Secreted Proteins from the Helminth Fasciola hepatica Inhibit the Initiation of Autoreactive T Cell Responses and Prevent Diabetes in the NOD Mouse

Lucienne Chatenoud,Maria E Lund,Andrew T Hutchinson,Ann M Simpson,John P Dalton,Mark W Robinson,Sheila Donnelly,Bronwyn A O'Brien

doi:10.1371/journal.pone.0086289

Lucienne Chatenoud, Maria E Lund + Show 6 more

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https://doi.org/10.1371/journal.pone.0086289

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Abstract

Infections with helminth parasites prevent/attenuate auto-inflammatory disease. Here we show that molecules secreted by a helminth parasite could prevent Type 1 Diabetes (T1D) in nonobese diabetic (NOD) mice. When delivered at 4 weeks of age (coincident with the initiation of autoimmunity), the excretory/secretory products of Fasciola hepatica (FhES) prevented the onset of T1D, with 84% of mice remaining normoglycaemic and insulitis-free at 30 weeks of age. Disease protection was associated with suppression of IFN-γ secretion from autoreactive T cells and a switch to the production of a regulatory isotype (from IgG2a to IgG1) of autoantibody. Following FhES injection, peritoneal macrophages converted to a regulatory M2 phenotype, characterised by increased expression levels of Ym1, Arg-1, TGFβ and PD-L1. Expression of these M2 genetic markers increased in the pancreatic lymph nodes and the pancreas of FhES-treated mice. In vitro, FhES-stimulated M2 macrophages induced the differentiation of Tregs from splenocytes isolated from naïve NOD mice. Collectively, our data shows that FhES contains immune-modulatory molecules that mediate protection from autoimmune diabetes via the induction and maintenance of a regulatory immune environment.

Highlights

Type 1 Diabetes (T1D) is a multifactorial autoimmune disease in which the insulin-secreting beta (b) cells within the pancreatic islets are destroyed
F. hepatica infections in sheep were performed at the approval of the Animal Ethic Committee (AEC) located at the Elizabeth Macarthur Agricultural Institute (EMAI, Menangle, New South Wales (NSW), Australia) and under the guidelines established by the Animal Research Review Panel (ARRP) of the NSW Department of Primary Industries (DPI)
We show that the administration of molecules excreted/secreted by the helminth parasite F. hepatica (FhES) to nonobese diabetic (NOD) mice, at a time co-incident with T cell priming events, inhibits the initiation and perpetuation of autoimmune sequalae to prevent T1D

Summary

Introduction

Type 1 Diabetes (T1D) is a multifactorial autoimmune disease in which the insulin-secreting beta (b) cells within the pancreatic islets are destroyed. Epidemiological studies have shown that the absence of endemic helminth infection is inversely correlated with the incidence of T1D [5,6]. This suggests that exposure to helminths represents a predominant protective environmental factor against the development of T1D, and auto-inflammatory diseases in general. It has been proposed that the controlled reintroduction of helminth infection into Western populations could represent an effective therapy for auto-inflammatory diseases [10,11]. Support for the therapeutic potential of helminth infection in the prevention of autoimmune diabetes has come from experimental studies showing that infection of mice with helminth parasites prevents the development of T1D [12,13,14,15,16,17]

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