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 4

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Anti-CD137 mAb treatment protects mice from developing proteinuria. Urin...
Anti-CD137 mAb treatment protects mice from developing proteinuria. Urine was collected from mice in each of the three groups enrolled in the serum anti-dsDNA autoantibody studies described in Figure 1 and tested for protein content by the Albustix method as described in Methods. (a–c) Ovals represent untreated mice and squares represent mice treated with anti-CD137 mAb’s. (a) One injection of anti-CD137 mAb was given at 8 weeks of age. (b) Mice received seven injections of anti-CD137 mAb’s beginning at 8 weeks of age and continuing once every third week. (c) Mice received their first of three anti-CD137 mAb injections at 25 weeks of age and one thereafter every third week for a total of three injections. All injections were administered intraperitoneally at a dose of 200 μg.