Systemic gene transfer of binding immunoglobulin protein (BiP) prevents disease progression in murine collagen-induced arthritis

AM Shields, LS Klavinskis, M Antoniou, PH Wooley, HL Collins, GS Panayi, SJ Thompson, VM Corrigall

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Recombinant human binding immunoglobulin protein (BiP) has previously demonstrated anti‐inflammatory properties in multiple models of inflammatory arthritis. We investigated whether these immunoregulatory properties could be exploited using gene therapy techniques. A single intraperitoneal injection of lentiviral vector containing the murine BiP (Lenti‐mBiP) or green fluorescent protein (Lenti‐GFP) transgene was administered in low‐ or high‐dose studies during early arthritis. Disease activity was assessed by visual scoring, histology, serum cytokine and antibody production measured by cell enzyme‐linked immunosorbent assay (ELISA) and ELISA, respectively. Lentiviral vector treatment caused significant induction of interferon (IFN)‐γ responses regardless of the transgene; however, further specific effects were directly attributable to the BiP transgene. In both studies Lenti‐mBiP suppressed clinical arthritis significantly. Histological examination showed that low‐dose Lenti‐mBiP suppressed inflammatory cell infiltration, cartilage destruction and significantly reduced pathogenic anti‐type II collagen (CII) antibodies. Lenti‐mBiP treatment caused significant up‐regulation of soluble cytotoxic T lymphocyte antigen‐4 (sCTLA‐4) serum levels and down‐regulation of interleukin (IL)‐17A production in response to CII cell restimulation. In‐vitro studies confirmed that Lenti‐mBiP spleen cells could significantly suppress the release of IL‐17A from CII primed responder cells following CII restimulation in vitro, and this suppression was associated with increased IL‐10 production. Neutralization of CTLA‐4 in further co‐culture experiments demonstrated inverse regulation of IL‐17A production. In conclusion, these data demonstrate proof of principle for the therapeutic potential of systemic lentiviral vector delivery of the BiP transgene leading to immunoregulation of arthritis by induction of soluble CTLA‐4 and suppression of IL‐17A production.
Original languageEnglish
Pages (from-to)210-219
Number of pages10
JournalClinical and Experimental Immunology
Volume179
Issue number2
Early online date17 Sep 2014
DOIs
Publication statusPublished - Feb 2015

Keywords

  • BiP
  • collagen-induced arthritis
  • gene therapy
  • lentiviral vector

Fingerprint

Dive into the research topics of 'Systemic gene transfer of binding immunoglobulin protein (BiP) prevents disease progression in murine collagen-induced arthritis'. Together they form a unique fingerprint.

Cite this