Cell Apoptosis

In lpr mice, CD137 engagement with anti-CD137 resulted in massive dimin-ishment of lymphocytes including DNTCs, CD4+ T cells and autoreactive B cells in a Fas and TNF-independent manner accompanied with increased apoptosis in those populations (Sun et al., 2002a).

In MRL/lpr mice, agonistic anti-CD137 treatment dramatically decreased both the total B cell and anti-DNA-secreting B cell populations in an IFN-y-dependent manner (Sun etal., 2002a). This was not likely due to a direct effect of the treatment, since CD137 was not detected on B cells. In B6/lpr mice, engagement of CD137 induced drastic IFN-y production as well as expansion of CD11b+/Gr-1 + macrophages/granulocytes population. Both B cell depletion and CD11b+/Gr-1 + cell expansion are IFN-y-dependent (Sun et al., 2002a). It has been shown that IFN-y is able to activate macrophages, which in turn induces apoptosis of activated lymphocytes by direct or indirect mechanisms (Ding etal., 1988; Haendeler etal., 1999; Williams etal., 1998). In B6/lpr mice, IFN-y activated macrophages indeed induced B-cell apoptosis in vitro (Sun et al., 2002a). In addition, anti-CD137 activated human monocytes induced B cell apoptosis as well (Kienzle and von Kempis, 2000). CD137 costimulation induced B cell apoptosis was also observed in cGVHD model (Kim et al., 2005). Anti-CD137 treatment increased host B cell apoptosis resulting in decreased host B cell number, and the deletion of both alloreactive CD4+ T cells and autoreactive B cells contributes to the inhibition of cGVHD by CD137 engagement.

Similarly, consistent CD137/CD137L interaction led to progressive B cell diminishment in transgenic mice expressing CD137L on class II positive cells (Zhu et al., 2001). These transgenic mice showed selective depletion of B cells and increase of macrophages in the peripheral, low levels of circulating IgG, and defective humoral responses to antigen challenge.

Above studies suggest that CD137 signaling augmented T cell IFN-y production that promoted the activation of macrophages/granulocytes, which in turn induced the apoptosis of activated autoreactive B cells, thereby resulting in decreased autoantibody production. In the mean time, insufficient T cell help due to the decreased CD4+ T cell number or function may also contribute to the suppression of autoantibody production.

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