Protection from experimental autoimmune diabetes in the non‐obese diabetic mouse with soluble interleukin‐1 receptor

Abstract

We have evaluated the effects of a treatment with soluble interleukin-1 receptor (sIL-1R) in the accelerated model of autoimmune diabetes induced by cyclophosphamide (CY) in the non-obese diabetic (NOD) mouse. Prior to the CY challenge (350 mgkg body weight), female euglycemic NOD mice were randomly divided into three groups (A-C). Groups B and C were treated daily from 1 day before to 13 days after the CY challenge with sIL-1R at doses of 0.2 and 2 mg/kg body weight. Group A was treated with PBS. By 2 weeks after CY administration, an acute form of autoimmune diabetes with glycosuria, hyperglycemia and severe insulitis occurred in the majority (13/20, 65%) of the control mice (group A). In contrast, repeated injections with sIL-1R protected NOD mice from insulin-dependent diabetes mellitus (IDDM) development in a dose-dependent fashion; the incidence of IDDM was 53.3% (8/15) in the mice treated with 0.2 mg/kg and only 6.7% (1/15) in those treated with 2 mg/kg. However, none of the doses of the sIL-1R reduced the extent of insulitis in NOD mice. Importantly, the anti-diabetogenic property of sIL-1R may not involve major T cell function impairment; accordingly, in parallel experiments, splenic lymphoid cells from NOD mice not challenged with CY, but treated with 2 mg/kg sIL-1R for 5 consecutive days showed a normal distribution of mononuclear cell subsets and maintained their capacity to secrete interferon-gamma and IL-2 and to proliferate in response to polyclonal mitogenic stimulation with concanavalin A.

IL-1 receptor antagonist inhibits recurrence of disease after syngeneic pancreatic islet transplantation to spontaneously diabetic non-obese diabetic (NOD) mice

“…However, studies in which cytokines are systemically administered may not be optimal for demonstration of their role in organspecific disorders like IDDM. Furthermore, in line with the present findings, Nicoletti et al have demonstrated powerful antidiabetogenic properties of treatment with a soluble murine IL-1 receptor (IL-1sR) in cyclophosphamide-challenged NOD mice [16]. The use of IL-1sR to block IL-1 activity is distinctly different from using receptor blockade with IL-1Ra.…”

Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection

“…During the pathogenic process preceding overt type 1 diabetes mellitus, these cytokines are secreted from activated macrophages and T helper cells infiltrating the islets of animal models [1]. Neutralisation of IL-1 and IFNγ signalling protects against type 1 diabetes mellitus in animal models [2][3][4][5]. Based on these observations, cytokines have been implicated as critical molecules in pathogenesis of type 1 diabetes [1].…”

IL-1 Receptor Deficiency Slows Progression to Diabetes in the NOD Mouse

“…Additionally, islet cell iNOS expression has been detected (16), presumably upregulated by the cytokines present in the inflammatory lesion in islets. Inhibition of IL-1 in vivo by injection of anti-IL-1␤ antisera had a modest effect on reducing the incidence of cyclophosphamide-induced diabetes (18), as did treatment with soluble IL-1R (19).…”