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Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease

Nature Medicine volume 8, pages 1405–1413 (2002)Cite this article

Abstract

Humans and mice deficient in Fas, a tumor necrosis factor (TNF)-receptor family member, cannot induce apoptosis of autoreactive cells, and consequently develop progressive lymphoproliferative disorders and lupus-like autoimmune diseases. Previous studies have shown that short-term administrations of agonistic monoclonal antibodies against CD137, another TNF-receptor family member, activate T cells and induce rejection of allografts and established tumors. Here we report that treatment with an agonistic monoclonal antibody to CD137 (2A) blocks lymphadenopathy and spontaneous autoimmune diseases in Fas-deficient MRL/lpr mice, ultimately leading to their prolonged survival. Notably, 2A treatment rapidly augments IFN-γ production, and induces the depletion of autoreactive B cells and abnormal double-negative T cells, possibly by increasing their apoptosis through Fas- and TNF receptor–independent mechanisms. This study demonstrates that agonistic monoclonal antibodies specific for costimulatory molecules can be used as novel therapeutic agents to delete autoreactive lymphocytes and block autoimmune disease progression.

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Figure 1: Effects of 2A treatment on lymphocyte populations and antibody production.
Figure 2: Mechanisms underlying in DNTC and B-cell depletion.
Figure 3: Administration of 2A ameliorates lymphadenopathy in MRL/lpr mice.
Figure 4: 2A administration completely blocks the development of skin lesions.
Figure 5: 2A treatment attenuates renal disease and auto-antibody production, and prolongs survival.
Figure 6: Therapeutic effects of 2A in MRL/lpr mice with advanced disease.

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Acknowledgements

This research was in part supported by NIH grants (HD-37104, DK-20595-25, and DK-58891) and JDFI (1-2000-875). J.C. was in part supported by the Howard Hughes Medical Institute undergraduate summer program.

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Authors and Affiliations

  1. Department of Pathology and Committee in Immunology, University of Chicago, Chicago, Illinois, USA

    Yonglian Sun, Helen M. Chen, Sumit K. Subudhi, Jonathan Chen, Rima Koka & Yang-Xin Fu

  2. Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA

    Lieping Chen

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Sun, Y., Chen, H., Subudhi, S. et al. Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat Med 8, 1405–1413 (2002). https://doi.org/10.1038/nm1202-796

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