Genetically modified pigs with α1,3-galactosyltransferase knockout and beyond: a comprehensive review of xenotransplantation strategies

Xenotransplantation holds promise to eliminate the shortage of organs intended
for humans in need. Pigs constitute the most suitable organ xenograft donor due
to the fact that their organ anatomy physiological metabolism and immune
system resemble those of humans. However, swine organs rapidly cause
hyperacute rejection (HAR) and acute humoral xenograft rejection (AHXR) after
transplantation. HAR and AHXR are caused by the presence of xenoreactive
natural immunoglobulins directed toward a galactose alpha1-3-galactose
(alpha-Gal) epitope on porcine vascular endothelium. In order to suppress
both types of rejection, pigs with alpha1,3-galactosyltransferase gene knockout
(GT-KO) and other genetic modifications (like simultaneous expression of the
human complementary regulatory proteins) are intensively investigated. This
review highlights the usefulness of GT-KO pig – derived organs such as kidney,
heart, corneal, and lung in xenotransplantation. To obtain transgenic pigs
researchers can use several techniques based on pronuclear and cytoplasmic
microinjection, somatic cell nuclear transfer (SCNT), viral transduction of DNA
and DNA transposable element -based technology, site specific nucleases and
modifications of the CRISPR/Cas bacterial immune system. Some additional
strategies like targeted immunosuppression or tolerance induction of B and T
cells will be essential for sustained survival of xenografts. Although
xenotransplantation with the use of pigs is a very rapidly evolving field, more
research is needed to create perfectly compatible with the human immune
system organs.