a phase Ib/IIa trial (NCT00671138), and subsequently underwent a wheat challenge for 5 days (16 g of gluten/day).…”

Hookworm Excretory/Secretory Products Induce Interleukin-4 (IL-4)+IL-10+CD4+T Cell Responses and Suppress Pathology in a Mouse Model of Colitis

“…Recent clinical trials performed by our laboratory have focused on the potential use for helminths that persist within the intestine, such as the hookworm Necator americanus, to alleviate intestinal inflammation associated with celiac disease (5,11,21). This hookworm-based therapy resulted in the suppression of proinflammatory anti-gliadin immune responses (21) and the induction of systemic and mucosal type 2 cytokine responses (7), although overt suppression of clinical disease was not observed (8). Although the potential benefits of parasite-derived therapies for IBD and other autoimmune diseases are apparent, the safety of such approaches has been questioned (9,10), and a "fear factor" reaction by the public, as well as logistical concerns for scale-up, may preclude their widespread use.…”

Helminthotherapy

“…Kancalı kurtların terapötik olarak ilk klinik denemesi Crohn hastalığı için daha sonrasında da çölyak hastalığı ve allerjik rinokonjunktivit için yapılmıştır [98,102,103] . Bu çalışmaların hiçbirinde patolojinin önemli derecede etkilendiği gözlene-memesine rağmen, çölyak hastalığı odaklı başka bir çalışmada, T H 1/T H 17 immün yanıtının T H 2 ve IL-10 yolaklarıyla baskılandığı rapor edilmiş-tir [104] .…”