The potentiation of human C1-inhibitor by dextran sulphate is transient invivo: studies in a rat model

C1-inhibitor (C1-Inh) is an important regulator of inflammatory reactions b ecause it is a potent inhibitor of the contact and complement system. C1-In h application in inflammatory disease is, however, restricted because of th e high doses required. The glycosaminoglycan-like molecule dextran sulphate (DXS) enhances C1-Inh function in vitro. Hence, we investigated whether co-administration with de xtran sulphate reduces the amount of C1-Inh required, through enhancement i n vivo. C1-Inh potentiation was measured in a newly developed C1s-inactivat ion assay that is based on activation of C4 by purified C1s. Activated C4 i n rat plasma was quantified with a newly developed ELISA. Human C1-Inh (2.5 muM) inhibited Cls in rat plasma 55-fold faster in the presence of dextran sulphate (15 kDa, 5 muM). To study the stability of the complex in vivo, r ats were given a mixture of C1-Inh (10 mg/kg) and dextran sulphate (3 mg/kg ), C1-Inh activity during 5 It was analyzed ex vivo with the C1s inactivati on assay. The noncovalent C1-Inh-dextran sulphate complex resulted in a tra nsient enhancement of the inhibitory capacity of C1-Inh, lasting for 60-90 min. Dextran sulphate did not affect plasma clearance of C1-Inh. We conclude that the enhanced inhibitory capacity of C1-Inh complexed to de xtran sulphate is transient in vivo. Hence, co-administration of these comp ounds seems a feasible approach to achieve short-term inhibition of complem ent in vivo. (C) 2001 Elsevier Science B.V. All rights reserved.