Preventive effects of Cyclosporin on diabetes in NOD mice

Mori, Yutaka; Suko, Matsunobu; Okudaira, Hirokazu; Matsuba, Ikuro; Tsuruoka, Akira; Sasaki, Akira; Yokoyama, Hiroshi; Tanase, Toshiki; Shida, Takao; Nishimura, Masahiko; Terada, Eiji; Ikeda, Yoshio

doi:10.1007/bf00454884

Cited by 152 publications

(49 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The effect of fusidin in these three models of human type 1 diabetes was particularly encouraging for possible translation to the clinical setting, as inhibition of diabetes development in all these models is not achieved by the T-cell immunosuppressant CyA, which has shown a moderate effect in patients with type 1 diabetes [1]. In fact, whilst CyA prevents disease development in the NOD mouse [17] and the DP-BB rat [18], it worsens the course of the disease in the murine model of MLDSZ-induced diabetes [19].…”

Section: Discussionmentioning

confidence: 96%

Lack of effect of intermittently administered sodium fusidate in patients with newly diagnosed type 1 diabetes mellitus: the FUSIDM trial

et al. 2005

View full text Add to dashboard Cite

Aims/hypothesis: We evaluated in a double-blind study the effect of early treatment with the immunomodulatory drug fusidin in patients with newly diagnosed type 1 diabetes mellitus. Methods: Twenty-eight adults with newly diagnosed type 1 diabetes were included in the study. The patients were randomly assigned (computergenerated random number sequence) to two experimental groups. Patients allocated to the fusidin (FUS) group (n=15) received sodium fusidate (fusidin; 500 mg orally three times daily for 4 weeks). Subsequently the drug was given at the same dose and scheduled for two consecutive weeks a month followed by 2 weeks a month without the drug for 20 weeks. Subjects allocated to the placebo (PCB) group (n=13) received placebo according to the same schedule and conditions described for sodium fusidate in the FUS group. All patients received a diet adjusted to their age and BMI, and intensive insulin therapy. Results: There were no statistically significant differences between the FUS and PCB groups in beta cell function, evaluated by basal and glucagon-stimulated C-peptide values during the follow-up (24 and 48 weeks). There was also no difference between the two groups in insulin requirement after 48 weeks (0.4± 0.2 and 0.4±0.2 U/kg body weight for the FUS and PCB groups, respectively). Antibody titres, including insulin autoantibodies, were similar in the two groups during the follow-up. Conclusions/interpretation: Early treatment of newly diagnosed type 1 diabetes patients with intermittently administered fusidin failed to influence the natural course of the disease.

show abstract

Section: Discussionmentioning

confidence: 96%

Lack of effect of intermittently administered sodium fusidate in patients with newly diagnosed type 1 diabetes mellitus: the FUSIDM trial

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Between 5 and 30% of adults presenting with mild hyperglycemia suggestive of type 2 diabetes may actually have a slowprogressive form of type 1 diabetes designated latent autoimmune diabetes of adults (Casteels et al, 1998). Immunosuppressive agents prevent the onset of type 1 diabetes in NOD mice and humans (Mori et al, 1986;Mahon et al, 1993;Casteels et al, 1998;Tabatabaie et al, 2000;Shapiro et al, 2002). Most of these agents have been studied in a prophylactic context, before the appearance of overt diabetes or insulitis (Mori et al, 1986;Mahon et al, 1993;Casteels et al, Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.…”

Section: Introductionmentioning

confidence: 99%

Preventive and Therapeutic Potential of p38α-Selective Mitogen-Activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes

Medicherla¹,

Protter²,

Jing³

et al. 2006

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Mitogen-activated protein kinases (MAPKs) and heat shock proteins (HSPs) are ubiquitous proteins that function within T cells in both normal and stress-related pathophysiological states, including type 1 diabetes. The nonobese diabetic (NOD) mouse spontaneously develops T cell-mediated autoimmune pancreatic beta cell destruction that is similar to type 1 diabetes in humans. Because p38 MAPKs have been shown to modulate T cell function, we studied the effects of a p38␣ MAPK-selective inhibitor, indole-5-carboxamide (SD-169), on the development and progression of type 1 diabetes in the NOD mouse. In preventive treatment studies, SD-169 significantly reduced p38 and HSP60 expression in T cells of the pancreatic beta islets. Following treatment, the incidence of diabetes as determined by blood glucose levels was significantly lower, and immunohistochemistry of pancreatic beta islet tissue demonstrated significant reduction in CD5 ϩ T cell infiltration in the SD-169 treatment group as compared with untreated NOD mice. In therapeutic studies using mildly and moderately hyperglycemic NOD mice, SD-169 treatment lowered blood glucose and improved glucose homeostasis. Furthermore, following cessation of SD-169 treatment, NOD mice showed significant arrest of diabetes. In conclusion, we report that this p38␣-selective inhibitor prevents the development and progression of diabetes in NOD mice by inhibiting T cell infiltration and activation, thereby preserving beta cell mass via inhibition of the p38 MAPK signaling pathway. These results have bearing on current prophylactic and therapeutic protocols using p38␣-selective inhibitors in the prediabetic period for children at high risk of type 1 diabetes, in the honeymoon period, and for adults with latent autoimmune diabetes.Type 1 diabetes is a multifactorial disease in which autoimmunity plays a prime role. The disease becomes clinically manifest when the majority of endocrine beta cells have been destroyed in a T cell-mediated process (Yoshida and Kikutani, 2000). Methods that predict the development of type 1 diabetes may allow the evaluation of pharmacological treatment strategies that halt or even prevent beta cell destruction (Debussche et al., 1993;Keymeulen and Somer, 1993;Mahon et al., 1993;Ryu et al., 2001;Shapiro et al., 2002). Following the initiation of insulin therapy, 60 to 80% of patients with type 1 diabetes will experience a transient remission known as the honeymoon period (Keymeulen and Somer, 1993), and therapeutic strategies have been described to prolong this period by slowing the ongoing self-destruction of the insulin-producing beta cells (Hosker and Turner, 1982;Heinze and Thon, 1985;Crump, 1987;Palmer and McCulloch, 1990;Herold et al., 2002;Shapiro et al., 2002). Between 5 and 30% of adults presenting with mild hyperglycemia suggestive of type 2 diabetes may actually have a slowprogressive form of type 1 diabetes designated latent autoimmune diabetes of adults (Casteels et al., 1998). Immunosuppressive agents prevent the onset of type 1 diab...

show abstract

“…Insulitis is noticed at clinical onset of the disease [1], particularly in patients younger than 15 years [2], and found to contain a mixture of reactive lymphocytes [3]. A form of insulitis was also detected in rodents developing autoimmune diabetes [4]. In (pre)diabetic non-obese diabetic mice (NOD), infiltrating lymphocytes and macrophages were shown to produce cytokines [5,6,7,8] that can destroy pancreatic beta cells in vitro [9,10].…”

Section: Introductionmentioning

confidence: 99%

Human pancreatic duct cells can produce tumour necrosis factor-α that damages neighbouring beta cells and activates dendritic cells

et al. 2004

View full text Add to dashboard Cite

Aims/hypothesis. In the human pancreas, a close topographic relationship exists between duct cells and beta cells. This explains the high proportion of duct cells in isolated human islet preparations. We investigated whether human duct cells are a source of TNFα-mediated interactions with beta cells and immune cells. This cytokine has been implicated in the development of autoimmune diabetes in mice. Methods. Human duct cells were isolated from donor pancreases and examined for their ability to produce TNFα following a stress-signalling pathway. Ductcell-released TNFα was tested for its in vitro effects on survival of human beta cells and on activation of human dendritic cells. Results. Exposure of human pancreatic duct cells to interleukin-1β (IL-1β) induces TNFα gene expression, synthesis of the 26,000 M r TNFα precursor and conversion to the 17,000 M r mature form, which is rapidly released. This effect is NO-independent and involves p38 MAPK and NF-κB signalling. Duct-cellreleased TNFα contributed to cytokine-induced apoptosis of isolated human beta cells. It also induced activation of human dendritic cells. Conclusions/interpretation. Human pancreatic duct cells are a potential source of TNFα that can cause apoptosis of neighbouring beta cells and initiate an immune response through activation of dendritic cells. They may thus actively participate in inflammatory and immune processes that threaten beta cells during development of diabetes or after human islet cell grafts have been implanted.

show abstract

Preventive effects of Cyclosporin on diabetes in NOD mice

Cited by 152 publications

References 7 publications

Lack of effect of intermittently administered sodium fusidate in patients with newly diagnosed type 1 diabetes mellitus: the FUSIDM trial

Lack of effect of intermittently administered sodium fusidate in patients with newly diagnosed type 1 diabetes mellitus: the FUSIDM trial

Preventive and Therapeutic Potential of p38α-Selective Mitogen-Activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes

Human pancreatic duct cells can produce tumour necrosis factor-α that damages neighbouring beta cells and activates dendritic cells

Contact Info

Product

Resources

About