Molecular regulation of xenoreactivity

The past year has seen several pig-to-baboon transplant studies using α1,3-galactosyltransferase-deficient donors. There are now sufficient data to begin to assess the impact of this important modification, and to review additional genetic strategies that may bring xenotransplantation to the clinic.

Survival of pig heart and kidney xenografts can now be measured in months rather than weeks, and the introduction of α1,3-galactosyltransferase-deficient donors has removed the requirement for depletion of anti-galactose-α1,3-galactose antibodies. The main obstacle to even longer survival is the development of antibodies to as yet unidentified non-galactose-α1,3-galactose antigens. Analysis of rejected grafts indicates that these antibodies activate graft endothelium, and the resulting prothrombotic state is poorly controlled because endogenous porcine anticoagulants fail to efficiently regulate primate clotting factors. Manipulation of the donor or graft to express anticoagulant and immunosuppressive molecules has produced encouraging results in small animal models. It is conceivable that expression of these molecules in pigs, in combination with the existing α1,3-galactosyltransferase-deficient and complement regulator transgenic modifications, will result in stable long-term xenograft survival.

The α1,3-galactosyltransferase-deficient pig has advanced the field and becomes the platform on which further genetic modifications are built.