Decreased alloreactivity using donor cells from mice expressing a CD200 transgene under control of a tetracycline-inducible promoter.

BACKGROUND: CD200 delivers an immunsuppressive signal that augments allograft survival following interaction with its receptor, CD200R1. We hypothesized that mice overexpressing CD200 as a trangene would also show a diminished alloresponsiveness and decreased allograft rejection.

METHODS: A transgenic mouse on a C57BL/6 background, expressing a murine CD200 cDNA genetically linked to a green fluorescent protein tag (GFP) under control of a tetracycline response element (TRE), was mated with a commercial transgenic mouse carrying the reverse tetracycline regulated transactivator gene under control of a human CMV promoter. F1 mice were examined for induction of alloimmunity in vivo/in vitro, and for their ability to reject skin allografts in vivo.

RESULTS: The F1 hybrid expressed CD200 after exposure to doxycyline (DOX), as assessed both by enhanced GFP expression in multiple organs and CD200-GFP expression. Splenocytes from F1 mice stimulated with LPS or allogeneic cells in vitro in the presence/absence of DOX showed reduced production of TNFalpha, and of allospecific CTL. Splenocytes from F1 mice used as stimulator cells in allogeneic MLCs in the presence of DOX were inefficient at induction of cytokines or CTL in vitro from normal allogeneic responder cells. Skin grafts from transgenic mice were inefficient at induction of CTL in vivo. Transgenic mice receiving DOX showed prolonged acceptance of skin allografts, which was abolished by infusion of anti-CD200 mAb.

CONCLUSIONS: Our data confirmed that overexpression of CD200 in transgenic mice, or in skin grafts from these mice, decreases alloimmunity. This has potential clinical utility in transplantation and other diseases.