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Immunosuppressive drugs in islet xenotransplantation: A tool for gaining further insights in the mechanisms of the rejection process
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Medical Genetics.
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2002 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 74, no 8, 1084-1089 p.Article in journal (Refereed) Published
Abstract [en]


The aim of the present study was to examine the effect of tacrolimus (TAC) and prednisolone (PRE) in islet xenotransplantation and to use the immunosuppressive effects of these drugs and others to further characterize the mechanisms behind islet xenograft rejection.


Fetal porcine islet-like cell clusters (ICCs) were transplanted under the kidney capsule in Lewis rats. The animals were treated with TAC, cyclosporine A (CsA) plus 15-deoxyspergualin (DSG), CsA plus sirolimus (SIR) or CsA plus leflunomide (LEF), with or without the addition of PRE. Rejection was assessed by immunohistological evaluation 12 days after transplantation. In selected groups, the intragraft cytokine mRNA expression was analyzed with real-time quantitative reverse-transcriptase polymerase chain reaction (RT-PCR).


In untreated rats, the ICC xenografts were completely rejected. Treatment with PRE alone had no, or only a marginal, protective effect. TAC alone at a dose of 1 or 0.5 mg/kg of body weight (BW) prevented xenograft rejection. The addition of PRE to TAC treatment had a paradoxical unfavorable effect. In contrast, when PRE was added to CsA-based protocols (CsA+DSG, CsA+SIR, or CsA+LEF), the immunosuppressive effect was slightly enhanced. In comparison with untreated rats, the messengers for interleukin (IL)-1beta, IL-2, IL-4, IL-10, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha were reduced in both CsA and TAC treated rats. Notably, the amount of IL-12p40 transcripts was only inhibited in rats given TAC alone, whereas this messenger was increased to approximately the same levels in untreated, CsA treated, and TAC plus PRE treated rats.


TAC exerted a pronounced immunosuppressive effect in the pig-to-rat islet xenotransplantation model. So far, no other single drug protocol has shown a comparable efficacy. Notably, the graft protective effect of TAC was markedly abrogated when PRE was added to the treatment protocol, suggesting that TAC exerts its effect by a unique mechanism of action. In contrast with the other studied immunosuppressive regimens, treatment with TAC alone inhibited intragraft mRNA expression of all the Th1 associated cytokines, indicating that Th1 response is one important rejection mechanism that needs to be inhibited to achieve islet xenograft survival.

Place, publisher, year, edition, pages
2002. Vol. 74, no 8, 1084-1089 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-90016PubMedID: 12438951OAI: oai:DiVA.org:uu-90016DiVA: diva2:162035
Available from: 2002-10-11 Created: 2002-10-11 Last updated: 2013-06-10Bibliographically approved
In thesis
1. Xenograft Rejection: A Study of Cytokine mRNA Expression in Experimental Models
Open this publication in new window or tab >>Xenograft Rejection: A Study of Cytokine mRNA Expression in Experimental Models
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acute cellular xenograft rejection of ICCs triggered mRNA expression of proinflammatory cytokines (IL-1b and TNF-a), Th1 associated cytokines (IL-12p40, IL-2 and IFN-g) and Th2 associated cytokines (IL-4 and IL-10). The peak values and the kinetics of the mRNA expression indicated that acute cellular xenograft rejection is enhanced by the proinflammatory response and mediated by the Th1 associated response, whereas the function of the Th2 associated response most likely is to counteract the Th1 associated cytokines and thereby inhibit bystander damage by the delayed type hypersensitivity like rejection process. Tacrolimus was shown to have a protective effect on the ICC xenografts, which was linked with inhibition of Th1 associated cytokines. This beneficial effect was paradoxically abrogated by prednisolone. The cytokines were interpreted to mediate the same response during cellular rejection of vascularized xenografts in the mouse-to-rat heart transplant model as in the non vascularized ICC model, even though the the response includes intragraft antibody deposits. Also the xenogeneic neural grafts implanted into the CNS displayed a similar cytokine response, but this process was slower and had less distinguished peak values compared to the ICC xenografts.

The shortage of organs is the major limitation for clinical allotransplantation. For making clinical xenotransplantation possible and thereby eliminate the organ shortage, issues regarding ethical dilemmas, microbiological hazards, physiological incompatibilities and immunological problems need to be addressed. The aim of the studies in this thesis was to investigate the mechanisms behind acute cellular xenograft rejection. The immunological response, with a focus on the cytokine mRNA expression, was analysed at different time points in rats transplanted with fetal porcine islet like cell clusters (ICCs), mouse hearts, or syngeneic, allogeneic, concordant or discordant xenogeneic neural tissue grafts.

In conclusion, both the cytokine mRNA expression and the morphology of acute cellular xenograft rejection bear a close resemblance to a delayed type hypersensitivity reaction, primarily mediated by indirect antigen presentation. This might explain why clinically used immunosuppressive protocols normally are inefficient for use in xenotransplantation, since these are presumed to primarily suppress T cell response triggered direct antigen presentation, which dominates during allogeneic acute rejection.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2002. 61 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1193
Oncology, Type 1 diabetes, Parkinson’s disease, xenotransplantation, islets, neural tissue, heart, mRNA, cytokines, rejection., Onkologi
National Category
Cancer and Oncology
Research subject
Clinical Immunology
urn:nbn:se:uu:diva-2686 (URN)91-554-5433-X (ISBN)
Public defence
2002-11-01, Rudbeck salen, Uppsala, 13:15
Available from: 2002-10-11 Created: 2002-10-11Bibliographically approved

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