EXTRACORPOREAL REMOVAL OF PRO-INFLAMMATORY CYTOKINES BY SPECIFIC ADSORPTION ONTO MICROSPHERES

Abstract

Elevated plasma concentrations of interleukin 1β (IL-1β) and tumor necrosis factor α (TNFα) derived from cellular stimulation have been found to correlate well with the systemic inflammatory response syndrome and clinical outcome of sepsis. Consequently, biologic inactivation and extracorporeal removal of these potent mediators gain increasing attractiveness as adjunctive therapeutic options. In realization of the latter strategy the authors developed specific adsorbents by covalently linking polyclonal antibodies against IL-1β and TNFα onto microspheres. The attachment process was characterized by high retention of antigen neutralizing activity. Batch testing of the adsorbents revealed specificity, biocompatibility, and high binding capacity (20.2 and 36.9 ng/mg of particles for IL-1β and TNFα, respectively). Employment of the particles in the Microspheres Based Detoxification System (MDS) resulted in efficient purification: human plasma spiked with recombinant IL-1β and TNFα (500 pg/ml) could be cleared at 42 ml/min (IL-1β) and 55 ml/min (TNFα) at a flow rate of 200 ml/min. These clearance rates are considerably higher than the values obtained with ultrafiltration. In conclusion, the microsphere technology allows efficient extracorporeal removal of cytokines from plasma. In addition, by combined application of IL-1β and TNFα binding particles and endotoxin adsorbents, such as cationically modified cellulose, it should be feasible to interfere with the complex pathobiochemical sequelae of sepsis.