Effect of CD80 and CD86 blockade and anti‐interleukin‐12 treatment on mouse acute graftversus‐host disease

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Abstract
We investigated the efficacy of a combination of anti‐CD80 and CD86 (CD80 + 86) monoclonal antibodies (mAb), anti‐interleukin (IL)‐12 mAb, or both, for prophylaxis in a mouse acute graft‐versus‐host‐disease (GVHD) model. The treatment with a combination of anti‐CD80 + 86 mAb efficiently reduced the lethality of GVHD, whereas mAb against either CD80 or CD86 alone had an effect. A delay in lymphocyte reconstitution and GVHD‐associated histological changes in organs was observed at 30 days post‐bone marrow transplantation (BMT) even in the anti‐CD80 + 86 mAb‐treated mice, although these manifestations were resolved by 100 days. In vitro, host alloantigen‐specific T cell proliferative responses and generation of CTL were significantly reduced by anti‐CD80 + 86 treatment. Furthermore, anti‐CD80 + 86 mAb preferentially inhibited the production of interferon (IFN)‐γ, but not IL‐4 and IL‐10, when cultures were assayed at 21 days. Although the anti‐IL‐12 mAb treatment alone inhibited the generation of cytotoxic T lymphocytes and IFN‐γ production in vitro, administration of anti‐IL‐12 mAb in vivo reversed the beneficial effects of anti‐CD80 + 86 treatment on host survival post‐BMT. The adverse effect of anti‐IL‐12 treatment seems to result from impairment of natural immunity and hematopoiesis, rather than as a consequence of an incomplete blockade of T helper (Th)1 responses. Our results suggest that the prevention of GVHD‐induced death results from the efficient blockade of Th1 cell activation by the anti‐CD80 + 86 treatment. However, further treatment is required for a complete prevention of GVHD, which seems to be partly mediated by Th2 cells.