TY - JOUR
T1 - Low-dose targeted complement inhibition protects against renal disease and other manifestations of autoimmune disease in MRL/lpr mice
AU - Atkinson, Carl
AU - Qiao, Fei
AU - Song, Hongbin
AU - Gilkeson, Gary S.
AU - Tomlinson, Stephen
PY - 2008/1/15
Y1 - 2008/1/15
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.180.2.1231
DO - 10.4049/jimmunol.180.2.1231
M3 - Article
C2 - 18178863
AN - SCOPUS:40449119706
SN - 0022-1767
VL - 180
SP - 1231
EP - 1238
JO - Journal of Immunology
JF - Journal of Immunology
IS - 2
ER -