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This Article Full Text Full Text (PDF) Extended Methods All Versions of this Article: jimmunol.0901826v1 183/9/5928    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Banda, N. K. Articles by Holers, V. M. PubMed PubMed Citation Articles by Banda, N. K. Articles by Holers, V. M.

Targeted Inhibition of the Complement Alternative Pathway with Complement Receptor 2 and Factor H Attenuates Collagen Antibody-Induced Arthritis in Mice¹

Nirmal K. Banda,^* Brandt Levitt,^* Magdalena J. Glogowska,^* Joshua M. Thurman, Kazue Takahashi, Gregory L. Stahl, Stephen Tomlinson,^¶ William P. Arend,^* and V. Michael Holers^2*

^*Division of Rheumatology and Division of Nephrology and Hypertension, University of Colorado Denver, School of Medicine, Aurora, CO 80045; Developmental Immunology, Massachusetts General Hospital for Children, Boston, MA 02114; Brigham and Women’s Hospital, Boston, MA 02115; and ^¶Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425

The alternative pathway (AP) of complement is required for the induction of collagen Ab-induced arthritis (CAIA) in mice. The objective of this study was to examine the effect of a recombinant AP inhibitor containing complement receptor 2 and factor H (CR2-fH) on CAIA in mice. CR2 binds to tissue-fixed activation fragments of C3, and the linked fH is a potent local inhibitor of the AP. CAIA was induced in C57BL/6 mice by i.p. injections of 4 mAb to type II collagen (CII) on day 0 and LPS on day 3. PBS or CR2-fH (250 or 500 µg) were injected i.p. 15 min after the mAb to CII on day 0 and 15 min after LPS on day 3; the mice were sacrificed on day 10. The disease activity score (DAS) was decreased significantly (p < 0.001) in both groups receiving CR2-fH compared with the PBS. Histology scores for inflammation, pannus, bone damage, and cartilage damage decreased in parallel with the DAS. C3 deposition in the synovium and cartilage was significantly reduced (p < 0.0001) in the mice treated with CR2-fH. In vitro studies with immune complexes containing type II collagen and mAb to CII showed that CR2-fH specifically inhibited the AP with minimal effect on the classical pathway (CP) and no effect on the lectin pathway (LP). The relative potency of CR2-fH in vitro was superior to mAbs to factor B and C5. Thus, CR2-fH specifically targets and inhibits the AP of complement in vitro and is effective in CAIA in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants R01 AR51749 and R01 DK076690 and the Sandler Program for Asthma Research.

² Address correspondence and reprint requests to Dr. V. Michael Holers, Division of Rheumatology, B115, University of Colorado Denver, School of Medicine, 1775 Aurora Court, Aurora, CO 80045. E-mail address: Michael.Holers{at}UCDenver.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; AP, alternative pathway; CAIA, collagen Ab-induced arthritis; CIA, collagen-induced arthritis; CP, classical pathway; CII, type II collagen; DAS, disease activity score; IC, immune complex; LP, lectin pathway; SCR, short consensus region; WT, wild type.

⁴ The online version of this article contains Extended Methods.