Xenografts are an achievable breakthrough.
The objective of this communication is to show that pig-to-human organ transplantation could be feasible through genetic engineering. By introducing into donor pigs several different tolerance promoting genetic modifications there can be a synergistic effect to produce extended tolerance for xenografted organs in human recipients. Nuclear-transfer cloning allows production of pigs with knockout mutations in the galactose-alpha-1,3-galactosyl transferase gene, in principle eliminating hyperacute rejection. Once hyperacute rejection is circumvented, long-term tolerance of xenografted organs should be possible through a combination of transgenic immunomodulating molecule, bone marrow chimerism and short to intermediate term use of immunosuppressive drugs. If immunomodulating transgenes are deleterious during pig development, inducible cre-recombinase excision of stop codons provides a means to delay expression of such transgenes until after transplantation. Zoonotic diseases can be circumvented via pathogen-free colonies and additional knockout mutations to disable porcine endogenous retrovirus and prion disease. Thus, there is now a technical and theoretical framework for serious efforts at cross-species transplantation.
Alisky
Joseph Martin
JM
Marshfield Clinic Research Foundation, 1000 Oak Avenue, Marshfield, WI 54449, USA. alisky.joseph@marshfieldclinic.org
D000818:Animals; D005700:Galactosyltransferases / Q000235:genetics*; D005818:Genetic Engineering / Q000379:methods*; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006801:Humans; D011994:Recombinant Proteins / Q000378:metabolism; D013552:Swine; D014181:Transplantation Immunology; D014183:Transplantation, Heterologous / Q000009:adverse effects / Q000379:methods*
D011994:Recombinant Proteins; D005700:Galactosyltransferases