Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose: Rheumatoid arthritis (RA) is a chronic destructive autoimmune disease and in most patients the disease follows an intermittent course with periods of exacerbation and remission. Today’s treatment is based on continuous immunosuppression, irrespective of the patient’s inflammatory status. An attractive alternative treatment would provide a disease-regulated therapy that offers flexible drug delivery, high during flares and low during remission. To explore this concept we expressed the anti-inflammatory cytokine interleukin (IL)-10 gene under the control of an inflammation dependent promoter in a mouse model of RA, the streptococcal cell wall arthritis (SCW).
Methods: C57Bl6/N mice were injected intra-articularly in the knee joint with lentiviral vectors expressing a luciferase reporter or the therapeutic protein IL-10. The disease-regulated proximal promoters of S100a8, Cxcl1, Mmp13, Saa3, IL-1b, and TSG6 were selected from endogenous genes differentially regulated in the inflamed synovium of arthritic mice. The constitutive PGK promoter was used as a positive control. Arthritis was induced by injection of 25µg SCW into the knee joint cavity 4 days after lentivirus injection. At 1, 4, and 7 days after arthritis induction, in-vivo bioluminescent imaging was performed or mice were sacrificed and knee joints were dissected for either histological analysis, or RNA isolation for qPCR analysis.
Results: The 6 disease-regulated promoters all showed a different activation profile during the course of the disease. Two promoters were selected for IL-10 overexpression in the SCW model; the Saa3 promoter which showed an immediate and high upregulation at day 1 after arthritis induction, and the MMP13 promoter which showed a delayed response and peaked at day 4. For both regulated promoters, overexpression of IL-10 showed significant less synovitis at day 4 after arthritis induction (decrease from 2.2±0.2 to 1.6±0.2) and significant less cartilage proteoglycan (PG) depletion at day 4 (decrease from 2.6±0.2 to 1.3±0.2) and day 7 (decrease from 2.2±0.3 to 0.7±0.3) after arthritis induction. At day 4, IL1-Ra and SOCS3 genes were upregulated by Saa3-IL10, whereas at day 7 both Saa3-IL10 and MMP13-IL10 caused an upregulation of IL1Ra and SOCS3 gene expression. IL-1Ra is known to counteract the detrimental effects of IL-1 on cartilage damage and SOCS3 can inhibit the JAK/STAT pathway and subsequent inflammation. Therefore, these IL-10 induced changes in gene expressions can explain the diminished synovitis and PG depletion. Probably because IL-10 is expressed in the synovial tissue at day 1 of SCW arthritis without any treatment, a major therapeutic difference between the MMP13 and SAA3 promoter was not evident in this study.
Conclusion: Local inflammation-dependent IL-10 gene therapy suppresses experimental arthritis and is a promising strategy in the development of novel treatments for RA.
Disclosure:
E. A. Vermeij,
None;
M. G. A. Broeren,
None;
M. B. Bennink,
None;
O. J. Arntz,
None;
I. Gjertsson,
None;
W. B. van den Berg,
None;
F. A. J. van de Loo,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/disease-regulated-local-interleukin-10-gene-therapy-diminishes-synovitis-and-articular-cartilage-damage-in-experimental-arthritis/