Targeted complement inhibition by C3d recognition ameliorates tissue injury without apparent increase in susceptibility to infection

J Clin Invest. 2005 Sep;115(9):2444-53. doi: 10.1172/JCI25208. Epub 2005 Aug 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CHO Cells
  • Communicable Diseases*
  • Complement Activation
  • Complement C3d* / antagonists & inhibitors
  • Complement C3d* / genetics
  • Complement C3d* / immunology
  • Cricetinae
  • Disease Susceptibility*
  • Humans
  • Immunoglobulins / genetics
  • Immunoglobulins / immunology
  • Intestines* / cytology
  • Intestines* / immunology
  • Intestines* / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Receptors, Complement / genetics
  • Receptors, Complement / immunology
  • Receptors, Complement 3b
  • Receptors, Complement 3d / genetics
  • Receptors, Complement 3d / immunology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Reperfusion Injury* / immunology
  • Reperfusion Injury* / pathology
  • Survival Rate


  • Cr1l protein, mouse
  • Immunoglobulins
  • Receptors, Complement
  • Receptors, Complement 3b
  • Receptors, Complement 3d
  • Recombinant Fusion Proteins
  • Complement C3d