|[Frontiers in Bioscience 1, e34-41, July 1, 1996]|
PIG alpha1,3GALACTOSYLTRANSFERASE: A MAJOR TARGET FOR GENETIC MANIPULATION IN XENOTRANSPLANTATION
Karen Strahan, Andrew Preece and Kenth Gustafsson
Division of Cell & Molecular Biology, Institute of Child Health, University of London, 30 Guilford St., London WC1N 1EH, UK
Received 06/21/96; Accepted 07/02/96; On-line 07/08/96
The major limiting factor in clinical transplantation is the shortage of suitable human donors. If problems regarding ethical, physiological, and immunological issues can be solved, pigs have been suggested to be a future alternative source for at least some organs (1-4). The obstacles in this species combination may appear overwhelming. However, recent technological progress have suggested that overcoming the first immunological hurdle, the 'hyperacute rejection' (HAR), may be possible (5-10).
As defined by the ubiquitous presence of high titers of pre-formed natural antibodies (NAb) binding to the foreign tissue (11), pig to man organ transplantation is an example of a discordant species combination. The binding of these NAb to target epitopes on the donor organ endothelium is believed to be the initiating event in discordant xenogeneic HAR. This binding, within minutes of perfusion of the donor organ with the recipient blood, is followed by complement activation, platelet and fibrin deposition, and ultimately by interstitial edema and hemorrhage in the donor organ (e.g. 12).
The efforts to avoid HAR in this species combination have been based on three lines of work: 1. depletion of anti-pig NAb (5-7); 2. provision of human complement inhibitors in the transplanted organ by transgenic means (8, 9); and 3. inhibition or eradication of the target epitopes for the NAb (10, 13). In this review we describe the background to and the on-going work aimed at down-regulating the main target epitope for the human anti-pig NAb in pig cells.