CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB × NZW F1 mice
Juergen Foell, … , Michael K. Hoffmann, Robert S. Mittler
Juergen Foell, … , Michael K. Hoffmann, Robert S. Mittler
Published May 15, 2003
Citation Information: J Clin Invest. 2003;111(10):1505-1518. https://doi.org/10.1172/JCI17662.
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Article Autoimmunity

CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB × NZW F1 mice

Abstract

Systemic lupus erythematosus (SLE) is a CD4+ T cell–dependent, immune complex–mediated, autoimmune disease that primarily affects women of childbearing age. Generation of high-titer affinity-matured IgG autoantibodies, specific for double-stranded DNA and other nuclear antigens, coincides with disease progression. Current forms of treatment of SLE including glucocorticosteroids are often inadequate and induce severe side effects. Immunological approaches for treating SLE in mice using anti-CD4 mAb’s or CTLA4-Ig and anti-CD154 mAb’s have proven to be effective. However, like steroid treatment, these regimens induce global immunosuppression, and their withdrawal allows for disease progression. In this report we show that lupus-prone NZB × NZW F1 mice given three injections of anti-CD137 (4-1BB) mAb’s between 26 and 35 weeks of age reversed acute disease, blocked chronic disease, and extended the mice’s lifespan from 10 months to more than 2 years. Autoantibody production in recipients was rapidly suppressed without inducing immunosuppression. Successful treatment could be traced to the fact that NZB × NZW F1 mice, regardless of their age or disease status, could not maintain pathogenic IgG autoantibody production in the absence of continuous CD4+ T cell help. Our data support the hypothesis that CD137-mediated signaling anergized CD4+ T cells during priming at the DC interface.

Authors

Juergen Foell, Simona Strahotin, Shawn P. O’Neil, Megan M. McCausland, Carolyn Suwyn, Michael Haber, Praveen N. Chander, Abhijit S. Bapat, Xiao-Jie Yan, Nicholas Chiorazzi, Michael K. Hoffmann, Robert S. Mittler

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Figure 1

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Inhibition of autoantibody production by anti-CD137 mAb’s. NZB/W F1 mice...
Inhibition of autoantibody production by anti-CD137 mAb’s. NZB/W F1 mice were injected intraperitoneally with anti-CD137 or control mAb’s, and serum samples were collected and assayed in triplicate by ELISA for anti-dsDNA antibodies. IgG or IgM anti-dsDNA autoantibody titers are expressed as the mean ± SD measuring the OD, at 495 nm, of triplicates for individual mice, using serially diluted serum samples. (a) Anti-dsDNA IgG serum titers of 41-week-old NZB/W F1 mice that were injected at weeks 14, 17, 20, 23, and 26 with anti-CD137 (open squares) or isotype-matched control mAb (filled circles), compared with serum from BALB/c mice (filled triangles). (b) Kinetics of IgM production in anti-CD137 mAb–treated mice (filled circles), mice treated with isotype-matched control mAb’s (open squares), and PBS-treated mice (filled triangles). (c) Kinetics of the appearance of IgG dsDNA-reactive autoantibodies in NZB/W F1 mice that received a single 200-μg intraperitoneal injection of anti-CD137 (filled squares) or control mAb (open squares) at 8 weeks of age. (d) Kinetics of IgG anti-dsDNA autoantibody production in mice in which anti-CD137 treatment (filled triangles) or isotype control mAb (open circles) 8-week-old were treated through 25 weeks of age (200 μg injected intraperitoneally every third week). (e) Kinetics of anti-dsDNA autoantibody production anti-CD137 treated (filled triangles) or control (open circles) mAb treated at 26 weeks of age after they had developed autoantibodies in their serum. (f) Clearance of serum anti-dsDNA IgG autoantibodies in proteinuric 40-week-old NZB/W F1 mice treated with a single injection of anti-CD137 (open triangles) or control mAb’s (filled circles).