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Immune Cell Infiltration, Cytokine Expression, and ß-Cell Apoptosis During the Development of Type 1 Diabetes in the Spontaneously Diabetic LEW.1AR1/Ztm-iddm Rat

¹ Centre of Anatomy, Hannover Medical School, Hannover, Germany
² Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany
³ Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany

The IDDM (LEW.1AR1/Ztm-iddm) rat is a type 1 diabetic animal model characterized by a rapid apoptotic pancreatic ß-cell destruction. Here we have analyzed the time course of islet infiltration, changes in the cytokine expression pattern, and ß-cell apoptosis in the transition from the pre-diabetic to the diabetic state. Transition from normoglycemia to hyperglycemia occurred when ß-cell loss exceeded 60–70%. At the early stages of islet infiltration, macrophages were the predominant immune cell type in the peripherally infiltrated islets. Progression of ß-cell loss was closely linked to a severe infiltration of the whole islet by CD8⁺ T-cells. With progressive islet infiltration, interleukin-1ß (IL-1ß) and tumor necrosis factor- (TNF-) were expressed in immune cells but not in ß-cells. This proinflammatory cytokine expression pattern coincided with the expression of inducible nitric oxide synthase (iNOS) and procaspase 3 in ß-cells and a peak apoptosis rate of 6.7%. Islet infiltration declined after manifestation of clinical diabetes, yielding end-stage islets devoid of ß-cells and immune cells without any sign of cytokine expression. The observed coincidence of IL-1ß and TNF- expression in the immune cells and the induction of iNOS and procaspase 3 mRNA expression in the ß-cells depicts a sequence of pathological changes leading to apoptotic ß-cell death in the IDDM rat. This chain of events provides a mechanistic explanation for the development of the diabetic syndrome in this animal model of human type 1 diabetes.

Abbreviations: IL-1ß, interleukin-1ß;; IFN-, interferon-;; iNOS, inducible nitric oxide synthase;; TNF-, tumor necrosis factor-;; TUNEL, TdT-mediated dUTP-biotin nick-end labeling

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