A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of Type 1 diabetes and multiple sclerosis.

Maria E Lund,Sheila Donnelly,Padraig Mccauley-Winter,Andrew T Hutchinson,Judith Greer,Joyce To,Aakanksha Dixit,Akane Tanaka,Bronwyn A O’Brien,Mark W Robinson,Raquel Alvarado,Ann M Simpson,John P Dalton

doi:10.1038/srep37789

Abstract

Helminth parasites secrete molecules that potently modulate the immune responses of their hosts and, therefore, have potential for the treatment of immune-mediated human diseases. FhHDM-1, a 68-mer peptide secreted by the helminth parasite Fasciola hepatica, ameliorated disease in two different murine models of autoimmunity, type 1 diabetes and relapsing-remitting immune-mediated demyelination. Unexpectedly, FhHDM-1 treatment did not affect the proliferation of auto-antigen specific T cells or their production of cytokines. However, in both conditions, the reduction in clinical symptoms was associated with the absence of immune cell infiltrates in the target organ (islets and the brain tissue). Furthermore, after parenteral administration, the FhHDM-1 peptide interacted with macrophages and reduced their capacity to secrete pro-inflammatory cytokines, such as TNF and IL-6. We propose this inhibition of innate pro-inflammatory immune responses, which are central to the initiation of autoimmunity in both diseases, prevented the trafficking of autoreactive lymphocytes from the periphery to the site of autoimmunity (as opposed to directly modulating their function per se), and thus prevented tissue destruction. The ability of FhHDM-1 to modulate macrophage function, combined with its efficacy in disease prevention in multiple models, suggests that FhHDM-1 has considerable potential as a treatment for autoimmune diseases.

Highlights

On alternate days beginning at 4 weeks of age
FhES can prevent autoimmune disease in mice[17], the same treatment regime was chosen to assess the efficacy of FhHDM-1 and F. hepatica cathepsin L1 (FhCL1) in preventing type 1 diabetes (T1D) in non-obese diabetic (NOD) mice
Examination of hematoxylin and eosin (H&E) stained sections of pancreas isolated from FhHDM-1-treated mice at 13 weeks of age showed a consistent and significant (p < 0.001) reduction in islet inflammation compared to PBS treated mice (Fig. 1b), which is in keeping with the ability of the peptide to prevent autoimmune diabetes

Summary

Introduction

On alternate days beginning at 4 weeks of age. Mice were monitored over 30 weeks, assessed for blood glucose weekly, and diagnosed as diabetic after two consecutive measurements >14 mmol/L. A safer and potentially more effective alternative to live infection is to deliver the specific immune-modulatory molecules produced by helminth parasites. This approach would allow the precise mechanisms of action of these molecules to be characterized, and their properties modified to increase therapeutic efficacy. Others have shown that FhES prevented disease development in chronic experimental autoimmune encephalomyelitis (EAE)[18], a murine model of multiple sclerosis (MS). We tested a synthetic 68-amino acid form of FhHDM-1 and a functionally active recombinant form of FhCL1, for their ability to replicate the protective effect of total FhES and prevent autoimmune disease in mouse models of T1D and MS

Methods

Results

Conclusion