Secreted proteins from the helminth Fasciola hepatica inhibit the initiation of autoreactive T cell responses and prevent diabetes in the NOD mouse.
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.
School of Medical and Molecular Biosciences, University of Technology Sydney, New South Wales, Australia.
Maria E
ME
Lund
School of Medical and Molecular Biosciences, University of Technology Sydney, New South Wales, Australia.
Bronwyn A
BA
O'Brien
School of Medical and Molecular Biosciences, University of Technology Sydney, New South Wales, Australia.
Andrew T
AT
Hutchinson
School of Biological Sciences, Queen's University Belfast, Belfast, Northern Ireland.
Mark W
MW
Robinson
School of Medical and Molecular Biosciences, University of Technology Sydney, New South Wales, Australia.
Ann M
AM
Simpson
Institute of Parasitology, McDonald Campus, McGill University, St. Anne de Bellevue, Quebec, Canada.
John P
JP
Dalton
The i3 Institute, University of Technology Sydney, New South Wales, Australia.
Sheila
S
Donnelly
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D060890:B7-H1 Antigen / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000469:parasitology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000469:parasitology; D005210:Fasciola hepatica / Q000276:immunology*; D005260:Female; D006376:Helminths / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology; D037102:Lectins / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000469:parasitology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000469:parasitology; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000469:parasitology*; D016212:Transforming Growth Factor beta / Q000276:immunology; D001619:beta-N-Acetylhexosaminidases / Q000276:immunology
D001323:Autoantibodies; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D037102:Lectins; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases