The role of natural anti-galα1–3gal antibodies in hyperacute rejection of pig-to-baboon cardiac xenotransplants

Lin, Song; Kooyman, David L.; Daniels, Larkin J; Daggett, Casey W.; Parker, William; Lawson, Jeffrey H.; Hoopes, Charles W.; Gullotto, Carmelo; Li, Li; Birch, Patrick; Davis, Robert D.; Diamond, Lisa E.; Logan, John S.; Platt, Jeffrey L.

doi:10.1016/s0966-3274(97)80040-8

Cited by 115 publications

(64 citation statements)

References 26 publications

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“…This rejection process can be largely averted by depletion of anti-Gal Abs (5,6) or systemic complement inhibition (7) or through the use of organs from transgenic pigs that provide intrinsic complement regulation by expressing human complement-regulating proteins (8 -11). When hyperacute rejection (HAR) is prevented, the grafts are rejected within a few days to weeks by a vascular rejection process termed acute vascular rejection (AVR) (12) or delayed xenograft rejection (13).…”

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confidence: 99%

The In Vitro and In Vivo Effects of Anti-Galactose Antibodies on Endothelial Cell Activation and Xenograft Rejection

Yin

Naziruddin

et al. 2003

The Journal of Immunology

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We have previously produced a series of antigalactose (anti-Gal) hybridomas and characterized their heavy chain gene usage. Here we have quantified the affinity of these Abs for the α-Gal epitope and characterized their in vitro effects on endothelial cell activation and apoptosis. We report that anti-Gal mAbs derived from Gal−/− mice show a range of affinity for the α-Gal epitope, and that affinity was generally increased as the VH gene usage transitioned from germline sequences to sequences exhibiting somatic maturation. Despite an 85-fold range in affinity, all the anti-Gal mAbs examined induced α-Gal-specific endothelial cell activation, and after prolonged exposure induced endothelial cell apoptosis in a complement-independent manner. Only murine anti-Gal mAbs of the IgM or IgG3 subclass, but not IgG1, were effective at initiating complement-dependent cell lysis. Using a novel rat to mouse xenograft model, we examined the in vivo ability of these mAbs to induce xenograft rejection and characterized the rejection using histology and immunohistochemistry. Infusion of complement-fixing IgG3 mAbs resulted in either hyperacute rejection or acute vascular rejection of the xenograft. Surprisingly, infusion of an equal amount of a high affinity anti-Gal IgG1 mAb, that fixed complement poorly also induced a rapid xenograft rejection, which we have labeled very acute rejection. These studies emphasize the importance of in vivo assays, in addition to in vitro assays, in understanding the role of anti-Gal IgG-mediated tissue injury and xenograft rejection.

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mentioning

confidence: 99%

The In Vitro and In Vivo Effects of Anti-Galactose Antibodies on Endothelial Cell Activation and Xenograft Rejection

Yin

Naziruddin

et al. 2003

The Journal of Immunology

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“…Xenoreactive antibodies are not detectable in the blood until rejection occurs on day 12. In separate studies in which an organ xenograft was not placed but antibodies were depleted, we found that xenoreactive antibodies return immediately to the circulation after depletion, despite treatment with immunosuppression [25,26]. The results of a typical experiment are shown in Figure 1.…”

Section: Accommodation In Experimental Modelsmentioning

confidence: 98%

Accommodation of grafts: Implications for health and disease

Tang

Platt

2007

Human Immunology

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Accommodation refers to the acquired resistance of a graft to immune-mediated injury. It is typically observed after antibodies that would cause rejection of a graft are removed from a recipient and then return. Besides being a condition so induced, accommodation can occur spontaneously, without the depleting of antibodies. Indeed, we postulate that spontaneous accommodation may be the most common outcome of clinical organ transplantation. This communication will review the current understanding of accommodation, emphasizing recent advances and important questions. Among the recent advances are the discoveries of potentially broader relevance of accommodation for biology and immunology and pathways by which accommodation may be achieved. To investigate these pathways and to understand how accommodation begins and how it evolves, clinical organ transplants might offer a useful and incisive model.

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“…Activation of complement is ampli¢ed because the complement regulatory proteins that limit complement activation are species speci¢c and thus porcine complement regulatory proteins fail to control primate complement proteins. Hyperacute rejection is e¡ectively prevented by the removal of xenoreactive antibodies from the recipient (Cooper et al 1988;Lin et al 1997), complement inhibition (Leventhal et al 1993a;Magee et al 1995;Pruitt et al 1994) or the expression of recipient compatible complement regulatory proteins in the donor (McCurry et al 1995;Pasternak et al 1985). Thus, preventing hyperacute rejection does not require the induction of tolerance.…”

Section: The Immune Response To Xenograftsmentioning

confidence: 99%

Xenotransplantation and tolerance

Samstein

Platt

2001

Phil. Trans. R. Soc. Lond. B

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The application of xenotransplantation faces daunting immunological hurdles, some of which might be overcome with the induction of tolerance. Porcine organs transplanted into primates are subject to several types of rejection responses. Hyperacute rejection mediated by naturally occurring xenoreactive antibodies and complement can be overcome without tolerance. Acute vascular rejection and cellular rejection, however, may present important opportunities for immunological tolerance, and humoral rejection might be approached by various mechanisms including (i) clonal deletion, (ii) anergy, (iii) immune deviation, (iv) induction of immunoregulatory or suppressor cells, or (v) veto cells. B-cell tolerance, useful for preventing humoral rejection, might be approached through clonal anergy. It remains to be determined, however, whether tolerance induction is required for xenotransplantation and by which means the various mechanisms of tolerance can be applied in the setting of xenotransplantation. Regardless, the study of tolerance will surely expand understanding of the physiology and pathophysiology of the immune system.

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The role of natural anti-galα1–3gal antibodies in hyperacute rejection of pig-to-baboon cardiac xenotransplants

Cited by 115 publications

References 26 publications

The In Vitro and In Vivo Effects of Anti-Galactose Antibodies on Endothelial Cell Activation and Xenograft Rejection

The In Vitro and In Vivo Effects of Anti-Galactose Antibodies on Endothelial Cell Activation and Xenograft Rejection

Accommodation of grafts: Implications for health and disease

Xenotransplantation and tolerance

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