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* Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425; and
Department of Medicine and
Department of Immunology, Division of Rheumatology, University of Colorado Denver School of Medicine, Denver, CO 80045
Bioavailability and therapeutic efficacy of soluble Crry, a mouse inhibitor of all complement activation pathways, is significantly enhanced when linked to a fragment of complement receptor 2 (CR2), a receptor that targets C3 activation products. In this study, we characterize alternative pathway-specific inhibitors consisting of a single or dimeric N-terminal region of mouse factor H (fH; short consensus repeats 1–5) linked to the same CR2 fragment (CR2-fH and CR2-fHfH). Both CR2-fH and CR2-fHfH were highly effective at inhibiting the alternative pathway in vitro and demonstrated a higher specific activity than CR2-Crry. CR2-fH was also more effective than endogenous serum fH in blocking target deposition of C3. Target binding and complement inhibitory activity of CR2-fH/CR2-fHfH was dependent on CR2- and C3-mediated interactions. The alternative pathway of complement plays a role in intestine ischemia/reperfusion injury. However, serum fH fails to provide protection against intestine ischemia/reperfusion injury although it can bind to and provide cell surfaces with protection from complement and is present in plasma at a high concentration. In a mouse model, CR2-fH and CR2-fHfH provided complete protection from local (intestine) and remote (lung) injury. CR2-fH targeted to the site of local injury and greatly reduced levels of tissue C3 deposition. Thus, the targeting mechanism significantly enhances alternative pathway-specific complement inhibitory activity of the N-terminal domain of fH and has the potential to reduce side effects that may be associated with systemic complement blockade. The data further indicate alternative pathway dependence for local and remote injury following intestinal ischemia/reperfusion in a clinically relevant therapeutic paradigm.
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1 This work was supported by grants from the National Institutes of Health (R01 HL082485 and RO1 AR51749) and Department of Defense (W81 XWH-07-2-003) and an National Institutes of Health grant for construction and upgrade of animal facilities (C06 RR015455).
2 Y.H. and F.Q. contributed equally to this article.
3 Address correspondence and reprint requests to Dr. Stephen Tomlinson, Department of Microbiology and Immunology, Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29425. E-mail: tomlinss{at}musc.edu
4 Abbreviations used in this paper: fH, factor H; SCR, short consensus repeat; CR2, complement receptor 2; IRI, ischemia/reperfusion injury; CHO, Chinese hamster ovary; fB, factor B; I/R, ischemia/reperfusion; fD, factor D; MBL, mannan-binding lectin.
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