Complement regulation in the GalT KO era

Abstract

A number of institutes have reported on the successful production of alpha-galactosyltransferase knockout (GalT-KO) pigs. After producing such pigs, hyperacute rejection appeared to no longer be a problem. However, acute vascular rejection (AVR)/acute humoral xenograft rejection (AHXR) is defined as a rejection that begins within 24 h after transplantation and gradually destroys the graft. The origin of AVR/AHXR continues to be a controversial topic, but is generally thought to be initiated by xeno-reactive antibodies, including non-Gal antibodies and subsequent activation of the graft endothelium, the complement and the coagulation systems. The complement is activated via the classical pathway by non-Gal antigens and ischemia-reperfusion injury, via the alternative pathway, especially on islets, and via the lectin pathway. Therefore the complement system is still an important recognition and effector mechanism of AVR/AHXR. In addition, quite recently, based on the relationship between complement and coagulation systems, a new pathway has been proposed. All complement regulatory proteins (CRPs) have the ability to regulate complement activation in different ways. Therefore, to effectively protect xenografts against AVR/AHXR, it appears reasonable to employ not only one but several CRPs including anti-complement drugs. Non-Gal antigens, such as the Hanganutziu-Deicher antigen, is still present on GalT-KO grafts. The further assessment of antigens continues to be an important issue in the area of clinical xenotransplantation. The above conclusions suggest that the expression of human CRPs on GalT-KO grafts is necessary. Moreover, multilateral inhibition of complement activation is required in conjunction with the regulation of the coagulation system.

Suppression of human macrophage-mediated cytotoxicity by transgenic swine endothelial cell expression of HLA-G

“…Pigs are an ideal source of organs because of their plentiful supply and anatomical and physiological similarities to humans, as well as the fact of our being able to genetically modify pigs. After producing hDAF transgenic and α1,3-galactosyltransferase (α1,3GT) knockout (KO) pigs, hyperacute rejection (HAR) [1,2] no longer appeared to be a problem [3]. However, acute humoral xenograft rejection (AHXR) [4] is defined as a rejection that begins within 24 h after transplantation and gradually destroys the graft.…”

Modifiers of complement activation for prevention of antibody-mediated injury to allografts

“…C1-INH is not only an inhibitor of the complement pathway but contributes to regulation of the kallikreinkinin systems which are involved in fibrinolysis and coagulation, both of which may contribute to AbMR [113][114][115][116]. Another potential advantage of C1NH is that it targets the classical pathway without significant effect on the alternative pathway and common pathway complement function which may result in less susceptibility to some microbiologic pathogens, though this remains unproven in humans.…”

Synthetic Biology in Cell and Organ Transplantation

“…Furthermore, incompatibilities between porcine CRPs and their human counterparts in the complement cascade prevent appropriate regulation of complement activation leading to ADCC-derived damage to porcine tissues. The overexpression of human CRPs helps to regulate ADCC activity and has been a focus of transgenic animals for xenotransplantation (Miyagawa et al 2010). The elimination of highly reactive antigens as described above, in combination with the expression of human CRPs, further reduces the risk of tissue destruction.…”