TRI microparticles prevent inflammatory arthritis in a collagen-induced arthritis model.

Ethan J. Bassin,Jon D. Piganelli,Steven R. Little,Abigail R. Buckley,Je-Min Choi

doi:10.1371/journal.pone.0239396

Ethan J. Bassin, Jon D. Piganelli + Show 3 more

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https://doi.org/10.1371/journal.pone.0239396

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Abstract

Despite recent progress in the treatment of rheumatoid arthritis (RA), many patients still fail to achieve remission or low disease activity. An imbalance between auto-reactive effector T cells (Teff) and regulatory T cells (Treg) may contribute to joint inflammation and damage in RA. Therefore, restoring this balance is a promising approach for the treatment of inflammatory arthritis. Accordingly, our group has previously shown that the combination of TGF-β-releasing microparticles (MP), rapamycin-releasing MP, and IL-2-releasing MP (TRI MP) can effectively increase the ratio of Tregs to Teff in vivo and provide disease protection in several preclinical models. In this study TRI MP was evaluated in the collagen-induced arthritis (CIA) model. Although this formulation has been tested previously in models of destructive inflammation and transplantation, this is the first model of autoimmunity for which this therapy has been applied. In this context, TRI MP effectively reduced arthritis incidence, the severity of arthritis scores, and bone erosion. The proposed mechanism of action includes not only reducing CD4+ T cell proliferation, but also expanding a regulatory population in the periphery soon after TRI MP administration. These changes were reflected in the CD4+ T cell population that infiltrated the paws at the onset of arthritis and were associated with a reduction of immune infiltrate and inflammatory myeloid cells in the paws. TRI MP administration also reduced the titer of collagen antibodies, however the contribution of this reduced titer to disease protection remains uncertain since there was no correlation between collagen antibody titer and arthritis score.

Highlights

Rheumatoid arthritis (RA) is an autoimmune disease of chronic joint inflammation affecting 0.5–1% of the population in Western countries, and approximately 1.5 million people in the U
Approaches aiming to maintain or restore Treg–Teff balance are of considerable interest because of the role this balance has in influencing disease progression, both in RA and the murine model of collagen-induced arthritis (CIA)
First all phosphate buffered saline (PBS) treated mice developed arthritis, only a small fraction had paws with substantial bone erosions. While this is likely a natural reflection of the fact that sufficient severity and duration of inflammation must occur to result in bone erosion, it means that differences between treatment groups will be harder to detect

Summary

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease of chronic joint inflammation affecting 0.5–1% of the population in Western countries, and approximately 1.5 million people in the U. Approaches to restore Treg-Teff balance that use auto-antigen and/or localized immunomodulatory agents could avoid many of these issues Several such approaches using citrullinated peptides [11,37], CII peptide-MHC II complex [38,39] or liposomes encapsulating antigen and NF-κB inhibitor [40] have demonstrated success in inflammatory arthritis models, but it remains unclear if these technologies will translate to RA. We reported the use of polymeric microparticles (MP) which release TGF-β, rapamycin, and IL-2 (TRI MP) [44] so that endogenous antigen can be presented in a tolerance-promoting local immunological microenvironment This combination was initially chosen due to the role of each of these factors in promoting Treg induction and expansion [44,45,46,47,48]. Anti-CII IgG antibodies were reduced by TRI MP administration, but not found to contribute to the arthritis prevention provided by this treatment

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