Helminths-based bi-functional molecule, tuftsin-phosphorylcholine (TPC), ameliorates an established murine arthritis.

Miri Blank,Jordan Lachnish,Yehuda Shoenfeld,Miriam Eisenstein,Dana Ben-Ami-Shor,Iris Barshack,Ora Shovman,Mati Fridkin,Tomer Bashi,Alexander Volkov,Dominique Heymann

doi:10.1371/journal.pone.0200615

Abstract

A novel small molecule named tuftsin-phosphorylcholine (TPC), which is linked to the biological activity of helminths, was constructed. The current study address the effect of TPC treatment in established collagen-induced arthritis (CIA) mice and propose TPC bi-functional activity. TPC treatment was initiated when clinical score was 2 to 4. Arthritis scores in TPC treated mice were lower compared to mice treated with vehicle (P < 0.001). Joint staining showed normal joint structure in TPC-treated mice compared to control groups treated with phosphate buffered saline (PBS), phosphorylcholine, or tuftsin, which exhibited severely inflamed joints. TPC enhanced anti-inflammatory response due to increased IL-10 secretion, and reduced pro-inflammatory cytokine secretion (IL-1-β, IL-6, TNF-αP < 0.001). Furthermore, TPC therapy increased expansion of CD4+CD25+FOXP3+T regulatory cells and IL-10+CD5+CD1d+B regulatory cells. We propose that the immunomodulatory activity of TPC can be a result of a bi-specific activity of TPC: (a) The tuftsin part of the TPC shifts RAW macrophage cells from pro-inflammatory macrophages M1 to anti-inflammatory M2-secreting IL-10 (P < 0.001) through neuropilin-1 and (b) TPC significantly reduce mouse TLR4 expression via NFkB pathway by HEKTM cells (P < 0.02) via the phosphorylcholine site of the molecule. Our results indicate that TPC, significantly ameliorated established CIA by its immunomodulatory activity. These data could lead to a novel self bi-functional small molecule for treating patients with progressive RA.

Highlights

Rheumatoid arthritis (RA) is a chronic, systemic autoinflammatory disease
collagen-induced arthritis (CIA) is a mouse model which imitates rheumatoid arthritis in genetically prone human patients, in which inflammation leads to the joint destruction
We investigated the effect of TPC administration in CIA mice and compared it with CIA mice treated, following disease establishment, with tuftsin (T), phosphorylcholine (PC), or phosphate buffered saline (PBS)

Summary

Introduction

Rheumatoid arthritis (RA) is a chronic, systemic autoinflammatory disease. It usually manifests as stiffness, pain, and swelling of the joints [1]. In RA patients, the function of T regulatory (Treg) cells is impaired and increases Treg cellscount is well-correlated with a better clinical response in patients and animal models [7,8]. Several studies of cells derived from RA patients indicated that the number of B10 regulatory (Breg) cells was inversely correlated with RA severity [9]. Impaired Breg activity and high levels of IFN-γ expressing cells suppressed Treg cell differentiation and worsened arthritis in a murine model [10]

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