EVIDENCE THAT INTRAVENOUSLY ADMINISTERED Α-Galactosyl CARBOHYDRATES REDUCE BABOON SERUM CYTOTOXICITY TO PIG KIDNEY CELLS (PK15) AND TRANSPLANTED PIG HEARTS

Ye, Y.; Neethling, Francisca A.; Niekrasz, Marek; Koren, Eugen; Richards, Stephen M.; Martin, M.; Kosanke, Stanley D.; Colobran, Roger; Cooper, D. K. C.

doi:10.1097/00007890-199408000-00014

Cited by 125 publications

(64 citation statements)

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“…It is possible that Gal-negative cells may be lysed by two different mechanisms: binding of xenoreactive antibodies to non-Gal epitopes (causing complement activation) or activation of the alternative complement pathway. Several reports have suggested that human preformed anti-Gal antibodies are the major, if not exclusive, xenoreactive antibodies responsible for hyperacute rejection (11,(30)(31)(32) and that adsorption of these antibodies may reduce the serum's cytotoxicity (33,34). However, it has also been shown that human anti-Gal antibodies are capable of recognizing alternative ligands, which still remain uncharacterized (35).…”

Section: Discussionmentioning

confidence: 99%

Expression of Gal alpha(1,3)gal on neonatal porcine islet beta-cells and susceptibility to human antibody/complement lysis.

Rayat

Rajotte²,

Elliott³

et al. 1998

Diabetes

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Neonatal porcine pancreases may be a potential source of islets for transplantation into patients with type 1 diabetes; however, whether these cellular grafts will be susceptible to damage by human natural antibody-mediated rejection remains controversial. Although we and others have demonstrated that porcine islets bind human IgG and IgM, it remains unknown if they express the xenoreactive antigen Gal alpha(1,3)Gal beta(1,4)GlcNAc-R (Gal epitope). In this study, by using the Gal-specific lectin IB4 for immunohistochemistry and fluorescence-activated cell sorter (FACS) analysis, we determined which cell types present in porcine neonatal islet cell (NIC) aggregates express the Gal epitope and which ones are susceptible to lysis by activation of the human complement. After FACS analysis, 30.0 +/- 3.0% of porcine NICs were shown to express Gal, whereas 70.0 +/- 2.0% did not. Histological assessment of Gal-expressing cells revealed that 54.9 +/- 8.8% stained positive for either insulin or glucagon. In contrast, 68.8 +/- 8.4% of the Gal-negative population stained positive for the pancreatic hormones insulin and glucagon. Incubation of either the Gal-positive or -negative cells with human AB serum plus complement for 1.5 h resulted in the lysis of >90% of the cells. These results demonstrate that porcine NIC aggregates are composed of Gal-expressing cells and that expression of Gal is not restricted to nonendocrine cells. Furthermore, both Gal-positive and Gal-negative cells are susceptible to human antibody/complement-mediated cytolysis, suggesting that this form of immunological destruction is an obstacle that will need to be overcome before porcine NIC aggregates can be used clinically.

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Section: Discussionmentioning

confidence: 99%

Expression of Gal alpha(1,3)gal on neonatal porcine islet beta-cells and susceptibility to human antibody/complement lysis.

Rayat

Rajotte²,

Elliott³

et al. 1998

Diabetes

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“…Specific treatments for the neutralization of anti-αGal antibodies have involved the continuous or intermittent infusion or injection in vivo of soluble sugars, αGal oligosaccharides or specific polymers expressing the αGal epitope. Infusion of high concentrations of melibiose and/or arabinogalactan in baboons was partially effective in eliminating the cytotoxicity of baboon sera on porcine kidney cells although such preparations proved toxic [158]. Intravenous infusion of αGal oligosaccharides showed less toxicity, allowing neutralization of anti-αGal activity and delay of HAR [164,165].…”

Section: Blocking Of Circulating Xenoreactive Antibodiesmentioning

confidence: 99%

“…Both protein A and protein G, which bind the Fc portion of antibodies, and anti-Ig affinity columns, allowed removal of immunoglobulins irrespective of their specificity [155][156][157]. Apheresis with plasma perfusion through specific antibody sorbents such as α-Galactosyl carbohydrates [158] and natural or synthetic αGal oligosaccharides [159][160][161] allowed efficient anti-αGal antibody removal. Finally, antiidiotypic antibodies directed against specific idiotypes of anti-αGal antibodies, were shown to be able to remove up to 90% of cytotoxic anti-pig antibodies from the circulation of treated baboons [157,162].…”

Section: Removal Of Xenoreactive Antibodiesmentioning

confidence: 99%

Antibody Mediated Rejection in Pig-To-Nonhuman Primate Xenotransplantation Models

Severo¹,

Bosio²,

Besenzon³

et al. 2005

CDTCHD

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Antibody-mediated mechanisms are central to the rejection that occurs when pig organs are transplanted into primates. In this article, the histopathological features of the humoral rejection process in these species combinations, namely hyperacute rejection and acute humoral xenograft rejection, will be illustrated. The profile of the natural and elicited antibodies involved will also be discussed. It has now been demonstrated that the natural immune response to a porcine xenograft is primarily directed to Galalpha1-3Gal (alphaGal) specificities, whilst the elicited immune response is directed to both alphaGal and non-alphaGal antigens. The principal characteristics of anti-alphaGal, anti-non-alphaGal and polyreactive antibodies will be described, together with the identification of the molecules recognised by natural and elicited xenoreactive antibodies. The role of the humoral immune response in the rejection of porcine islets in the primate is still uncertain and the current views on the subject will be discussed. Finally, a concise but comprehensive review of the different strategies that have been attempted to prevent the onset of antibody-mediated rejection is presented. These strategies encompass approaches aimed at interfering with the binding of xenoreactive antibodies with their targets, the use of conventional or novel immunosuppressants and splenectomy. It is undeniable that significant progress has been recently achieved in understanding the humoral rejection process of pig organs transplanted into primates. It is expected that a more comprehensive elucidation of the mechanisms underlying accommodation and tolerance may, in the not too distant future, further extend survival of pig organs transplanted into primates.

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“…The Ab bound to the intravenously infused Gal-conjugate, and was excreted with it through the liver and kidneys. Initial exploration used melibiose, a relatively non-specific oligosaccharide, 35 but this was not suitable for prolonged administration. More specific glycoconjugates were developed, some of which were administered intermittently and others by continuous intravenous (IV) infusion.…”

Section: Phase V: Continuous "Depletion" or "Neutralization" Of Anti-mentioning

confidence: 99%

Pig–to–Non-human Primate Heart Transplantation: Immunologic Progress Over 20 Years

Zhu¹,

Dor²,

Cooper³

2007

The Journal of Heart and Lung Transplantation

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EVIDENCE THAT INTRAVENOUSLY ADMINISTERED Α-Galactosyl CARBOHYDRATES REDUCE BABOON SERUM CYTOTOXICITY TO PIG KIDNEY CELLS (PK15) AND TRANSPLANTED PIG HEARTS

Cited by 125 publications

References 0 publications

Expression of Gal alpha(1,3)gal on neonatal porcine islet beta-cells and susceptibility to human antibody/complement lysis.

Expression of Gal alpha(1,3)gal on neonatal porcine islet beta-cells and susceptibility to human antibody/complement lysis.

Antibody Mediated Rejection in Pig-To-Nonhuman Primate Xenotransplantation Models

Pig–to–Non-human Primate Heart Transplantation: Immunologic Progress Over 20 Years

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