GENE THERAPY OF ENTOTHELIAL CELLS WITH ANTI-APOPTOTIC PROTEINS FOR TRANSPLANTATION AND INFLAMMATORY CONDITIONS

摘要

A method of genetically modifying mammalian, especially endothelial cells to render them less susceptible to an inflammatory or other immunological activation stimulus is described, which comprises inserting in that cell or a progenitor thereof DNA encoding an anti-apoptotic polypeptide capable of inhibiting NF- kappa B and expressing the protein, whereby NF- kappa B in the cell is substantially inhibited in the presence of a cellular activating stimulus. Suitable polypeptides are selected from those having activity of a mammalian A20, BCL-2, BCL-XL (MCL-1) or A1 protein, including homologs and truncated forms of the native proteins. The BCL-2, BCL-XL or A1 active polypeptides can also be employed as homodimers or as heterodimers with another anti-apoptotic polypeptide of the BCL family. The method, which can be carried out in vivo or ex vivo or in vitro, is particularly useful in connection with allogeneic or, especially, xenogeneic transplantation, as well as to treat systemic or local inflammatory conditions. Transgenic or somatic recombinant non-human mammals can be prepared expressing such a polypeptide on a regulable basis by the endothelial cells thereof, and tissues or organs comprising such cells can be obtained for grafting into a mammalian recipient.