Immune cell infiltration, cytokine expression, and beta-cell apoptosis during the development of type 1 diabetes in the spontaneously diabetic LEW.1AR1/Ztm-iddm rat.
The IDDM (LEW.1AR1/Ztm-iddm) rat is a type 1 diabetic animal model characterized by a rapid apoptotic pancreatic beta-cell destruction. Here we have analyzed the time course of islet infiltration, changes in the cytokine expression pattern, and beta-cell apoptosis in the transition from the pre-diabetic to the diabetic state. Transition from normoglycemia to hyperglycemia occurred when beta-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 beta-cell loss was closely linked to a severe infiltration of the whole islet by CD8+ T-cells. With progressive islet infiltration, interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) were expressed in immune cells but not in beta-cells. This proinflammatory cytokine expression pattern coincided with the expression of inducible nitric oxide synthase (iNOS) and procaspase 3 in beta-cells and a peak apoptosis rate of 6.7%. Islet infiltration declined after manifestation of clinical diabetes, yielding end-stage islets devoid of beta-cells and immune cells without any sign of cytokine expression. The observed coincidence of IL-1beta and TNF-alpha expression in the immune cells and the induction of iNOS and procaspase 3 mRNA expression in the beta-cells depicts a sequence of pathological changes leading to apoptotic beta-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.
Jörns
Anne
A
Centre of Anatomy, Hannover Medical School, Hannover, Germany.
Günther
Armin
A
Hedrich
Hans-Jürgen
HJ
Wedekind
Dirk
D
Tiedge
Markus
M
Lenzen
Sigurd
S
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology*; D003433:Crosses, Genetic; D016207:Cytokines / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D005786:Gene Expression Regulation / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew
D016207:Cytokines