Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease

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-gamma 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.

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.…”

“…These studies suggest the diametric effect of CD137 costimulation on CD4 ϩ T cells. Our previous study showed that agonistic anti-CD137 treatment greatly reduced autoantibody production in Fas-deficient mice accompanied by a diminishment of the number of CD4 ϩ T cells and autoantibody-producing B cells (26). 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.…”

“…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).…”

“…First, it inhibits Th cell function through numerous mechanisms (25)(26)(27)(28). Secondly, it promotes B cell reduction (26). Thirdly, CD137 costimulation induces a T cell-dependent down-regulation of FDC networks, which, as Ag-trapping accessory cells within GCs, are essential for the development of humoral immune responses and memory.…”