Accommodation — The Role of Natural Antibody and Complement in Discordant Xenograft Rejection

Bach, Fritz H.; Platt, Jeffrey L.; Cooper, D. K. C.

doi:10.1007/978-3-642-97323-9_6

Cited by 22 publications

(15 citation statements)

References 25 publications

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“…As the binding of xenoreactive antibody to the graft would take place immediately after transplantation [15], extensive efforts should be directed towards both reduction of αGal epitopes on the donor organ and suppression of anti‐αGal antibody in the recipient. Reduction of αGal expression should be maintained until accommodation is established, if this can occur [28–30]. In the present study, reappearance of αGal epitopes was clearly observed 24 h after administration of EndoGalC.…”

Section: Discussionsupporting

confidence: 57%

Enzymatic removal of αGal antigen in pig kidneys by ex vivo and in vivo administration of endo‐β‐galactosidase C

Liu

Kobayashi

Yokoyama

et al. 2002

Xenotransplantation

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Xenotransplantation using the pig as a donor species is considered to be a promising solution to the serious shortage of organ donors. Both hyperacute and acute vascular rejection (AVR) are believed to be associated with xenoreactive antibody binding to alphaGal epitopes on the pig vascular endothelial cells. Thus, suppression of this antigen-antibody reaction would appear essential for successful long-term xenograft survival. The purpose of this study was to examine the efficacy of ex vivo and in vivo administration of recombinant endo-beta-galactosidase C (EndoGalC which, in previous in vitro studies, has been proven to digest alphaGal antigens completely) on alphaGal epitopes expressed in pig kidneys. Excised pig kidneys were perfused with University of Wisconsin solution containing EndoGalC and preserved for 4 h. After cold storage, the pig kidney was transplanted into another pig. Ex vivo perfusion and cold storage with EndoGalC reduced alphaGal epitope expression on vascular endothelial cells to an undetectable level. However, alphaGal antigens began to be expressed again as early as 1 day after transplantation. The digestion of alphaGal epitopes by EndoGalC did not cause any damage to the kidney graft. EndoGalC was intravenously administered to two pigs (15 kg), without causing any serious adverse effect. Twelve hours later, >98% of alphaGal antigens on pig red blood cells (RBCs) had been digested. Immunohistochemical study revealed almost complete elimination of alphaGal expression on vascular endothelial cells of the kidney graft 4 and 8 h after in vivo administration, but reappearance within 24 h. EndoGalC was administered to a baboon after an interval of 2 months. The second administration did not result in any serious toxicity or reduction in efficacy. These results suggest that ex vivo and in vivo administration of EndoGalC is simple and useful in removing alphaGal epitopes from pig organs. As the effect of EndoGalC is temporary, multiple in vivo administrations of EndoGalC would be required to inhibit the reappearance of alphaGal epitopes. Alternatively, transgenic techniques of introducing the gene for EndoGalC into the donor organ might permanently prevent alphaGal expression.

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Section: Discussionsupporting

confidence: 57%

Enzymatic removal of αGal antigen in pig kidneys by ex vivo and in vivo administration of endo‐β‐galactosidase C

Liu

Kobayashi

Yokoyama

et al. 2002

Xenotransplantation

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“…Plasmapheresis was performed before heart perfusion to eliminate circulating antibodies and complement in the negative control group, as reported by Bach et al 12 The hearts were snap frozen and 5-m sections were stained on human IgM, IgG, C5c and C5b (membraneattack complex, MAC) with fluorescein-isothiocyanateconjugated antibodies (Serotec, Germany) using a technique described elsewhere. 13 All sections analyzed were stained simultaneously to eliminate procedure-related variances.…”

Section: Ex Vivo Heart Perfusionmentioning

confidence: 99%

FK778 in Experimental Xenotransplantation: A Detailed Analysis of Drug Efficacy

Schrepfer

Deuse

Koch-Nolte

et al. 2007

The Journal of Heart and Lung Transplantation

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“…Based on advancing knowledge in the field of immunohematology, kaleidoscopic approaches have been formulated to regulate hyperacute graft rejection. Exchange of the recipient's plasma with albumin, fresh frozen plasma, or other volume replacement fluids has been successfully used to reduce the xenoantibody titers from the recipient's blood 62. Although this technique has been proven to prolong graft survival, it is nonspecific and hence depletes many biologically important immunoglobulins, which may compromise the recipient's residual defense mechanism against microbial infections.…”

Section: Approaches To Overcoming Xenorejectionmentioning

confidence: 99%

“…Moreover, due to exhaustion of important plasma proteins such as PC and ATIII (refer to Figs. 5 and 6 for their specific role), the coagulation cascade is deregulated 62. However, this technique has resulted in a 23‐fold prolonged survival of a discordant graft in a guinea pig‐to‐rat cardiac xenotransplantation 63.…”

Section: Approaches To Overcoming Xenorejectionmentioning

confidence: 99%

Intervention Strategies and Agents Mediating the Prevention of Xenorejection

Ghebremariam

Smith

Anderson

et al. 2005

Annals of the New York Academy of Sciences

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Xenotransplantation, the transplantation of cells, tissues, and/or organs across species, has proven to be an enormous challenge, resulting in only limited achievements over the last century. Unlike allotransplantation, the immunologic barriers involved in xenotransplant rejection are aggressive and usually occur within minutes in a hyperacute fashion. The use of organs from phylogenetically related concordant species may not be practical. Discordant xenotransplantation is characterized by hyperacute graft rejection, and to use nonprimate discordant organs for human benefit will require manipulation of the taxonomic differences. The hyperacute rejection process is primarily due to the attachment of preformed xenoreactive antibodies to the donor vascular endothelium, which results in hyperactivation of the complement system beyond the control of the natural complement regulatory proteins. Understanding the complex and diverse immune components involved in hyperacute, acute, and accelerated rejections has resulted in the development of different hematologic and molecular strategies. Plasmapheresis has been used to remove xenoantibodies, and xenoperfusion techniques are used to create a suitable and familiar environment for the xenograft. Various molecular approaches, such as the development of transgenic animals expressing human complement regulatory proteins such as CD59 or decay accelerating factor (DAF), to downregulate complement activation or the production of pigs lacking the xenoreactive antigen by knockout of the Gal alpha-1,3-galactosyl transferase gene have also been attempted. A combination of these techniques together with the administration of soluble complement inhibitors such as the vaccinia virus complement control protein (VCP) may well contribute to prolong graft survival. However, various issues including the possible emergence of new viral infections have confounded the topic of xenotransplantation. Here the different modulatory approaches and agents mediating interventions in xenorejection are discussed.

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Accommodation — The Role of Natural Antibody and Complement in Discordant Xenograft Rejection

Cited by 22 publications

References 25 publications

Enzymatic removal of αGal antigen in pig kidneys by ex vivo and in vivo administration of endo‐β‐galactosidase C

Enzymatic removal of αGal antigen in pig kidneys by ex vivo and in vivo administration of endo‐β‐galactosidase C

FK778 in Experimental Xenotransplantation: A Detailed Analysis of Drug Efficacy

Intervention Strategies and Agents Mediating the Prevention of Xenorejection

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