Purchase this article with an account.
P. Gjorstrup, A. Dubrovskiy, D. Dodge, A. Savinainen, T. Crandall, L. Wu, S. Qin; RX-10001 (RvE1) an Endogenously Formed Immune Modulator Attenuates Clinical Signs of Autoimmune Disease in the Rat CIA Model Concurrent With Inhibition of T-Cell Dependent Cytokines in Mixed Cell Populations From Draining Lymph Nodes. Invest. Ophthalmol. Vis. Sci. 2009;50(13):819.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Resolvins and resolvin analogs are being developed for the treatment of various inflammatory eye indications. Using an established model of antigen recall challenge we now wanted to investigate the therapeutic potential of resolvins in autoantigen dependent conditions.
Arthritis was induced in Lewis female rats with type II collagen in Freund’s complete adjuvant by injection on Day 0 and rechallenge on Day 6. Clinical signs of disease are commonly apparent on Day 9 with subclinical disease from Day 7. Animals were dosed with RX-10001 (RvE1) (0.3 mg/kg BID) or vehicle (BID) either during the induction phase Day 0-10, or during the effector phase Day 7-17. Ankle joint swelling was measured with calipers. In a second set of animals that received the same treatment regimen the draining lymph nodes were harvested on either Day 6 or Day 17 and single cell suspensions of mixed lymph node cells were exposed to collagen challenge ex vivo and T-cell dependent cytokines measured. Single cell suspensions were obtained from freshly harvested lymph nodes by pressing the lymph node through a 40 um nylon strainer (BD Falcon). Cells were washed and resuspended to 4E6 cells/mL in RPMI-1640/10% FCS. Cells were incubated overnight in a tissue culture incubator (37°C, 5% CO2). Supernatants were harvested and stored at -80°C until analysis.
Compared to vehicle treated animals RX-10001 significantly reduced clinical scores of disease in animals receiving either prophylactic treatment (Day 0-10) or therapeutic treatment (Day 10-17) with a 53% and 29% reduction in disease scores, respectively. This was paralleled by a reduction in the release of T-cell dependent cytokines from the mixed lymph node cell cultures when challenged on either Day 6 or 17. The Th1 dependent cytokine INFγ was reduced by 77% in animals treated with RX-10001 during the induction phase and by 47% during the effector phase. For IL-17 released from Th17 cells the corresponding reductions were 90% and 82%.
The results suggest that RX-10001 downregulates antigen presenting cell (APC) dependent activation of T-cells critical for both the induction and maintenance of an antigen dependent inflammatory response. RX-10001 and other resolvins may have a role in the treatment chronic inflammatory eye conditions are considered autoantigen dependent. Experiments are now planned in models of uveitis/iritis.
This PDF is available to Subscribers Only