Complement regulation in the GalT KO era.
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.
Division of Organ Transplantation, Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan. miyagawa@orgtrp.med.osaka-u.ac.jp
Shuji
S
Miyagawa
Aki
A
Yamamoto
Katsuyoshi
K
Matsunami
Dandan
D
Wang
Yuichi
Y
Takama
Takehisa
T
Ueno
Masaru
M
Okabe
Hiroshi
H
Nagashima
Masahiro
M
Fukuzawa
D000818:Animals; D030801:Animals, Genetically Modified; D003167:Complement Activation / Q000276:immunology; D003165:Complement System Proteins / Q000276:immunology*; D005700:Galactosyltransferases / Q000235:genetics / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D006801:Humans; D014183:Transplantation, Heterologous / Q000276:immunology
D003165:Complement System Proteins; D005700:Galactosyltransferases; C047006:N-acetyllactosaminide alpha-1,3-galactosyltransferase