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A new murine model of islet xenograft rejection: Graft destruction is dependent on a major histocompatibility-specific interaction between T-cells and macrophages
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
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2003 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 52, no 5, 1111-1118 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2003. Vol. 52, no 5, 1111-1118 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-91265DOI: 10.2337/diabetes.52.5.1111PubMedID: 12716740OAI: oai:DiVA.org:uu-91265DiVA: diva2:163936
Available from: 2004-01-15 Created: 2004-01-15 Last updated: 2010-10-11Bibliographically approved
In thesis
1. Islet Xenotransplantation: An Experimental Study of Barriers to Clinical Transplantation
Open this publication in new window or tab >>Islet Xenotransplantation: An Experimental Study of Barriers to Clinical Transplantation
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Xenotransplantation av Langerhanska öar : Experimentiella studier av hinder för klinisk tillämpning
Abstract [en]

In the field of transplantation, the increasing deficit of human donors have lead to an interest in animals as an alternative source of organs and tissues.

Different in vitro systems and rodent models of xenotransplantation were used to examine the most significant barriers that have to be overcome, before isolated islets of Langerhans from pigs can be used as a cure for insulin-dependent diabetes mellitus in humans.

In clinical transplantation, islets are infused into the liver through the portal vein. During this procedure the islets are susceptible to harmful innate reactions triggered in blood. Adenoviral vectors generating transgenic expression of human complement regulatory proteins were evaluated in pig islets and shown to confer protection against acute complement-mediated damage.

Transplanted islets escaping this immediate destruction will be targets of a cellular immune response. Using a new mouse model of islet xenograft rejection, it was demonstrated that macrophages, effector cells in the rejection, were part of an MHC-restricted xenospecific immune response mediated by T cells. In a strain of knockout mice it was further shown that this process can proceed in the absence of an important signalling system, mediated by Toll-like receptors, between cells in innate and adaptive immunity. These findings illustrate some of the mechanistic differences compared to cellular islet allograft rejection which partly explain why immunosuppressive drugs used in clinical allotransplantation is not sufficient for preventing xenograft rejection.

Porcine endogenous retroviruses (PERV) remain a safety concern in xenotransplantation. Characterization of PERV in pig islets indicated that virus expression is low in vitro but increases during the immediate time period following transplantation. This suggests that antiviral therapies administered at the time of transplantation could be used for preventing the risk of PERV transmission after xenotransplantation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 55 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1317
Medicine, xenotransplantation, islets of Langerhans, rejection, diabetes, porcine endogenous retroviruses, quantitative RT-PCR, cytokines, animal models, Medicin
National Category
Dermatology and Venereal Diseases
urn:nbn:se:uu:diva-3942 (URN)91-554-5850-5 (ISBN)
Public defence
2004-02-06, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskölds väg 20, Uppsala, 09:15
Available from: 2004-01-15 Created: 2004-01-15Bibliographically approved

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