Antigen-Specific Gene Therapy after Immunisation Reduces the Severity of Collagen-Induced Arthritis

Tove Eneljung,Pernilla Jirholt,Kenth Gustafsson,Rikard Holmdahl,Inger Gjertsson,Sara Tengvall,Louise Henningsson

doi:10.1155/2013/345092

Abstract

Reestablishment of tolerance induction in rheumatoid arthritis (RA) would be an optimal treatment with few, if any, side effects. However, to develop such a treatment further insights in the immunological mechanisms governing tolerance are needed. We have developed a model of antigen-specific tolerance in collagen type II (CII) induced arthritis (CIA) using lentivirus-based gene therapy. The immunodominant epitope of CII was inserted into a lentivirus vector to achieve expression on the MHC class II molecule and the lentiviral particles were subsequently intravenously injected at different time points during CIA. Injection of lentiviral particles in early phases of CIA, that is, at day 7 or day 26 after CII immunisation, partially prevented development of arthritis, decreased the serum levels of CII-specific IgG antibodies, and enhanced the suppressive function of CII-specific T regulatory cells. When lentiviral particles were injected during manifest arthritis, that is, at day 31 after CII immunisation, the severity of arthritis progression was ameliorated, the levels of CII-specific IgG antibodies decreased and the proportion of T regulatory cells increased. Thus, antigen-specific gene therapy is effective when administered throughout the inflammatory course of arthritis and offers a good model for investigation of the basic mechanisms during tolerance in CIA.

Highlights

A hallmark of autoimmune diseases such as rheumatoid arthritis (RA) is immune responses directed against selfantigens and loss of tolerance against self
In a previous study we show that prophylactic gene therapy using lentiviral particles encoding the invariant chain fused to the immunodominant Collagen type II (CII) peptide (LNT-IiCII) induces antigen-specific tolerance and suppresses the development of arthritis [30]
Lentiviral particles were injected in the early phase of CII-induced arthritis (CIA)—7 days after CII immunisation (Figure 2(a))

Summary

Introduction

A hallmark of autoimmune diseases such as rheumatoid arthritis (RA) is immune responses directed against selfantigens and loss of tolerance against self. About one-third of patients with active RA do not respond to available treatments or suffer from severe side effects [2, 3]. In animal models of autoimmune diseases, the autoantigen is used to induce disease but can be used as a tolerance-inducing antigen (tolerogen); for example, administration with soluble CII peptides or whole protein can suppress the development of CIA [12,13,14]. The effect is limited due to rapid degradation of the peptide, and repeated or continuous administration of high doses of the tolerogen is necessary [13, 15, 18,19,20,21,22,23]. In order to minimize these limitations, modified CII peptides have been used in complex with major histocompatibility

Methods

Results

Conclusion