Abstract
The recent precipitous rise in autoimmune diseases is placing an increasing clinical and economic burden on health systems worldwide. Current therapies are only moderately efficacious, often coupled with adverse side effects. Here, we show that recombinant human insulin-like growth factor-1 (rhIGF-1) stimulates proliferation of both human and mouse regulatory T (Treg) cells in vitro and when delivered systemically via continuous minipump, it halts autoimmune disease progression in mouse models of type 1 diabetes (STZ and NOD) and multiple sclerosis (EAE) in vivo. rhIGF-1 administration increased Treg cells in affected tissues, maintaining their suppressive properties. Genetically, ablation of the IGF-1 receptor specifically on Treg cell populations abrogated the beneficial effects of rhIGF-1 administration on the progression of multiple sclerotic symptoms in the EAE model, establishing a direct effect of IGF-1 on Treg cell proliferation. These results establish systemically delivered rhIGF-1 as a specific, effective stimulator of Treg cell action, underscoring the clinical feasibility of manipulating natural tolerance mechanisms to suppress autoimmune disease.
Highlights
ResultsThe immune system protects adult mammals against pathogens while restricting those responses to avoid harm to the host
We report on the direct activation of human and mouse Treg cell proliferation by recombinant human insulin-like growth factor-1 (rhIGF-1) and demonstrate how a confined period of continuous systemic rhIGF-1 delivery using a clinically relevant, accepted method for delivering drugs in humans (Yaturu, 2013) is a feasible and readily applicable therapeutic avenue for the treatment of autoimmune and inflammatory diseases
In this study, we prove the feasibility of a novel in rhIGF-1-treated mice (IGF-1) delivery method in combating autoimmune disease and identify IGF-1 as a naturally occurring growth factor that leads to Treg cell expansion, activation and migration into affected tissues, producing long-term immune tolerance and improved clinical outcome
Summary
The immune system protects adult mammals against pathogens while restricting those responses to avoid harm to the host. Active suppression of inflammation and immune responses by regulatory T (Treg) cells is essential in maintaining this equilibrium and immunological self-tolerance (O’Garra & Vieira, 2004; Littman & Rudensky, 2010). Treg cell-based therapies have held rhIGF-1 stimulates proliferation of human and mouse Treg cells ex vivo. To assess the potential effects of rhIGF-1 on Treg cell populations, Treg (CD4+ CD25+ CD127low) cells were FACS-sorted from human peripheral blood and analyzed for the transcription factor forkhead. Mouse Biology Unit, European Molecular Biology Laboratory (EMBL), Monterotondo, Italy. National Heart and Lung Institute, Imperial College, London, UK. Australian Regenerative Medicine Institute/EMBL Australia, Monash University, Clayton, Vic., Australia a 2014 The Authors. IGF-1 suppresses autoimmune disease Daniel Bilbao et al % of Max C FOXP3
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