IMMUNOSUPPRESSION BY BLOCKING T CELL CO-STIMULATION SIGNAL 2 (B7/CD28 INTERACTION)

摘要

The invention provides means and methods for inhibiting T-cell mediatedrejection of a xenotransplanted organ by blocking the delivery of co-stimulatory signal 2 (the B7/CD28 interaction) in order to prevent theactivation of xenoreactive T-cells in the recipient. In a first aspect, co-stimulation is prevented by administration to the organ recipient of a solubleform of CTLA-4 from the xenogeneic donor organism. This preferentially bindsB7 on the xenograft and blocks the interaction between B7 on the xenogeneicdonor cells and CD28 on recipient T-cells. In a second aspect, co-stimulationis antagonised by expressing a ligand for CTLA-4 on the xenogeneic donorcells. This ligand binds to CTLA-4 on activated T-cells of the recipient andantagonises signal 2. In a third aspect, co-stimulation is prevented byexpressing recipient organism MHC class II on the surface of the cells of thexenogeneic donor organ. The donor cells are thus able to present xenoantigensto a recipient T-cell in the context of self-MHC class II. If the donor cellsdo not express B7, or if B7 is blocked, the xenoreactive recipient T-cellbecomes anergic.