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Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes

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Abstract

Aims/hypothesis

Research on the pathogenesis of type 1 diabetes relies heavily on good animal models. The aim of this work was to study the translational value of animal models of type 1 diabetes to the human situation.

Methods

We compared the four major animal models of spontaneous type 1 diabetes, namely the NOD mouse, BioBreeding (BB) rat, Komeda rat and LEW.1AR1-iddm rat, by examining the immunohistochemistry and in situ RT-PCR of immune cell infiltrate and cytokine pattern in pancreatic islets, and by comparing findings with human data.

Results

After type 1 diabetes manifestation CD8+ T cells, CD68+ macrophages and CD4+ T cells were observed as the main immune cell types with declining frequency, in infiltrated islets of all diabetic pancreases. IL-1β and TNF-α were the main proinflammatory cytokines in the immune cell infiltrate in NOD mice, BB rats and LEW.1AR1-iddm rats, as well as in humans. The Komeda rat was the exception, with IFN-γ and TNF-α being the main cytokines. In addition, IL-17 and IL-6 and the anti-inflammatory cytokines IL-4, IL-10 and IL-13 were found in some infiltrating immune cells. Apoptotic as well as proliferating beta cells were observed in infiltrated islets. In healthy pancreases no proinflammatory cytokine expression was observed.

Conclusions/interpretation

With the exception of the Komeda rat, the animal models mirror very well the situation in humans with type 1 diabetes. Thus animal models of type 1 diabetes can provide meaningful information on the disease processes in the pancreas of patients with type 1 diabetes.

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Abbreviations

BB:

BioBreeding

DIG:

Digoxigenin

FoxP3:

Forkhead box P3

iNOS:

Inducible nitric oxide synthase

NFκB:

Nuclear factor κB

TGF-β1:

Transforming growth factor β1

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Acknowledgements

We thank D. Lischke and U. Sommerfeld (both from the Institute of Clinical Biochemistry, Hannover Medical School) for skilful technical assistance.

Funding

This work was supported by grants from the Deutsche Forschungsgemeinschaft (JO 395/2-1), from the European Union (Collaborative Project NAIMIT in the 7th Framework Programme, Contract No. 241447) to PM, CM and SL and from the Canadian Institutes of Health Research and the Canadian Diabetes Association and Cure Diabetes to FWS. CM is a clinical researcher at the FWO-Vlaanderen.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

AJ designed and performed experiments, analysed data, and wrote manuscript. TA, AMV, JK, DW, H-JH, LM, PM, NH, YN, G-SW FWS, CG and CM contributed to acquisition of data and revised the manuscript according to the discussion section. G-SW and CM drafted the article and revised it critically for important intellectual content. SL designed experiments, contributed to the discussion and wrote the manuscript. All authors revised and approved the final version to be published.

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Authors and Affiliations

  1. Institute of Clinical Biochemistry, Hannover Medical School, 30623, Hannover, Germany

    Anne Jörns, Tanja Arndt & Sigurd Lenzen

  2. Centre of Anatomy, Hannover Medical School, Hannover, Germany

    Anne Jörns

  3. Department of General, Visceral and Transplantation Surgery, Hannover Medical School, Hannover, Germany

    Andreas Meyer zu Vilsendorf & Jürgen Klempnauer

  4. Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany

    Dirk Wedekind & Hans-Jürgen Hedrich

  5. Islet Cell Laboratory, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

    Lorella Marselli & Piero Marchetti

  6. Institute of Health Biosciences, Department of Nutrition and Metabolism, University of Tokushima Graduate School, Tokushima, Japan

    Nagakatsu Harada & Yutaka Nakaya

  7. Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Canada

    Gen-Sheng Wang & Fraser W. Scott

  8. Clinical and Experimental Endocrinology, Catholic University of Leuven, Leuven, Belgium

    Conny Gysemans & Chantal Mathieu

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  1. Anne Jörns
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Correspondence to Sigurd Lenzen.

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Jörns, A., Arndt, T., zu Vilsendorf, A.M. et al. Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes. Diabetologia 57, 512–521 (2014). https://doi.org/10.1007/s00125-013-3125-4

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