Rat extracorporeal circulation model for evaluation of systemic immunotoxicity

We have applied a rat extracorporeal circulation (EC) model as an evaluation system for the immunotoxicity of medical devices in contact with the blood stream. Combining popular hemodialysis (HD) membranes [a non-biocompatible membrane, Cupurophane® (CUP), and more biocompatible membranes, Cu–ammonium rayon (CAR) and polyacrylonitrile (PAN)] with rat EC, we evaluated the elicitation of acute and delayed immunological responses, as well as the effect of repeated EC. Acute effect markers such as the production of tumor necrosis factor (TNF)-α and complement activity during EC, and delayed effect markers such as β 2-microglobulin (β 2-M), IgG, and complement 3 levels, were monitored. Acute markers after EC passage showed responses similar to those previously reported in patients with long-term hemodialysis such as TNF-α production and increased complement activity. Although β 2-M and IgG levels increased to 3- to 5-fold of the initial concentration within 4 weeks after rat EC, the trend of IgG increase was inversely correlated with membrane biocompatibility (CUP>CAR=PAN), but this did not occur for elevations in β 2-M (PAN>CAR>CUP). These data suggest that this EC model can reproduce similar immunological responses as seen in HD patients, and can be employed to evaluate medical devices and materials for their delayed, systemic, and repeated exposure effects with respect to immunotoxicity.