Islet xenotransplantation: progress towards a clinical therapy

O’Connell, Philip J.; Lew, Andrew M.; Cowan, Peter J.; Londrigan, Sarah L.; Hawthorne, Wayne J.; Nottle, Mark B.; d’Apice, Anthony J.F.

doi:10.1097/01.mot.0000218932.27397.19

Cited by 3 publications

(2 citation statements)

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“…Therefore, for the prevention or inhibition of IBMIR, several trials are being carried out using special drugs, not only anti-complement drugs but also such as heparin [169], the thrombin inhibitor, melagatran [170], activated protein C [22], low molecular weight dextran sulfate [106], and so on [165].…”

Section: The Instant Blood-mediated Inflammatory Reactionmentioning

confidence: 99%

“…stated that the first trigger of this reaction is the production of IgG and IgM antibodies, followed by complement activation, and the secondary tissue factor then activates the coagulation system via the extrinsic pathway [164]. However, instant blood‐mediated inflammatory reaction (IBMIR) is thought to be triggered by tissue factor expression on islets by some groups [165,166].…”

Section: Reactions Of Human Complement On Api and Npccmentioning

confidence: 99%

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Complement regulation in the GalT KO era

Miyagawa

Yamamoto

Matsunami

et al. 2010

Xenotransplantation

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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.

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