Background We previously reported that ARANESP™ alleviates ACD in a rodent model of peptidoglycan-polysaccharide polymer (PG-APS) mediated inflammation. We report here the further characterisation of this model and the effects of ARANESP™ treatment on ACD.
Methods Immunisation of Lewis rats with PG-APS induces chronic systemic inflammation characterised by relapsing arthritis and hepatic granulomas. Associated with the inflammation is acute, severe anaemia followed by chronic, moderately severe anaemia. As previously established, a 30 μg/kg dose of ARANESP™ every 2 weeks starting day 36 normalised peripheral blood (PB) haemoglobin levels by day 64.
Results Acutely anaemic rats had greatly enhanced mean PB reticulocyte counts and greatly reduced mean RBC counts. Mean PB reticulocyte and RBC counts normalised during chronic anaemia, but RBC remained hypochromic and microcytic. Individual anaemic rats had transient increases in serum erythropoietin (EPO) concentrations. However, there was no significant difference in mean EPO concentrations compared to controls, which suggests EPO production was blunted. Histology of day 36 and day 112 anaemic rat spleen sections revealed greatly enhanced iron retention by splenic macrophages. In contrast, bone marrow (BM) macrophages were nearly devoid of iron. Serum iron concentratioans were significantly reduced by day 7 and remained low throughout the study. Interestingly, ARANESP™ treated rats showed decreased iron retention in macrophages and increased serum iron starting day 98. To identify which cytokines may contribute to the chronic anaemia of this model, peritoneal exudate cells (PEC) were isolated and challenged with PG-APS in vitro. Unstimulated PEC produced little or no cytokines. PG-APS challenged PEC from anaemic rats produced IL-1α, TNF-α, and IFN-γ. PG-APS challenged PEC from ARANESP™ treated anaemic rats trended towards reduced levels of these cytokines relative to anaemic PEC cultures.
Conclusion In summary, we have shown this ACD model is similar to human ACD. Importantly, ARANESP™ treatment alleviates ACD in this model, thus indicating its potential therapeutic utility for human ACD.
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