Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Administration of IL-18BP by Gene Therapy Reduces Inflammation in Rat AIA
Marotte1, Hubert, Ruth1, Jeffrey H., Ahmed2, Salahuddin, Amin1, Mohammad A., Campbell1, Phillip L., Dudler3, Jean, Koch4, Alisa E.
University of Michigan Medical School, Ann Arbor, MI
University of Toledo, Toledo, OH
Service de Rhumatologie, Médecine Physique et Rééducation, Epalinges, Switzerland
Veteran's Administration and University of Michigan. Ann Arbor, MI
Interleukin-18 (IL-18) is a proinflammatory cytokine that is of pivotal importance for the induction of production of T helper (Th)1 cells. Enhanced production of IL-18 has been linked to the pathogenesis of diseases such as rheumatoid arthritis (RA). The natural inhibitor of IL-18 is the IL-18 binding protein (IL-18BP), which appears to be a promising novel therapeutic strategy for RA. This study examined expression of rat IL-18 and IL-18BP at various time points in the rat adjuvant-induced arthritis (AIA) model. Then, the benefit of ankle intra-articular injection of adenovirus (Ad) producing murine (m) IL-18BP-IgG1 (which cross-reacts with rat IL-18) was explored in the rat AIA model, in which arthritis is maximal at days 1418 post-adjuvant injection.
After induction of rat AIA, 3 rats were sacrificed at various time points (Day 0, 7, 11, 14, 18, 25, and 45). Ankle joints were homogenized and used for mRNA isolation. Rat IL-18 and IL-18BP expression at the mRNA level was assessed using qRT-PCR. In a preventative study, rats were divided into an AdmIL-18BP-IgG1 group (n=8) and an Ad green fluorescent protein (AdGFP) group (n=7). On day 8 after AIA induction, 1 × 108 plaque-forming units of the adenovirus (AdmIL-18BP-IgG1 or AdGFP) were injected into each ankle in a 10 mL volume. Clinical parameters (body weight, circumference, volume of both ankles, and articular score) were assessed on days 0, 2, 4, 7, 9, 11, 14, 16, 17, and 18 after adjuvant injection.
IL-18 and IL-18BP were both expressed in joints during development of rat AIA. We found a time-dependent increase of both IL-18 and IL-18BP. Furthermore, we observed a decrease in the [IL-18BP/IL-18] expression (roughly 40%) from day 7 to day 45. Administration of AdmIL-18BP-IgG1 decreased articular index scores at days 15 and 17 compared to AdGFP therapy (mean ± SEM; 2.9 ± 0.3 vs. 3.7 ± 0.2; p < 0.05 at day 15 and 3.1 ± 0.3 vs. 3.9 ± 0.1; p < 0.05, respectively); and paw volume at day 18 (2.1 ml ± 0.1 vs. 2.6 ml ± 0.1; p < 0.05). We found a decrease in the change in ankle circumference (minus day 0) values at day 18 compared to day 0 in the AdmIL-18BP-IgG1 group versus the AdGFP group (19.4 mm ± 2.3 vs. 25.2 mm ± 1.8; p < 0.05).
In rat AIA, we observed a decrease in the [IL-18BP/IL-18] expression before and during arthritis development. Preventatively, AdmIL-18BP-IgG1 restored IL-18BP expression and reduced joint inflammation in rat AIA, suggesting a potential benefit of similar therapy in RA.
To cite this abstract, please use the following information:
Marotte, Hubert, Ruth, Jeffrey H., Ahmed, Salahuddin, Amin, Mohammad A., Campbell, Phillip L., Dudler, Jean, et al; Administration of IL-18BP by Gene Therapy Reduces Inflammation in Rat AIA [abstract]. Arthritis Rheum 2009;60 Suppl 10 :3