Gene Therapy Induces Antigen-Specific Tolerance in Experimental Collagen-Induced Arthritis.

Sara Tengvall,Olof Turesson,Tove Eneljung,Pernilla Jirholt,Anna Stern,Inga-Lill Mårtensson,Kenth Gustafsson,Kajsa Wing,Inger Gjertsson,Rikard Holmdahl,Louise Henningsson,Jan Kihlberg

doi:10.1371/journal.pone.0154630

Abstract

Here, we investigate induction of immunological tolerance by lentiviral based gene therapy in a mouse model of rheumatoid arthritis, collagen II-induced arthritis (CIA). Targeting the expression of the collagen type II (CII) to antigen presenting cells (APCs) induced antigen-specific tolerance, where only 5% of the mice developed arthritis as compared with 95% of the control mice. In the CII-tolerized mice, the proportion of Tregs as well as mRNA expression of SOCS1 (suppressors of cytokine signaling 1) increased at day 3 after CII immunization. Transfer of B cells or non-B cell APC, as well as T cells, from tolerized to naïve mice all mediated a certain degree of tolerance. Thus, sustainable tolerance is established very early during the course of arthritis and is mediated by both B and non-B cells as APCs. This novel approach for inducing tolerance to disease specific antigens can be used for studying tolerance mechanisms, not only in CIA but also in other autoimmune diseases.

Highlights

The main feature of rheumatoid arthritis (RA) is loss of tolerance to self-antigens followed by inflammation and joint destruction
In this study we demonstrate that transfer of hematopoietic stem cells expressing the collagen type II (CII)-peptide on major histocompatibility complex type II (MHCII) Aq (LNT-CII) to lethally irradiated mice induces an almost complete antigenspecific tolerance collagen II-induced arthritis (CIA)
We found that early events including up-regulation of SOCS1 and an increased proportion of Tregs associated with resistance to arthritis development

Summary

Introduction

The main feature of rheumatoid arthritis (RA) is loss of tolerance to self-antigens followed by inflammation and joint destruction. Immunosuppressive drugs reduce the immune response to self-antigens but they increase the risk for infections [1]. An ideal way to treat RA would be to re-establish tolerance without a general suppression of the immune system. The most commonly used mouse model for RA is collagen type II (CII)-induced arthritis (CIA). CII-specific tolerance in CIA depends on presentation of an already identified CII-peptide (amino acids (aa) 259–270) [3] in complex with the major histocompatibility complex type II (MHCII) Aq molecule [4,5].

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Results

Conclusion