Pig organs are very close to human organs in structure, size and physiological function, and are the main research objects of xenotransplantation.However, due to the natural alpha-galactosyl antibody (Gal) of the human carrier, cross-species xenotransplantation can cause severe hyperacute rejection.The antibody binds to the vascular endothelial cells of the graft and activates the complement system, causing vascular endothelial edema and microvascular thrombosis, which in turn causes necrosis of the transplanted organ.
On Apr 15, 2019 , the David K. C. Cooper team of the Alabama University published a review article entitled "Justification of specific genetic modifications inpigs for clinical organ xenotransplantation" at Xenotransplantation. A systematic review of genetic modification schemes that have been found to promote xenotransplantation has been conducted.This review article covers the expression or knockout of nine genes : knock out of pig GGTA1, CMAH and β4GALNT2, expression of human CD46,CD55, TBM, ERCP, CD47, and HO-1.
The authors say that based on current technology, donor pigs for xenotransplantation must be “TKO pigs”, which knock out pig endogenous genes: GGAT1, CMAH and β4GalNT2. These three genes, which are abundantly expressed in pig organs and tissues, are the three major antigens that cause xenograft immune rejection. The "TKO pig" produced by CRISPR/Cas9 technology can greatly reduce its immunogenicity.
In addition, genetically edited pigs expressing human proteins can also significantly reduce xenotransplant rejection, vascular endothelial edema and microvascular thrombosis. Combinatorial expression can provide better inhibition, for example, human complement regulatory proteins (CD46, CD55), human thrombomodulin (TBM, EPCR). Related experiments showed that the "TKO pig" expressing human CD55 had a heterologous kidney transplantation survival time of up to 90 days, while the "TKO pig" that did not express the protein has a kidney survival time of 83 days.Other studies have shown that the expression of HO-1 and CD47 can further improve the survival time of pig xenografts .In order to further reduce immune rejection, pig endogenous leukocyte antigens can also be knocked out.
As a practical application of xenotransplantation products, genetically edited pigs still require further experimental and clinical data support. In the future, more gene editors will be included in pig xenografts.

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