Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Systemic, Lentiviral Gene Delivery of the Stress Protein BiP (Binding Immunoglobulin Protein) Improves Clinical, Histological and Immunological Parameters of Collagen-Induced Arthritis Via Suppression of IL-17.
Shields2, Adrian M., Wooley3, Paul H., Alyahya2, Rana, Panayi1, Gabriel S., Thompson2, Stephen J., Corrigall2, Valerie M.
Rheumatoid arthritis is an autoimmune disease principally manifesting as an autoimmune polyarthritis in the small diarthrodial joints. It is also characterised by multiple systemic sequelae.
Gene therapy offers a novel therapeutic approach to multisystem inflammatory diseases by permitting highly specific and disease-response, temporal and spatial expression of therapeutic genes.
The endoplasmic reticulum (ER) stress protein BiP (Binding immunoglobulin Protein) has demonstrated profound anti-inflammatory activity in human myeloid lineage cells and impressive therapeutic efficacy in multiple animal models of inflammatory arthritis. This study investigated the therapeutic potential of lentiviral gene therapy using BiP in the murine collagen-induced arthritis (CIA) model.
The murine BiP gene was manipulated to facilitate efficient protein secretion from transduced cells and cloned into a 3rd generation, self-inactivating HIV-1 lentiviral vector backbone containing the CMV immediate-early promoter and the WPRE stabilisation element (Lenti-BiP). An equivalent vector containing the GFP gene was produced as a control (Lenti-GFP). CIA was established in DBA/1 mice and lentiviral vectors were administered intraperitoneally at arthritis onset. Clinical, histological and immunological parameters of disease were studied.
2×10-7 infectious viral particles encoding the murine BiP gene significantly suppressed clinical disease scores compared to Lenti-GFP treated animals when delivered at disease onset (Figure) (day 55: Lenti-GFP - 8.6±0.6 vs. Lenti BiP 5.1±0.7, p=0.001).
Figure 1.Lenti-BiP modulates collagen induced arthritis.
Lower doses of Lenti-BiP (1×10|$$^7) also suppressed clinical and histological manifestations of disease, but not signficantly. The mechanism of Lenti-BiP mediated disease suppression depends on the inhibition of IL-17. The splenocytes of Lenti-BiP treated animals produced significantly less IL-17 in response to collagen-II restimulation compared to Lenti-GFP treated animals (Lenti-GFP - 3819±1502pg/ml vs. Lenti-BiP 2087±722pg/ml, p<0.05). Furthermore, Lenti-BiP treatment facilitated the development of regulatory cells; in admixing experiments, splenocytes from Lenti-BiP treated animals significantly suppressed IL-17 production from CII primed responder cells compared to Lenti-GFP treated animals (Lenti-GFP - 6119±689pg/ml vs. Lenti BiP 2697±444pg/ml, p<0.05). This was associated with significantly greater IL-10 secretion in co-cultures containing Lenti-BiP treated cells (Lenti-GFP 519±18pg/ml vs. Lenti BiP 662±49pg/ml, p<0.05)
Lentiviral delivery of the murine BiP gene modulates clinical, histological and immunological parameters of CIA. Further experiments are underway to examine the mechanism of Lenti-BiP mediated suppression and to target anti-inflammatory gene expression using stress-responsive promoters.
To cite this abstract, please use the following information:
Shields, Adrian M., Wooley, Paul H., Alyahya, Rana, Panayi, Gabriel S., Thompson, Stephen J., Corrigall, Valerie M.; Systemic, Lentiviral Gene Delivery of the Stress Protein BiP (Binding Immunoglobulin Protein) Improves Clinical, Histological and Immunological Parameters of Collagen-Induced Arthritis Via Suppression of IL-17. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1729