Cytokines as Immune Effector Molecules in Autoimmune Endocrine Diseases with Special Reference to Insulin-Dependent Diabetes Mellitus

Mandrup-Poulsen, Thomas; Helqvist, Steffen; Mølvig, Jens; Wogensen, Lise; Nerup, Jørn

doi:10.3109/08916938909003049

Cited by 78 publications

(39 citation statements)

References 139 publications

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“…Based on these observations, it has been proposed that cytokines released from activated macrophages within the pancreatic islets may cause a progressive p cell destruction, finally leading to insulin-dependent diabetes mellitus (IDDM)' (10). However, this notion has been difficult to verify in vivo, since direct effects exerted by the cytokines are impossible to separate from effects induced by the immunocompetent cells.…”

Section: Introductionmentioning

confidence: 99%

Characterization of mixed syngeneic-allogeneic and syngeneic-xenogeneic islet-graft rejections in mice. Evidence of functional impairment of the remaining syngeneic islets in xenograft rejections.

Korsgren¹,

Jansson²

1994

J. Clin. Invest.

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Allogeneic mouse islets or xenogeneic rat islets, or fetal porcine islets were implanted under the renal capsule ofC57BL/6 mice either alone or carefully mixed with syngeneic islets. With this experimental model the syngeneic islets, although not rejected themselves, are exposed to cytokines and inflammatory mediators released during either allograft or xenograft rejection. No differences in insulin content could be observed between mixed islet grafts and pure syngeneic islet grafts 6 wk after transplantation. Neither was there any morphological evidence of a nonspecific destruction of syngeneic islets. These findings suggest that the mechanisms of both allograft and xenograft rejections are highly specific. The hormone release from the mixed syngeneic-allogeneic grafts was similar to that from pure syngeneic islet grafts. In contrast, a pronounced impairment of both the first and second phases of insulin release was observed 2 wk after implantation in mixed syngeneic-xenogeneic islet grafts. When perfusing the mixed islet graft after completed rejection of the concordant xenogeneic rat islets (6 wk after implantation), the insulin release from the remaining syngeneic mouse islets was identical to that of control grafts. However, syngeneic mouse islets exposed to the rejection mechanism of the discordant xenogenic pig islet-like cell clusters did not attain a complete functional recovery. (J. Clin. Invest. 1994. 93:1113-1119

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Section: Introductionmentioning

confidence: 99%

Characterization of mixed syngeneic-allogeneic and syngeneic-xenogeneic islet-graft rejections in mice. Evidence of functional impairment of the remaining syngeneic islets in xenograft rejections.

Korsgren¹,

Jansson²

1994

J. Clin. Invest.

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“…5,6 Beta-cell maturation is dependent on sequential activation of different transcription factors, including pdx-1, 5 and is accompanied by increased sensitivity to the toxic effects of interleukin 1b (IL-1b). 7 Cytokines have been shown to play a key role in the destruction of beta cells, 8 and we have demonstrated an increased sensitivity to IL-1b in INS-1ab overexpressing pdx-1. 6 Extensive microarray analysis was carried out with these cells treated with IL-1b for different periods of time.…”

Section: Introductionmentioning

confidence: 67%

Transcriptional profiling of type 1 diabetes genes on chromosome 21 in a rat beta-cell line and human pancreatic islets

et al. 2007

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We recently finemapped a type 1 diabetes (T1D)-linked region on chromosome 21, indicating that one or more T1D-linked genes exist in this region with 33 annotated genes. In the current study, we have taken a novel approach using transcriptional profiling in predicting and prioritizing the most likely candidate genes influencing beta-cell function in this region. Two arraybased approaches were used, a rat insulinoma cell line (INS-1ab) overexpressing pancreatic duodenum homeobox 1 (pdx-1) and treated with interleukin 1b (IL-1b) as well as human pancreatic islets stimulated with a mixture of cytokines. Several candidate genes with likely functional significance in T1D were identified. Genes showing differential expression in the two approaches were highly similar, supporting the role of these specific gene products in cytokine-induced beta-cell damage. These were genes involved in cytokine signaling, oxidative phosphorylation, defense responses and apoptosis. The analyses, furthermore, revealed several transcription factor binding sites shared by the differentially expressed genes and by genes demonstrating highly similar expression profiles with these genes. Comparable findings in the rat beta-cell line and human islets support the validity of the methods used and support this as a valuable approach for gene mapping and identification of genes with potential functional significance in T1D, within a region of linkage.

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“…cells and thyroid epithelial cells are susceptible to cytokine-mediated damage. In particular, the deleterious eflects of IL-1^ on pancreatic fi islet cells in vitro have been clearly established [61][62][63][64][65]. It has also been demonstrated that the exposure of fi islet cells to this cytokine leads to a potent inhibition of cell function.…”

Section: Cytokines and Effector Mechanisms In Autoimmune Diseasesmentioning

confidence: 87%

“…The eflect of IL-1 on fi islet cells in culture was found to be both time-and dose-dependent. Thus, acute exposure to IL-l/3 produced a stimulation of fi islet cell function with increased insulin production, whilst long-term exposure suppressed insulin production and release, ultimately leading to fi islet cell death [61,65]. The eflects described appear to be mediated by the binding of IL-1 to specific receptors [66] which has been demonstrated on both fi islet cells and thyrocytes [67,68], and seems to involve the generation of oxygen free radicals [69,70].…”

Section: Cytokines and Effector Mechanisms In Autoimmune Diseasesmentioning

confidence: 99%

Cytokines and autoimmunity

Cavallo

Pozzilli

Thorpe

1994

Clinical and Experimental Immunology

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SUMMARYAlthough the immunopathology of most autoimmune diseases has been well defined, responsible for the breakdown of self-tolerance and which lead to the development of syste organ-specific autoaggression are still unclear. Evidence has accumulated which supports a role for a disregulated production of cytokines by leucocytes and possibly other cells in the pathogenesis of some autoimmune diseases. However, due to the complexity and heterogeneity of cytokine effects in the regulation of the immune response, it is difficult to determine whether abnormalities in the patterns of eytokine production are primary or secondary to the pathological process. Confusion is also caused by the fact that the biological activities of cytokines are multiple and often overlapping, and consequently it is difficult to focus on a unique effect of any one cytokine. Characterization of the potential and actual involvement of cytokines is important not only for a better understanding of the pathogenesis of autoimmune conditions, but particularly because of the implications for the development of immunotherapeutic strategies for the prevention and treatment of the diseases.

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Cytokines as Immune Effector Molecules in Autoimmune Endocrine Diseases with Special Reference to Insulin-Dependent Diabetes Mellitus

Cited by 78 publications

References 139 publications

Characterization of mixed syngeneic-allogeneic and syngeneic-xenogeneic islet-graft rejections in mice. Evidence of functional impairment of the remaining syngeneic islets in xenograft rejections.

Characterization of mixed syngeneic-allogeneic and syngeneic-xenogeneic islet-graft rejections in mice. Evidence of functional impairment of the remaining syngeneic islets in xenograft rejections.

Transcriptional profiling of type 1 diabetes genes on chromosome 21 in a rat beta-cell line and human pancreatic islets

Cytokines and autoimmunity

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