XENOGRAFT REJECTION OF PORCINE ISLET-LIKE CELL CLUSTERS IN IMMUNOGLOBULIN- OR Fc-RECEPTOR ??-DEFICIENT MICE1

Benda, Birgitta; Karlsson‐Parra, Alex; Ridderstad, Anna; Korsgren, Olle

doi:10.1097/00007890-199611150-00003

Cited by 51 publications

(35 citation statements)

References 19 publications

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“…As mentioned above, results obtained in our previous studies [2,3,10,17,37,38,50] demonstrate that ICC xenograft rejection in rodents resembles the immune response associated with a TH1-dependent DTH-reaction with infiltration of macrophages and peripherally accumulated T cells. In contrast, other investigators have reported that eosinophils dominate the cellular response following discordant islet xenotransplantation [20, 24, 28, 42, 431.…”

Section: > Imentioning

confidence: 53%

“…Here, we demonstrate that IL-6-deficient mice readily reject fetal porcine ICC xenografts and suggest that, in the pig-to-mouse model, the role of IL-6 in ICC xenograft rejection is minor. Several investigators have reported that eosinophils dominate the cellular response following discordant islet xenotransplantation [20,24,28,42, 431, whereas our previous studies [2,3,10,17,37,38, 501 have shown that macrophages predominate. Using a technique based on histochemical visualization of cyanide-resistant endogenous peroxidase activity for specific detection of eosinophils [45], we show that the cellular response following fetal porcine ICC xenograft rejection is dominated by F4/80+ and Mac-1' positive macrophages, and not eosinophils.…”

Section: Discussionmentioning

confidence: 73%

“…Findings in our earlier work [2,3,10,17,37,38, 501 suggest that the process of islet-like cell cluster (ICC) rejection in both rats and mice is a T helper (TH)l-dependent delayed-type hypersensitivity (DTH)-like reaction. Similarly, experimental autoimmune encephalomyelitis, an inflammatory demyelinating disease that serves as a model for multiple sclerosis, is a DTH-like reaction believed to be mediated by T,1-cytokines [48].…”

Section: > Imentioning

confidence: 99%

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Interleukin-6 in islet xenograft rejection

Benda

Korsgren

2001

Transplant International

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Earlier work on primate cardiac xenotransplantation has demonstrated a correlation between interleukin (1L)-6 levels and severity of vascular rejection. IL-6 was originally identified as a lymphokine inducing final maturation of B lymphocytes into antibody-secreting cells. The present study aimed to evaluate the role of IL-6 in fetal porcine islet-like cell cluster (ICC) xenograft rejection. Moreover, other authors have reported that eosinophils dominate the cellular response following discordant islet xenograft transplantation. Here, a technique for specific detection of eosinophils was applied. IL-6-deficient mice and wild-type controls were implanted with fetal porcine ICCs under the kidney capsule and killed 4-, 7-, and 10 days after transplantation. Xenografts were histologically evaluated, and serum samples were analyzed for IgM and IgG antibodies against ICC membrane antigens. IL-6-deficient mice and wild-type controls readily rejected the xenograft. On day 7 after transplantation, abundant numbers of F4/ 80' and Mac-l+ cells were found distributed throughout the collapsing graft accompanied by small amounts of eosinophils and peripherally accumulated CD3' T cells (predominantly CD4'). Significantly lower serum levels of IgM and IgG antibodies against ICC membrane antigens were observed in IL-6-deficient mice on day 4 or 7 after transplantation when compared to wild-type controls. No significant differences were seen on day 10 after transplantation. In both experimental groups, specific IgM and IgG antibody levels remained stable over time. In the pig-to-mouse model, IL-6 seems to be of minor importance to fetal porcine ICC xenograft rejection. Macrophages, and not eosinophils, dominate the cellular response associated with this process.

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Section: > Imentioning

confidence: 53%

Section: Discussionmentioning

confidence: 73%

Section: > Imentioning

confidence: 99%

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Interleukin-6 in islet xenograft rejection

Benda

Korsgren

2001

Transplant International

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“…FcR␥ Chain-deficient Mice-FcR␥ chain-deficient C57BL/6 (B6) mice have been previously described (25) and were kindly provided by Dr. Olle Korsgren (26). Normal B6 mice were used as controls.…”

Section: Methodsmentioning

confidence: 99%

Aggretin, a Heterodimeric C-type Lectin from Calloselasma rhodostoma (Malayan Pit Viper), Stimulates Platelets by Binding to α2β1 Integrin and Glycoprotein Ib, Activating Syk and Phospholipase Cγ2, but Does Not Involve the Glycoprotein VI/Fc Receptor γ Chain Collagen Receptor

Navdaev

Clemetson

Polgár

et al. 2001

Journal of Biological Chemistry

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Aggretin, a potent platelet activator, was isolated from Calloselasma rhodostoma venom, and 30-amino acid N-terminal sequences of both subunits were determined. Aggretin belongs to the heterodimeric snake Ctype lectin family and is thought to activate platelets by binding to platelet glycoprotein ␣ 2 ␤ 1 . We now show that binding to glycoprotein (GP) Ib is also required. Aggretin-induced platelet activation was inhibited by a monoclonal antibody to GPIb as well as by antibodies to ␣ 2 ␤ 1 . Binding of both of these platelet receptors to aggretin was confirmed by affinity chromatography. No binding of other major platelet membrane glycoproteins, in particular GPVI, to aggretin was detected. Aggretin also activates platelets from Fc receptor ␥ chain (Fc␥)-deficient mice to a greater extent than those from normal control mice, showing that it does not use the GPVI/Fc␥ pathway. Platelets from Fc␥-deficient mice expressed fibrinogen receptors normally in response to collagen, although they did not aggregate, indicating that these platelets may partly compensate via other receptors including ␣ 2 ␤ 1 or GPIb for the lack of the Fc␥ pathway. Signaling by aggretin involves a dose-dependent lag phase followed by rapid tyrosine phosphorylation of a number of proteins. Among these are p72 SYK , p125 FAK , and PLC␥2, whereas, in comparison with collagen and convulxin, the Fc␥ subunit neither is phosphorylated nor coprecipitates with p72 SYK . This supports an independent, GPIb-and integrin-based pathway for activation of p72 SYK not involving the Fc␥ receptor.Platelet-collagen interactions are integral to primary hemostasis (1, 2). Resting platelets using several receptors adhering to subendothelium of damaged blood vessels are activated and spread to provide finally a new nonthrombogenic surface until vasculature regeneration occurs. Reversible binding between GPIb-V-IX 1 and von Willebrand factor, associated with collagen, is crucial to slow down the platelet (especially under high shear) so that it can bind more firmly via other receptors (3, 4). This mechanism strongly parallels that of the selectins in leukocyte adhesion (5). Another important receptor is the ␣ 2 ␤ 1 integrin, which is essential for anchoring the platelet to collagen in the subendothelium (6) and for linking to the platelet cytoskeleton to prevent the receptor being torn from the membrane by the forces that it has to withstand. Activation induces the release of storage granules and the expression of new receptors on the platelet surface (7) as well as changes in other receptors such as the fibrinogen receptor, ␣ IIb ␤ 3 , which is critical for spreading. Although GPIb-V-IX and ␣ 2 ␤ 1 also participate in signaling to the platelet interior (8, 9), recent studies, particularly in patients with platelet receptor deficiencies, have implicated GPVI/Fc␥ as a major collagen receptor for platelet activation (10 -12). Patients with platelets lacking any one of these receptors (GPIb-V-IX, ␣ 2 ␤ 1 , or GPVI/Fc␥) have increased bleeding times, and platelet adhesio...

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“…A thymic (nu/nu) mice permanently accept fetal porcine islet-like cell cluster (ICC) xenografts (1), whereas rejection occurs within 1 week after transplantation in normal mice (2)(3)(4)(5)(6)(7). CD4…”

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A New Murine Model of Islet Xenograft Rejection

et al. 2003

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A new murine model of porcine islet-like cell cluster (ICC) xenograft rejection, avoiding interference of unspecific inflammation, was introduced and used to investigate rejection mechanisms. Athymic (nu/nu) mice were transplanted with syngeneic, allogeneic, or xenogeneic islets under the kidney capsule. After the original transplantation, immune cells in porcine ICC xenografts undergoing rejection in native immunocompetent mice were transferred to the peritoneal cavity of the athymic mice. At defined time points after transfer, the primary grafts were evaluated by immunohistochemistry and real-time quantitative RT-PCR to estimate cytokine and chemokine mRNA expression. Transfer of immunocompetent cells enabled athymic (nu/nu) mice to reject a previously tolerated ICC xenograft only when donor and recipient were matched for major histocompatibility complex (MHC). In contrast, allogeneic and syngeneic islets were not rejected. The ICC xenograft rejection was mediated by transferred T-cells. The main effector cells, macrophages, were shown to be part of a specific immune response. By day 4 after transplantation, there was an upreglation of both Th1-and Th2-associated cytokine transcripts. The transferred T-cells were xenospecific and required MHC compatibility to induce rejection. Interaction between the TCR of transferred T-cells and MHC on host endothelial cells and/or macrophages seems necessary for inducing ICC xenograft rejection.

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XENOGRAFT REJECTION OF PORCINE ISLET-LIKE CELL CLUSTERS IN IMMUNOGLOBULIN- OR Fc-RECEPTOR ??-DEFICIENT MICE1

Cited by 51 publications

References 19 publications

Interleukin-6 in islet xenograft rejection

Interleukin-6 in islet xenograft rejection

Aggretin, a Heterodimeric C-type Lectin from Calloselasma rhodostoma (Malayan Pit Viper), Stimulates Platelets by Binding to α2β1 Integrin and Glycoprotein Ib, Activating Syk and Phospholipase Cγ2, but Does Not Involve the Glycoprotein VI/Fc Receptor γ Chain Collagen Receptor

A New Murine Model of Islet Xenograft Rejection

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