《基因,蛋白,免疫 课程之蛋白组学 6》由会员分享，可在线阅读，更多相关《基因,蛋白,免疫 课程之蛋白组学 6（3页珍藏版）》请在金锄头文库上搜索。
1、Genetic Engineering of the Donor as an Approach to Clinical XenotransplantationE. Cozzi, B. Soin, B. Holmes, and D. WhiteXENOTRANSPLANTATION may provide a potential solution to the lack of human organs available for transplantation. However, for xenotransplantation to be- come a clinical reality, th
2、e immunological mechanisms that underlie the rejection of xenografts must be controlled. The recent elucidation of part of these immunologicalmechanisms, together with the advances in the field of genetic engineering, has led to the production of transgenic animals whose organs are less susceptible
3、to the immuno- logical damage responsible for xenograft rejection.This article will briefly summarize the recent advances inthis field. Particular attention will be placed on the pig-to- primate model, since this species combination provides the most relevant model for clinical xenotransplantation.T
4、HE IMMUNOLOGICAL BARRIER TO PIG-TO-PRIMATE XENOTRANSPLANTATIONHyperacute RejectionTransplantation of pig organs into primates is usually followed by hyperacute rejection (HAR) of the graft. It is the binding of xenoreactive natural antibodies to porcine endothelial cells that triggers the onset of H
5、AR. Thespecificity of the antibodies involved in this process hasrecently been identified as the carbohydrate moiety Gala1- 3Galb1-4GlcNAc-R (aGal).1,2This is predominantly found on glycoproteins and is widely expressed in all pig tissues. The binding of anti-aGal antibodies to their target leads to
6、 massive activation of the complement cascade and activa- tion of endothelial cells, which results in the loss of their barrier function, hemorrhage, thrombosis, and ischemia. Several genetic approaches have been attempted to over- come the role played by the elements responsible for the onset HAR a
7、nd thus allow long-term xenograft survival. Strategies Aimed at Interfering With the Interaction Between XNA and Their Target. Several groups have been successful in reducing the expression of theaGal epitope on the surface of porcine endothelial cells.35The approach de- rives from the observation t
8、hataGal residues are the result of the addition of a galactose molecule to lactosamine moieties by the enzymea-1,3-galactosyltransferase. In the absence of knockout technology in the pig, porcine embryos have been microinjected with the gene fora-1,2-fucosyl- transferase that competes witha-1,3-gala
9、ctosyltransferase for lactosamine as an acceptor substrate.5As a result of thissuccessful manipulation, pigs that express high levels of the H-antigen and low levels ofaGal epitopes have been obtained. In vivo data on transplantation of these organs into primates have yet to be published. However, a
10、t least two considerations suggest that thisapproach alone may not be sufficient to obtain long-term survival of a xenograft. First, anti-aGal antibodies are only one of the many aspects of the anti-pig immune response observed in primates. While this humoral immune response is certainly the most im
11、portant prior to transplantation, onecannot rule out that other specificities might become more important once a primate is exposed to porcine tissues for long periods. Second, it has been suggested that in the pig-to-primatecombination,complementactivation through the alternative pathway may also p
12、lay a role in determining the fate of the graft. Strategies Aimed at Interfering With the Role of the Com- plement Cascade. The validity of approaches aimed at interfering with the activation of the complement cascade to prevent HAR and prolong the survival of a xenograft has already been investigat
13、ed. It has previously been reportedthat in humans complement activation is finely modulated by the existence of species-restricted regulators such as decay-accelerating factor (DAF), membrane cofactor pro- tein (MCP), and CD59.6In vitro, expression of human DAF (HDAF) on porcine aortic endothelial c
14、ells was able to protect them from lysis by human complement. This obser- vation led to the hypothesis that expression of human complement regulators on endothelial cells of porcine tissues would allow the use of pig organs for xenotransplan- tation into humans. Pigs transgenic for HDAF, MCP, and CD
15、59 have recently been produced.7Pigs transgenic for HDAF have been shown to express very high levels of the protein in all the transplantable organs analyzed, and some of these animals expressed levels of HDAF even higher than those observed in the equivalent human organ.8 HDAF was still expressed i
16、n the tissues from transgenicFrom Imutran Ltd (A Novartis Pharma AG Company) (E.C., B.S., B.H., D.W.), Cambridge, United Kingdom and Department of Surgery, Addenbrookes Hospital, Cambridge University (E.C., B.S., D.W.), Cambridge, United Kingdom. Address reprint requests to Dr Emanuele Cozzi, Imutran Ltd, PO Box 399, Cambridge, CB2 2YP, United Kingdom. 2000 by Elsevier Science Inc.0041-1345/00/$see front matter 655 Avenue of the Americas, New York, NY 10010PII S0041-1345(00)01848-0Transplant
