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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

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CD137 is expressed on activated T cells and ligands to this costimulatory molecule have clinical potential for amplifying CD8 T cell immunity to tumors and viruses, while suppressing CD4 autoimmune T cell responses.To understand the basis for this dichotomy in T cell function, CD4 and CD8 antiviral immunity was measured in lymphocytic choriomeningitis virus (LCMV) Armstrong-or A/PR8/34 influenza-infected mice injected with anti-CD137 mAbs. We found that the timing of administration of anti-CD137 mAbs profoundly altered the nature of the antiviral immune response during acute infection. Antiviral immunity progressed normally for the first 72 hours when the mAb was administered early in infection before undergoing complete collapse by day 8 postinfection. Anti-CD137-injected LCMV-infected mice became tolerant to, and persistently infected with, LCMV Armstrong. Elevated levels of IL-10 early in the response was key to the loss of CD4 + T cells, whereas CD8 + T cell deletion was dependent on a prolonged TNF-α response, IL-10, and upregulation of Fas. Blocking IL-10 function rescued CD4 antiviral immunity but not CD8 + T cell deletion. Anti-CD137 treatment given beyond 72 hours after infection significantly enhanced antiviral immunity. Mice treated with anti-CD137 mAb 1 day before infection with A/PR8/34 virus experienced 80% mortality compared with 40% mortality of controls. When treatment was delayed until day 1 postinfection, 100% of the infected mice survived. These data show that anti-CD137 mAbs can induce T cell activation-induced cell death or enhance antiviral immunity depending on the timing of treatment, which may be important for vaccine development. Introduction CD137, a TNF receptor family member, is an activation-inducible T cell costimulatory receptor (1, 2) that is expressed on cells of the innate and adaptive immune system (reviewed in ref.3). CD137 ligands induce T cell proliferation and cytokine production in vitro (4-8), whereas CD137 ligands confer potent costimulatory effects upon CD8 + T cells in vivo (9, 10). Although CD137 crosslinking costimulates CD4 + T cells to proliferate in vitro, remarkably, it suppresses the development of T cell-dependent humoral immunity in vivo (11). Both attributes have made this reagent attractive for therapeutic use in treating cancer and autoimmune disease, and it is currently being evaluated for use as an adjuvant in vaccine design (12). Herein we assess the effect of altering the timing of anti-CD137 treatment during viral infection and in so doing reconcile the dichotomy between CD137-induced CD8 + T cell activation and CD4 + T cell suppression. We found that virusspecific CD4 + and CD8 + T cell proliferation proceeds normally over the first 3 days of infection. By day 8 postinfection (P.I.), large numbers of virus-specific CD4 + and CD8 + T cells were deleted, thus leading to the loss of humoral and T cell-mediated antiviral immune responses. Anti-CD137-injected lymphocytic choriomeningitis virus-infected (LCMV-infected) mice rapidly produced high

SUMMARYAgonistic antibodies against CD137 act as costimulators in the activation of CD8 T cells. They enhance the immune response against syngeneic tumour grafts and suppress T cell-dependent humoral immune responses in vivo. The present study was undertaken to determine whether suppression of antibody production by anti-CD137 mAb affects the development of collageninduced arthritis (CIA). Male DBA ⁄1J mice were immunized with bovine collagen II (CII) and treated with an agonistic anti-CD137 mAb or an isotype-matched control mAb. Mice were assessed regularly for macro-and microscopic signs of arthritis and for the appearance of collagen-specific antibody production. Interferon (IFN)-c determination, FACS analysis of splenocytes and histopathological joint examinations were performed after the animals were killed. Administration of anti-CD137 mAb at the time of collagen immunization blocked the development of disease and inhibited the humoral immune response against CII. Agonistic anti-CD137 mAb exhibited therapeutic efficacy even after the immune response to CII had succeeded and the disease became apparent. Furthermore, it induced a protective memory in the animals, enabling resistance to subsequent challenges with the pathogenic antigen. Our results suggest a key role for CD137 in the pathogenesis of CIA. This model provides insights into immunoregulatory conditions that control the pathogenesis of autoimmune diseases.