Triple immunosuppression protects murine intracerebral, hippocampal xenografts in adult rat hosts: effects on cellular infiltration, major histocompatibility complex antigen induction and blood-brain barrier leakage.

Abstract Recently, we reported protection of intracerebral mouse to rat hippocampal xenografts upon treatment with a combination of cyclosporin A, prednisolone and azathioprine. These findings are now supported in an extended analysis of graft-infiltrating cells. Host T-cell and macrophage infiltration and the immunocytochemical level of cellular expression of major histocompatibility complex class I and II antigens, measured by densitometric analysis, were compared between recipient rats receiving cyclosporin A alone or cyclosporin A in combination with prednisolone and azathioprine. The combination therapy resulted in a much improved survival of the xenografted hippocampal tissue with preservation of organotypic granule and pyramidal cell layers. Graft infiltration by T-cells and macrophages was significantly lower, and the level of major histocompatibility complex class I and II antigen expression by the infiltrating cells markedly reduced. Lower expression of donor-type major histocompatibility complex class I antigen was also found in the xenografts in the trimedicated recipients, together with reduced blood–brain barrier leakage and astrogliosis at the host–graft interface. The results demonstrate the benefits of using combined immunosuppressive strategies for protection of histoincompatible brain xenografts in the central nervous system.