Discordant Xenograft Rejection in an Antibody-Free Model

Johnston, Peter; Wang, Mingwei; Lim, Susan M. L.; Wright, Les; White, David J.

doi:10.1097/00007890-199210000-00001

Cited by 49 publications

(12 citation statements)

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“…Our observation that porcine NICs were destroyed in the absence of xenoreactive antibodies with rabbit complement alone agrees with others from in vitro studies using porcine endothelial (24) or adult islet (22) cells. Although the role of classical and alternative pathways in complement activation within different species combinations remains controversial (24)(25)(26)(27)(28)(29), several other xenotransplant models have also demonstrated hyperacute rejection of discordant xenografts mediated by complement activation via the alternative pathway (28,29). The present study suggests that Gal expression on porcine NICs might not be a critical factor in inducing complement-mediated lysis, since Gal-negative cells were also killed.…”

Section: Discussionmentioning

confidence: 59%

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: 59%

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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“…Our results have potential implications regarding the role of locally-derived complement not only in allograft rejection, where the role of complement has been little studied [49-511, but also in xenotransplantation, where strategies to avoid damage arising from the activation of complement are a current focus of interest [52]. Greater account may need to be taken of the role of local production of complement in these processes, and of the regulation of local complement synthesis in the control of tissue injury.…”

Section: Discussionmentioning

confidence: 99%

Expression and tissue localization of donor‐specific complement C3 synthesized in human renal allografts

et al. 1995

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Recent evidence suggests that the third component of complement, C3, is synthesized in renal tissue, and that increased C3 synthesis occurs in allograft rejection and immune complex-mediated nephritis. However, it is unclear whether intrinsic renal cells or migratory cells in the inflammatory infiltrate, possibly of recipient bone marrow origin, are the source of the C3 detected. This was investigated by determining the C3 allotypes of mRNA and protein produced by transplanted human kidney. Twenty donor-recipient pairs were examined, of which nine pairs had C3 allotypes that were informatively mismatched at the C3 F/S locus. Reverse transcriptase polymerase chain reaction (RT-PCR) followed by amplification refractory mutation system analysis showed intracellular donor-specific mRNA expression in six of these nine cases, at up to 61 days post-transplantation. Nested PCR reactions and the size of PCR products excluded contamination by genomic DNA. Allotype-specific staining of frozen sections of renal cortex demonstrated donor-derived C3 protein in both glomeruli and tubules of all biopsies examined, in a predominantly tubular distribution. These results imply that at least some of the pro-inflammatory effects of complement arise from intrinsic tissue synthesis of donor C3, and that this may represent a previously unrecognized source of tissue injury. The occurrence of local synthesis of C3 of donor allotype may have functional implications related to C3 allotype, and may also be relevant to strategies to inhibit intrarenal complement-mediated injury.

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“…The mechanisms involved in xenograft rejection, therefore, have been the focus of extensive research investigation in recent years. The present understanding of cardiac xenograft rejection is that hyperacute rejection (within minutes to hours) takes place in discordant animal models (1)(2)(3)(4)(5), whereas delayed type of rejection (2-10 days) takes place in concordant models (6 -8). Hyperacute rejection is mediated by preformed xenoreactive natural antibodies that are directed at limited carbohydrate epitopes (5, 9 -12).…”

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confidence: 99%

Predominant expression of Th2 cytokines and interferon-γ in xenogeneic cardiac grafts undergoing acute vascular rejection1

et al. 2003

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Discordant Xenograft Rejection in an Antibody-Free Model

Cited by 49 publications

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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.

Expression and tissue localization of donor‐specific complement C3 synthesized in human renal allografts

Predominant expression of Th2 cytokines and interferon-γ in xenogeneic cardiac grafts undergoing acute vascular rejection1

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