Department of Pediatric Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
International Institute for Bio-Resource Research, Meiji University, Kanagawa, Japan.
Front Immunol. 2022 Apr 14;13:860165. doi: 10.3389/fimmu.2022.860165. eCollection 2022.
After producing triple (Gal, H-D and Sd)-KO pigs, hyperacute rejection appeared to no longer be a problem. However, the origin of xeno-rejection continues to be a controversial topic, including small amounts of antibodies and subsequent activation of the graft endothelium, the complement recognition system and the coagulation systems. The complement is activated via the classical pathway by non-Gal/H-D/Sda antigens and by ischemia-reperfusion injury (IRI), via the alternative pathway, especially on islets, and via the lectin pathway. The complement system therefore is still an important recognition and effector mechanism in xeno-rejection. All complement regulatory proteins (CRPs) regulate complement activation in different manners. Therefore, to effectively protect xenografts against xeno-rejection, it would appear reasonable to employ not only one but several CRPs including anti-complement drugs. 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 sufficient levels of human CRPs on Triple-KO grafts is necessary. Moreover, multilateral inhibition on local complement activation in the graft, together with the control of signals between macrophages and lymphocytes is required.
在产生三倍（Gal、H-D 和 Sd）-KO 猪后，超急性排斥似乎不再是一个问题。然而，异种排斥的起源仍然是一个有争议的话题，包括少量的抗体和随后移植内皮细胞、补体识别系统和凝血系统的激活。补体通过非 Gal/H-D/Sda 抗原和缺血再灌注损伤（IRI）通过经典途径激活，通过替代途径激活，特别是在胰岛中，通过凝集素途径激活。因此，补体系统仍然是异种排斥反应中的一个重要的识别和效应机制。所有补体调节蛋白（CRPs）以不同的方式调节补体激活。因此，为了有效地保护异种移植物免受异种排斥，似乎合理的是不仅使用一种而是几种包括抗补体药物的 CRPs。抗原的进一步评估在临床异种移植领域仍然是一个重要问题。上述结论表明，在 Triple-KO 移植物上表达足够水平的人 CRPs 是必要的。此外，需要在移植物中局部抑制补体激活，并控制巨噬细胞和淋巴细胞之间的信号。
