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

Regulation of Follicular Dendritic Cell Networks by Activated T Cells: The Role of CD137 Signaling

“…Furthermore, our study shows that CD137 costimulation is not only able to down-regulate FDCs and prevent GC formation, it also can diminish FDCs and eliminate existing GC after the initiation of a humoral immune response. This is consistent with the idea that anti-CD137 treatment interferes with autoantibody production even after autoimmune disease establishment (26,27). Similarly, 2A treatment can abolish the formation of FDC networks in Fasdeficient mice in the absence of exogenous Ags, followed by a diminished production of autoantibodies (data not shown).…”

“…Agonistic mAbs against CD137 have been shown to be effective in promoting T cell-mediated immune responses in vivo (22)(23)(24), but they paradoxically also inhibit Tdependent humoral immunity (25) and prevent autoantibody production in various autoimmune disease models (26 -28). Previous studies attributed CD137-mediated suppression of Tdependent Ab responses to the inhibition of Th cells due to the induction of their anergy, activation-induced cell death, or induction of CD11c ϩ CD8 ϩ suppressor T cells and to the depletion of B cells (25)(26)(27)(28). Our current study unexpectedly found that CD137 costimulation dramatically down-regulates FDC networks in a T cell-dependent manner.…”

“…It is possible that the lack of FDC may reduce the survival of autoantibody-producing B cells, because FDC could provide a survival signal for activated B cells. Conversely, in lupus-prone NZB ϫ NZW F 1 female mice, Mittler et al (27) found that agonistic anti-CD137 treatment rapidly suppressed autoantibody production regardless of the age or disease a The mice were treated with 100 g of 2A with or without 1 ϫ 10 8 SRBC and/or 100 g of KLH immunization i.p. Two weeks later, spleens were harvested.…”

“…It is likely that multiple mechanisms are involved in the suppression of T cell-dependent humoral immune responses by CD137 costimulation. First, it inhibits Th cell function through numerous mechanisms (25)(26)(27)(28). Secondly, it promotes B cell reduction (26).…”

Enhancement of CD4 and CD8 immunity by anti-CD137 (4-1BB) monoclonal antibodies during hepatitis C vaccination with recombinant adenovirus

“…It has been described that the agonistic anti-CD137 antibodies in vivo have a preferential role as a costimulation molecule for CD8 + T cells, with no detectable effect on CD4 + T cells [34][35][36]51]. Moreover, some experiments have suggested that CD137 stimulation might induce CD4 + T cell anergy [52,53] or activationinduced T cell death [54]. However, there are several reports in in vitro models supporting the costimulatory effect of CD137 on CD4 + T cell proliferation and survival activation.…”