The Mechanism of Discordant Xenograft Rejection

Miyagawa, Shuji; Shirakura, R; Naka, Yoshihumi; Nakata, S; Kawashima, Yasunaru; Seya, Tsukasa; Matsumoto, Misako; Uenaka, Akiko; Kitamura, Hajime

doi:10.1097/00007890-198812000-00007

Cited by 229 publications

(89 citation statements)

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“…Third, while the pathogenesis of acute vascular rejection is generally thought to reflect activation of endothelial cells in the transplant (6,17,18), the course of hyperacute rejection proceeds too rapidly to allow the most significant effects of endothelial cell activation to be manifest. Fourth, acute vascular rejection develops when the complement system of the recipient is inactivated (6, 7), a condition that invariably precludes the development of hyperacute rejection (19,20).…”

Section: Introductionmentioning

confidence: 99%

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

Lin

Weidner²,

Byrne³

et al. 1998

J. Clin. Invest.

259

161

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Long-term success in xenotransplantation is currently hampered by acute vascular rejection. The inciting cause of acute vascular rejection is not yet known; however, a variety of observations suggest that the humoral immune response of the recipient against the donor may be involved in the pathogenesis of this process. Using a pig-to-baboon heterotopic cardiac transplant model, we examined the role of antibodies in the development of acute vascular rejection. After transplantation into baboons, hearts from transgenic pigs expressing human decay-accelerating factor and CD59 underwent acute vascular rejection leading to graft failure within 5 d; the histology was characterized by endothelial injury and fibrin thrombi. Hearts from the transgenic pigs transplanted into baboons whose circulating antibodies were depleted using antiimmunoglobulin columns (Therasorb, Unterschleisshein, Germany) did not undergo acute vascular rejection in five of six cases. Biopsies from the xenotransplants in Ig-depleted baboons revealed little or no IgM or IgG, and no histologic evidence of acute vascular rejection in the five cases. Complement activity in the baboons was within the normal range during the period of xenograft survival. In one case, acute vascular rejection of a xenotransplant occurred in a baboon in which the level of antidonor antibody rose after Ig depletion was discontinued. This study provides evidence that antibodies play a significant role in the pathogenesis of acute vascular rejection, and suggests that acute vascular rejection might be prevented or treated by therapies aimed at the humoral immune response to porcine antigens. (

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Section: Introductionmentioning

confidence: 99%

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

Lin

Weidner²,

Byrne³

et al. 1998

J. Clin. Invest.

259

161

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“…It plays an important role in host defence, inflammation, and allergic reactions (Sundsmo andFair, 1983: Kuby, 1994). The activation of complement releases C3 a , C4 a , and C5 a , but they result in organ transplant rejection (Miyagawa et al, 1988;Dimond, 1995), asthma, allergy, atopys dermatitis (Groggel et al, 1983;Rother et al, 1985;Strunk et al, 1988;Alexandef et al, 1988;McGeer and McGeer, 1995), arthritis, systemic lupus erythematosus and ARDS (Carson, 1985;Murry et al, 1988;Zvaifler, 1989). For the prevention and treatment of these diseases, anticomplementary polysaccharides, for example, lipopolysaccharide (Gewurz et al, 1968;Marcus et al, 1971), 6-* Author to whom correspondence should be addressed.…”

Section: Introductionmentioning

confidence: 99%

ANTICOMPLEMENTARY ACTIVITY AND COMPLETE ¹³C NMR ASSIGNMENT OF CITROSTADIENOL FROM SCHIZANDRA CHINENSIS

Lee

Jung

et al. 1997

International Journal of Pharmacognosy

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“…It is primarily mediated by activation of the human complement cascade following the interaction of ␣-Gal epitopes on pig cells and anti-␣-Gal xenoreactive antibodies naturally present in humans and in Old World primate serum (1,15,41). Due to its nonspecific nature, the complement system is regulated by a family of complement-regulatory proteins (CRPs) thought to function in a species-specific manner (23). The suggestion that human CRPs (hCRP) expressed on pig organs may prevent HAR has led to the development of pigs transgenic for hCRPs, including decay-accelerating factor (DAF; CD55), membrane cofactor protein (CD46), and membrane inhibitor of reactive lysis (CD59) (3,14,18,54).…”

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confidence: 99%

Reduced Sensitivity to Human Serum Inactivation of Enveloped Viruses Produced by Pig Cells Transgenic for Human CD55 or Deficient for the Galactosyl-α(1-3) Galactosyl Epitope

Magre

Takeuchi

Langford

et al. 2004

J Virol

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Complement activation mediated by the major xenogeneic epitope in the pig, galactosyl-␣(1-3) galactosyl sugar structure (␣-Gal), and human natural antibodies could cause hyperacute rejection (HAR) in pig-tohuman xenotransplantation. The same reaction on viruses bearing ␣-Gal may serve as a barrier to zoonotic infection. Expressing human complement regulatory proteins or knocking out ␣-Gal epitopes in pig in order to overcome HAR may therefore pose an increased risk in xenotransplantation with regard to zoonosis. We investigated whether amphotropic murine leukemia virus, porcine endogenous retrovirus, and vesicular stomatitis virus (VSV) budding from primary transgenic pig aortic endothelial (TgPAE) cells expressing human CD55 (hCD55 or hDAF) was protected from human-complement-mediated inactivation. VSV propagated through the ST-IOWA pig cell line, in which ␣-galactosyl-transferase genes were disrupted (Gal null), was also tested for sensitivity to human complement. The TgPAE cells were positive for hCD55, and all pig cells except the Gal-null ST-IOWA expressed ␣-Gal epitopes. Through antibody binding, we were able to demonstrate the incorporation of hCD55 onto VSV particles. Viruses harvested from TgPAE cells were relatively resistant to complement-mediated inactivation by the three sources of human sera tested. Additionally, VSV from Gal-null pig cells was resistant to human complement inactivation. Such protection of enveloped viruses may increase the risk of zoonosis from pigs genetically modified for pig-to-human xenotransplantation.

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The Mechanism of Discordant Xenograft Rejection

Cited by 229 publications

References 0 publications

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

ANTICOMPLEMENTARY ACTIVITY AND COMPLETE ¹³C NMR ASSIGNMENT OF CITROSTADIENOL FROM SCHIZANDRA CHINENSIS

Reduced Sensitivity to Human Serum Inactivation of Enveloped Viruses Produced by Pig Cells Transgenic for Human CD55 or Deficient for the Galactosyl-α(1-3) Galactosyl Epitope

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The Mechanism of Discordant Xenograft Rejection

Cited by 229 publications

References 0 publications

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

ANTICOMPLEMENTARY ACTIVITY AND COMPLETE 13C NMR ASSIGNMENT OF CITROSTADIENOL FROM SCHIZANDRA CHINENSIS

Reduced Sensitivity to Human Serum Inactivation of Enveloped Viruses Produced by Pig Cells Transgenic for Human CD55 or Deficient for the Galactosyl-α(1-3) Galactosyl Epitope

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ANTICOMPLEMENTARY ACTIVITY AND COMPLETE ¹³C NMR ASSIGNMENT OF CITROSTADIENOL FROM SCHIZANDRA CHINENSIS