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Low-Dose Targeted Complement Inhibition Protects against Renal Disease and Other Manifestations of Autoimmune Disease in MRL/lpr Mice¹

Carl Atkinson^*, Fei Qiao^*, Hongbin Song^*, Gary S. Gilkeson^, and Stephen Tomlinson^2,*

^* Department of Microbiology and Immunology and Children’s Research Institute and Department of Medicine and Children’s Research Institute, Medical University of South Carolina, Charleston, SC 29425; and Medical Research Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29425

Complement appears to play a dual role in the progression of systemic lupus erythematosus, serving a beneficial role in enhancing immune complex clearance, while serving a pathogenic role in inducing local inflammation. To investigate these different roles of complement in a therapeutic setting, MRL/lpr mice were treated with the targeted murine C3 complement inhibitor, CR2-Crry, from 16 to 24 wk of age (after the development of proteinuria). The targeting moiety, CR2, binds to C3 breakdown products deposited at sites of complement activation and has the potential to provide complement inhibition locally without causing systemic inhibition. Administration of CR2-Crry i.v., at a dose of 0.25 mg once a week, was associated with a significant survival benefit, improved kidney function, and a significant reduction in glomerulonephritis and renal vasculitis. The presence of skin lesions and lung bronchiolar and vascular inflammation was also dramatically reduced by CR2-Crry treatment. CR2-Crry treatment also resulted in a significant reduction in autoantibody production, as measured by anti-dsDNA Ab levels, and did not cause an increase in circulating immune complex levels. These effects on autoimmunity and circulating immune complexes represent significant potential advantages over the use of Crry-Ig in MRL/lpr mice, a systemic counterpart of CR2-Crry. CR2-Crry localized preferentially to the kidneys in 16-wk MRL/lpr mice with a kidney-localized half-life of 24 h. Thus, targeted complement inhibition at the C3 level is an effective treatment in murine lupus, even beginning after onset of disease.

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 a grant from the Alliance for Lupus Research, the Department of Defense (W81 XWH-07-1-0161), and the National Institutes of Health (C06 RR015455 for construction and upgrade of animal facilities).

² 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 address: tomlinss{at}musc.edu

³ Abbreviations used in this paper: SLE, systemic lupus erythematosus; CR2, complement receptor 2; SUN, serum urea nitrogen.

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