Transgenic strategies to overcome cell-mediated and acute vascular rejection of pig-to-human xenografts.

The development of α(1,3)-galactosyltransferase deficient pigs along with overexpression of complement regulatory proteins was an important step to overcome hyperacute rejection of pig organs transplanted into primates. However, the lack of galactose-α(1,3)-galactose (αGal) epitopes does not protect against subsequent rejection mechanisms, such as acute vascular rejection and rejection by immune cells which play crucial roles to achieve prolonged graft survival in pig-to-human xenotransplantation models. Our task within the DFG Transregio Research Unit “Xenotransplantation” is primarily the development of transgenic strategies to overcome cell mediated rejection of pig-to-primate xenografts. Our first target was the lysis of porcine cells by activated human natural killer (NK) cells, which involves antibody-dependent and -independent mechanisms. A majority of human NK cells express the inhibitory receptor CD94/NKG2A, which binds specifically HLA-E, a trimeric complex consisting of the HLA-E heavy chain, β2-microglobulin (β2m) and a peptide derived from the leader sequence of some MHC class I molecules. To use this mechanism for protection of pig tissues against human NK cell-mediated cytotoxicity... [ABSTRACT FROM AUTHOR]

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