Intragraft cytokine mRNA expression in rejecting and non‐rejecting vascularized xenografts

Lorant, Tomas; Krook, Henrik; Wilton, Jacob; Olausson, Michael; Tufveson, Gunnar; Korsgren, Olle; Johnsson, Cecilia

doi:10.1034/j.1399-3089.2003.02032.x

Cited by 8 publications

(8 citation statements)

References 28 publications

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“…The targets for those antibodies are not clearly identified. Some are probably also present on mouse blood cells because there are high titres of haemagglutinating and lymphocytotoxic antibodies present in the rat sera after rejection, as our previous study confirmed (14). Moreover, passive transfer of antierythrocyte or antilymphocyte sera shortly after transplantation induces hyperacute rejection (9).…”

Section: Discussionsupporting

confidence: 58%

Antibody responses to xenogenic antigens—a study in the mouse‐to‐rat system

et al. 2006

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Antibodies play a crucial role in the rejection of an organ that has been transplanted between different animal species, i.e. xenotransplantation. In previous work, we have induced a state of humoral tolerance where mouse-to-rat heart grafts continued to beat under ciclosporine A monotherapy. Initially, a combined treatment with ciclosporine A and 15-deoxyspergualin was given. This state of tolerance could not be reproduced when the vascularised heart graft was replaced with a free tissue graft or xenogeneic blood transfusions. To gain further insight into the humoral response against mouse antigens, we studied the antibody production in naive rats and rats challenged with heart transplants, heart cells, mononuclear cells (MNC) and erythrocytes from mice. Rats not challenged with any mouse cells or organs had a moderate amount of antibodies targeted against mouse MNC as well as rosette-forming cells in the spleen targeted against mouse erythrocytes. A challenge with either mouse MNC or erythrocytes lead to immunisation with antibodies of both IgM and IgG subtype directed against both MNC and erythrocytes. Antibody titres against mouse erythrocytes in animals challenged with MNC were not detectable until day 7, whereas antibody titres against mouse MNC in animals challenged with erythrocytes were detected on day 1. Immunisation with mouse erythrocytes raised the titre of rosette-forming cells in the spleen compared with naive rats (P < 0.05). Our data indicate that different xenogeneic antigens in the mouse-to-rat system are shared between heart cells, MNC and erythrocytes; however, the immunisation patterns differ regarding the time when antibodies are first detected.

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Section: Discussionsupporting

confidence: 58%

Antibody responses to xenogenic antigens—a study in the mouse‐to‐rat system

et al. 2006

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“…One limitation of this approach in the experimental setting is that evaluation of composite EC-MSC islet grafts in small animal models are not easily performed because of several significant species-specific differences in important areas such as angiogenesis, tissue repair, and innate immunity (31). Also, severely immunodeficient mice (SCID, nu/nu, and Rag) trigger strong innate immune responses that mainly target the vasculature of a transplanted organ due to the phylogenetic disparity between the two species, i.e., human-to-mouse is a discordant xenotransplantation model triggering activation of neutrophils, natural killer cells, macrophages, the complement and coagulation systems, and naturally occurring xenoreactive antibodies (32)(33)(34)(35)(36)(37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Formation of Composite Endothelial Cell–Mesenchymal Stem Cell Islets

et al. 2008

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OBJECTIVE-Mesenchymal stem cells (MSCs) contribute to endothelial cell (EC) migration by producing proteases, thereby paving the way into the tissues for ECs. MSCs were added to our previously described composite EC islets as a potential means to improve their capacity for islet angiogenesis.RESEARCH DESIGN AND METHODS-Human islets were coated with primary human bone marrow-derived MSCs and dermal microvascular ECs. The capacity of ECs, with or without MSCs, to adhere to and grow into human islets was analyzed. The survival and functionality of these composite islets were evaluated in a dynamic perifusion assay, and their capacity for angiogenesis in vitro was assessed in a three-dimensional fibrin gel assay.RESULTS-ECs proliferated after culture in MSC-conditioned medium, and MSCs improved the EC coverage threefold compared with EC islets alone. Islet survival in vitro and the functionality of the composite islets after culture were equal to those of control islets. The EC-MSC islets showed a twofold increase in total sprout formation compared with EC islets, and vascular sprouts emanating from the EC-MSC-islet surface showed migration of ECs into the islets and also into the surrounding matrix, either alone or in concert with MSCs. T he islets of Langerhans are micro-organs, with afferent and efferent blood vessels connecting the capillary network of the islets to the circulation system (1). Intra-islet endothelial cells (ECs) are fenestrated, and the density of the capillary network in the islets is ϳ10 times higher than that of the surrounding exocrine tissue (2,3). During the process of islet isolation before transplantation, the ECs in the islets lose their external vascular support; this situation contributes to their dedifferentiation, apoptosis, and necrosis during subsequent in vitro culture (4). CONCLUSIONS-ECThe formation of new capillaries during revascularization is a complex process that involves digestion of the vascular wall by proteases and the migration, proliferation, and differentiation of ECs (5). When blood vessels are assembled, ECs produce platelet-derived growth factor, which attracts supportive cells, including mesenchymal stem cells (MSCs) that can differentiate into pericytes (6).We hypothesized that adding MSCs to our previously described composite EC islets (7) might improve the adherence of the ECs to the islets and subsequent vascularization because MSCs contribute to EC migration by producing proteases, thereby paving the way into the surrounding tissue for the immature EC sprouts (8). MSCs have also been shown to upregulate the expression of angiopoietin and vascular endothelial growth factor (VEGF) in ECs, contributing to an increase in angiogenesis and stabilization of the vasculature (9). Moreover, MSCs have been shown to possess important immune-modulating properties (10), and they do not trigger adaptive immune reactions, which could make them ideal in islet transplantation setting (11,12).The present study describes a gentle and reproducible technique for forming EC-MSC i...

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“…Whether IFN-␥ promotes or protects against xenograft rejection is unclear. A study by Wang et al (51) found that IFN-␥ together with IL-12 was protective against AHXR, whereas other studies have demonstrated that high levels of IFN-␥ are associated with rejection (52)(53)(54)(55). The precise role of IFN-␥ in xenotransplantation remains to be elucidated.…”

Section: ϫ/ϫmentioning

confidence: 99%

Cytokine Secretion Depends on Galα(1,3)Gal Expression in a Pig-to-Human Whole Blood Model

Sæthre

Schneider

Lambris

et al. 2008

The Journal of Immunology

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Transplants from α1,3-galactosyltransferase (Gal) gene-knockout pigs to nonhuman primates are largely protected from hyperacute but not acute humoral xenograft rejection. The present study investigates the role of Gal in cytokine responses using a novel pig-to-human whole blood in vitro model, developed for species-specific analysis of porcine and human cytokines. Porcine (n = 7) and human (n = 27) cytokines were measured using ELISA or multiplex technology, respectively. Porcine aortic endothelial cells from control (Gal+/+) and Gal-deficient (Gal−/−) pigs were incubated with human lepirudin anticoagulated whole blood from healthy donors. E-selectin expression was measured by flow cytometry. The C3 inhibitor compstatin and a C5aR antagonist were used to study the role of complement. Cytokine species specificity was documented, enabling detection of 2 of 7 porcine cytokines and 13 of 27 human cytokines in one single sample. Gal+/+ porcine aortic endothelial cells incubated with human whole blood showed a marked complement C5b-9 dependent up-regulation of E-selectin and secretion of porcine IL-6 and IL-8. In contrast, Gal−/− cells responded with E-selectin and cytokine expression which was so weak that the role of complement could not be determined. Human IL-6, IL-8, IFN-γ, MIP-1α, MIP-1β, eotaxin, and RANTES were detected in the Gal+/+ system, but virtually no responses were seen in the Gal−/− system (p = 0.03). The increase in human cytokine release was largely complement dependent and, in contrast to the porcine response, mediated through C5a. Species-specific analysis of cytokine release revealed a marked, complement-dependent response when Gal+/+ pig cells were incubated with human whole blood, compared with Gal−/− cells which induced virtually no cytokine release.

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Intragraft cytokine mRNA expression in rejecting and non‐rejecting vascularized xenografts

Cited by 8 publications

References 28 publications

Antibody responses to xenogenic antigens—a study in the mouse‐to‐rat system

Antibody responses to xenogenic antigens—a study in the mouse‐to‐rat system

Formation of Composite Endothelial Cell–Mesenchymal Stem Cell Islets

Cytokine Secretion Depends on Galα(1,3)Gal Expression in a Pig-to-Human Whole Blood Model

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