title: Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection.
abstract: Previous studies indicate a pivotal role for complement in mediating both local and remote injury following ischemia and reperfusion of the intestine. Here, we report on the use of a mouse model of intestinal ischemia/reperfusion injury to investigate the strategy of targeting complement inhibition to sites of complement activation by linking an iC3b/C3dg-binding fragment of mouse complement receptor 2 (CR2) to a mouse complement-inhibitory protein, Crry. We show that the novel CR2-Crry fusion protein targets sites of local and remote (lung) complement activation following intestinal ischemia and reperfusion injury and that CR2-Crry requires a 10-fold lower dose than its systemic counterpart, Crry-Ig, to provide equivalent protection from both local and remote injury. CR2-Crry has a significantly shorter serum half-life than Crry-Ig and, unlike Crry-Ig, had no significant effect on serum complement activity at minimum effective therapeutic doses. Furthermore, the minimum effective dose of Crry-Ig significantly enhanced susceptibility to infection in a mouse model of acute septic peritonitis, whereas the effect of CR2-Crry on susceptibility to infection was indistinguishable from that of PBS control. Thus, compared with systemic inhibition, CR2-mediated targeting of a complement inhibitor of activation improved bioavailability, significantly enhanced efficacy, and maintained host resistance to infection.
authors.affiliation: Department of Microbiology and Immunology, Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Hongbin
authors.initials: H
authors.lastname: Song
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
authors.forename: Fei
authors.initials: F
authors.lastname: Qiao
authors.forename: Tara A
authors.initials: TA
authors.lastname: Burns
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
authors.forename: Stephen
authors.initials: S
authors.lastname: Tomlinson
mesh_terms: D000818:Animals; D016466:CHO Cells; D003141:Communicable Diseases; D003167:Complement Activation; D015933:Complement C3d / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D006224:Cricetinae; D004198:Disease Susceptibility; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D007422:Intestines / Q000166:cytology / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011951:Receptors, Complement / Q000235:genetics / Q000276:immunology; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D015427:Reperfusion Injury / Q000276:immunology / Q000473:pathology; D015996:Survival Rate
chemical_list: C081470:Cr1l protein, mouse; D007136:Immunoglobulins; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D017464:Receptors, Complement 3d; D011993:Recombinant Fusion Proteins; D015933:Complement C3d