Adjuvant\induced arthritis (AIA) was induced by subcutaneously injecting rats at the base of the tail with 100?l of complete Freunds adjuvant (CFA) containing 10?mg/ml heat\killed H37RA (Difco Laboratories, Detroit, MI, USA). beneficial biological effects [19]. Through its anti\inflammatory properties, AS101 confers protection, reverses damage and prevents progression of diseases in several autoimmune animal models [20, 21, 22, 23, 24] and septic mice [25]. In light of the above, our study explored the potential anti\inflammatory and anti\arthritic effects of AS101 in the widely used adjuvant\induced arthritis (AIA) rat model. Material and methods Animals and experimental design Experimental arthritis was induced in 6C8\week old Lewis female rats (Harlan Laboratories, Jerusalem, Israel). Rats were maintained in a conventional animal housing facility at Sheba Medical Center and kept in individually ventilated cages. All experiments were approved and executed according to the protocols of the ethics committee of the Israeli Ministry of Health (no. 665/11/ANIM). Adjuvant\induced arthritis (AIA) was induced by subcutaneously injecting rats at the base of the tail with 100?l of complete Freunds adjuvant (CFA) containing 10?mg/ml heat\killed H37RA (Difco Laboratories, Detroit, MI, USA). AIA rats were allocated into two groups: phosphate\buffered saline (PBS)\treated rats (the AS101 group [analyzed by repeated\measures analysis of variance (anova) test]. Open in a separate window Fig. 2 AS101 alleviates clinical symptoms of arthritic rats. Severe clinical symptoms such, as swelling and distortion, can be noted in phosphate\buffered saline (PBS)\treated rats. Prophylactic intraperitoneal (i.p.) S101 treatment, 15 mg/kg, starting on day 0, three times per week, markedly alleviates these symptoms. The photographs of rat hind\paws shown above are representative photographs of the other rats in each group (PBS\treated rats (08??026 181??026, respectively, 5 rats per group. Histopathology score was determined (day?40) as described in Materials and methods. AS101 treatment significantly reduced histopathology score (E). The results shown are mean??standard error of the mean (s.e.m.) (the PBS group (analyzed by Students 08??01, PBS group (analyzed by Students control; *IL\1 alone. (c) AS101 does not affect NHDF proliferation. NHDF cells were seeded into 96 wells (5% FBS) with/without AS101 at increasing concentrations (05, 1, 25 and 5?g/ml) for 24 or 48?h. Proliferation was assayed by XXT assay. Optical density (OD) levels were compared to control which was normalized to 100% (10). Statistical analysis was performed by one\way analysis of variance (anova). Results are presented as means??standard error (s.e.) of three distinct experiments. Discussion Understanding of the pathogenic mechanisms underlying the inflammatory process involved in RA has resulted in the revolutionization of therapeutic modalities during the past two decades, reflected by improved disease outcomes, preservation of synovial joints and maintenance of functional capacity. Undeniably, reappraisal of these therapies has uncovered several shortcomings, including significant financial burden, the need for long\term therapy, increased susceptibility to serious infections and malignancies, frequent need for drug discontinuation/switching due to inefficacy or intolerability, lack of cure and difficulty in tapering and de\escalation of biological therapies without aggravating the disease course [1, 4]. The non\toxic immunomodulator AS101 provides a beacon of hope and is currently under clinical investigation for the treatment of cervical cancer and age\related macular degeneration. AS101 has been previously shown to AMD3100 (Plerixafor) exhibit profound anti\inflammatory properties in various experimental inflammatory/autoimmune diseases, owing to its Te(IV) redox chemistry [17, 18, 20, 21, 22, 23]. The ability of AS101 to react with vicinal thiols results in the functional inhibition of inflammatory integrins such as 41 (VLA\4) and 47, and the prevention of inflammatory/autoreactive lymphocytes (41 and 47\expressing T cells and macrophages) extravasation into the relevant sites of inflammation. Similarly, treatment with AS101 was previously shown to reduce proinflammatory cytokines such as AMD3100 (Plerixafor) tumor necrosis factor (TNF)\, IL\1, interferon (IFN)\, IL\17, IL\6 and IL\18, with a concomitant increase of regulatory cells [16, 17, 20, 21, 24, 28, 29]. The putative anti\inflammatory capacity of AS101 provided the basis for our Rabbit Polyclonal to MBL2 investigation in the RA animal model. To this end, we used the AIA rat model and our data supported the role of prophylactic treatment AMD3100 (Plerixafor) with AS101 in the prevention of RA disease progression (Fig. ?(Fig.1),1), demonstrated by the amelioration of clinical manifestations such as joint distortion, redness and swelling (Fig. ?(Fig.2).2). This response was mediated by the prevention of inflammatory lymphocyte migration into.
