Limits...
Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice.

Emamaullee JA, Davis J, Merani S, Toso C, Elliott JF, Thiesen A, Shapiro AM - Diabetes (2009)

Bottom Line: Insulitis scoring and immunofluorescence staining revealed that both anti-IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates.GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell-mediated dominant protective effect against autoimmunity.Further development of Th17-targeted therapeutic agents may be of benefit in this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta,Canada. juliete@ualberta.ca

ABSTRACT

Objective: The T helper 17 (Th17) population, a subset of CD4-positive T-cells that secrete interleukin (IL)-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear. The effect of neutralizing anti-IL-17 and recombinant IL-25 on the development of diabetes in NOD mice, a model of spontaneous autoimmune diabetes, was investigated in this study.

Research design and methods and results: Although treatment with either anti-IL-17 or IL-25 had no effect on diabetes development in young (<5 weeks) NOD mice, either intervention prevented diabetes when treatment was started at 10 weeks of age (P < 0.001). Insulitis scoring and immunofluorescence staining revealed that both anti-IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates. Both treatments also decreased GAD65 autoantibody levels. Analysis of pancreatic lymph nodes revealed that both treatments increased the frequency of regulatory T-cells. Further investigation demonstrated that IL-25 therapy was superior to anti-IL-17 during mature diabetes because it promoted a period of remission from new-onset diabetes in 90% of treated animals. Similarly, IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation, whereas anti-IL-17 was of no benefit. GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell-mediated dominant protective effect against autoimmunity.

Conclusions: These studies suggest that Th17 cells are involved in the pathogenesis of autoimmune diabetes. Further development of Th17-targeted therapeutic agents may be of benefit in this disease.

Show MeSH

Related in: MedlinePlus

Treatment with IL-25, but not anti–IL-17, can reverse new-onset diabetes and delay recurrent autoimmunity after syngeneic islet transplantation. Naïve spontaneously diabetic (blood glucose >18 mmol/l) NOD mice were randomly assigned to receive either anti–IL-17 (100 μg i.p. every other day), IL-25 (1 μg s.c. daily), or control (IgG for anti–IL-17, vehicle for IL-25). A: Treatment with anti–IL-17 did not reverse hyperglycemia after new-onset diabetes in NOD mice. B: Treatment with IL-25 resulted in a period of normoglycemia (mean 8.53 ± 2.77 days) in 9 of 10 animals, whereas none of the controls returned to normoglycemia (P < 0.0001 by ANOVA). One IL-25–treated animal experienced permanent remission beyond 100 days and after the discontinuation of IL-25 treatment at day 30 (data not shown). C: Although anti–IL-17 treatment did result in prolongation of syngeneic islet graft survival in 2 of 5 animals, no significant difference in recurrent autoimmunity was observed compared with IgG-treated controls. P = 0.346 by log-rank. D: Treatment with IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation (mean survival time of 7.2 ± 0.2 days in IL-25–treated animals vs. 4.2 ± 0.8 days in vehicle-treated animals; P = 0.0013 by log-rank).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2682686&req=5

Figure 5: Treatment with IL-25, but not anti–IL-17, can reverse new-onset diabetes and delay recurrent autoimmunity after syngeneic islet transplantation. Naïve spontaneously diabetic (blood glucose >18 mmol/l) NOD mice were randomly assigned to receive either anti–IL-17 (100 μg i.p. every other day), IL-25 (1 μg s.c. daily), or control (IgG for anti–IL-17, vehicle for IL-25). A: Treatment with anti–IL-17 did not reverse hyperglycemia after new-onset diabetes in NOD mice. B: Treatment with IL-25 resulted in a period of normoglycemia (mean 8.53 ± 2.77 days) in 9 of 10 animals, whereas none of the controls returned to normoglycemia (P < 0.0001 by ANOVA). One IL-25–treated animal experienced permanent remission beyond 100 days and after the discontinuation of IL-25 treatment at day 30 (data not shown). C: Although anti–IL-17 treatment did result in prolongation of syngeneic islet graft survival in 2 of 5 animals, no significant difference in recurrent autoimmunity was observed compared with IgG-treated controls. P = 0.346 by log-rank. D: Treatment with IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation (mean survival time of 7.2 ± 0.2 days in IL-25–treated animals vs. 4.2 ± 0.8 days in vehicle-treated animals; P = 0.0013 by log-rank).

Mentions: In the NOD mouse model, the initiation and effector phases of disease, before the onset of hyperglycemia, carry the lowest threshold for disease prevention (rev. in (28)). However, once the autoimmune response has matured and resulted in hyperglycemia, reversal of diabetes and prevention of recurrent autoimmunity after β-cell replacement represent significant barriers, with only a few therapeutic strategies regulating type 1 diabetes in the NOD mouse at these late-stage disease time points (28). Thus, to understand the role of Th17 cells after the development of overt diabetes, a series of experiments were conducted in two different models: at the time of diabetes onset (attempt to reverse new-onset diabetes) and after a period of rest after diabetes onset with subsequent β-cell replacement via syngeneic islet transplantation (recurrent autoimmunity). Data inFig. 5A illustrates that anti–IL-17 had no effect once diabetes was established, with all animals remaining persistently diabetic throughout the treatment period. However, daily treatment with IL-25 resulted in remission in 90% of treated animals, versus none of the controls (P < 0.0001 by ANOVA, and P = 0.002 by Fisher's exact test) (Fig. 5B). Ultimately, most animals returned to hyperglycemia by 10 days after initiation of treatment, despite ongoing therapy, although one animal did exhibit persistent normoglycemia for >100 days even after IL-25 treatment withdrawal at day 30 (data not shown). This enhanced efficacy of IL-25 compared with anti–IL-17 was also observed in recurrent autoimmunity after syngeneic islet transplantation, where IL-25 nearly doubled islet graft survival time from 4.2 ± 0.8 days in control animals to 7.2 ± 0.2 days in treated animals (P = 0.0013 by log-rank test). These studies indicate that IL-25, which is known to directly inhibit Th17 populations, is superior to IL-17 neutralization in regulating a mature autoimmune response after the onset of hyperglycemia.


Inhibition of Th17 cells regulates autoimmune diabetes in NOD mice.

Emamaullee JA, Davis J, Merani S, Toso C, Elliott JF, Thiesen A, Shapiro AM - Diabetes (2009)

Treatment with IL-25, but not anti–IL-17, can reverse new-onset diabetes and delay recurrent autoimmunity after syngeneic islet transplantation. Naïve spontaneously diabetic (blood glucose >18 mmol/l) NOD mice were randomly assigned to receive either anti–IL-17 (100 μg i.p. every other day), IL-25 (1 μg s.c. daily), or control (IgG for anti–IL-17, vehicle for IL-25). A: Treatment with anti–IL-17 did not reverse hyperglycemia after new-onset diabetes in NOD mice. B: Treatment with IL-25 resulted in a period of normoglycemia (mean 8.53 ± 2.77 days) in 9 of 10 animals, whereas none of the controls returned to normoglycemia (P < 0.0001 by ANOVA). One IL-25–treated animal experienced permanent remission beyond 100 days and after the discontinuation of IL-25 treatment at day 30 (data not shown). C: Although anti–IL-17 treatment did result in prolongation of syngeneic islet graft survival in 2 of 5 animals, no significant difference in recurrent autoimmunity was observed compared with IgG-treated controls. P = 0.346 by log-rank. D: Treatment with IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation (mean survival time of 7.2 ± 0.2 days in IL-25–treated animals vs. 4.2 ± 0.8 days in vehicle-treated animals; P = 0.0013 by log-rank).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2682686&req=5

Figure 5: Treatment with IL-25, but not anti–IL-17, can reverse new-onset diabetes and delay recurrent autoimmunity after syngeneic islet transplantation. Naïve spontaneously diabetic (blood glucose >18 mmol/l) NOD mice were randomly assigned to receive either anti–IL-17 (100 μg i.p. every other day), IL-25 (1 μg s.c. daily), or control (IgG for anti–IL-17, vehicle for IL-25). A: Treatment with anti–IL-17 did not reverse hyperglycemia after new-onset diabetes in NOD mice. B: Treatment with IL-25 resulted in a period of normoglycemia (mean 8.53 ± 2.77 days) in 9 of 10 animals, whereas none of the controls returned to normoglycemia (P < 0.0001 by ANOVA). One IL-25–treated animal experienced permanent remission beyond 100 days and after the discontinuation of IL-25 treatment at day 30 (data not shown). C: Although anti–IL-17 treatment did result in prolongation of syngeneic islet graft survival in 2 of 5 animals, no significant difference in recurrent autoimmunity was observed compared with IgG-treated controls. P = 0.346 by log-rank. D: Treatment with IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation (mean survival time of 7.2 ± 0.2 days in IL-25–treated animals vs. 4.2 ± 0.8 days in vehicle-treated animals; P = 0.0013 by log-rank).
Mentions: In the NOD mouse model, the initiation and effector phases of disease, before the onset of hyperglycemia, carry the lowest threshold for disease prevention (rev. in (28)). However, once the autoimmune response has matured and resulted in hyperglycemia, reversal of diabetes and prevention of recurrent autoimmunity after β-cell replacement represent significant barriers, with only a few therapeutic strategies regulating type 1 diabetes in the NOD mouse at these late-stage disease time points (28). Thus, to understand the role of Th17 cells after the development of overt diabetes, a series of experiments were conducted in two different models: at the time of diabetes onset (attempt to reverse new-onset diabetes) and after a period of rest after diabetes onset with subsequent β-cell replacement via syngeneic islet transplantation (recurrent autoimmunity). Data inFig. 5A illustrates that anti–IL-17 had no effect once diabetes was established, with all animals remaining persistently diabetic throughout the treatment period. However, daily treatment with IL-25 resulted in remission in 90% of treated animals, versus none of the controls (P < 0.0001 by ANOVA, and P = 0.002 by Fisher's exact test) (Fig. 5B). Ultimately, most animals returned to hyperglycemia by 10 days after initiation of treatment, despite ongoing therapy, although one animal did exhibit persistent normoglycemia for >100 days even after IL-25 treatment withdrawal at day 30 (data not shown). This enhanced efficacy of IL-25 compared with anti–IL-17 was also observed in recurrent autoimmunity after syngeneic islet transplantation, where IL-25 nearly doubled islet graft survival time from 4.2 ± 0.8 days in control animals to 7.2 ± 0.2 days in treated animals (P = 0.0013 by log-rank test). These studies indicate that IL-25, which is known to directly inhibit Th17 populations, is superior to IL-17 neutralization in regulating a mature autoimmune response after the onset of hyperglycemia.

Bottom Line: Insulitis scoring and immunofluorescence staining revealed that both anti-IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates.GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell-mediated dominant protective effect against autoimmunity.Further development of Th17-targeted therapeutic agents may be of benefit in this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta,Canada. juliete@ualberta.ca

ABSTRACT

Objective: The T helper 17 (Th17) population, a subset of CD4-positive T-cells that secrete interleukin (IL)-17, has been implicated in autoimmune diseases, including multiple sclerosis and lupus. Therapeutic agents that target the Th17 effector molecule IL-17 or directly inhibit the Th17 population (IL-25) have shown promise in animal models of autoimmunity. The role of Th17 cells in type 1 diabetes has been less clear. The effect of neutralizing anti-IL-17 and recombinant IL-25 on the development of diabetes in NOD mice, a model of spontaneous autoimmune diabetes, was investigated in this study.

Research design and methods and results: Although treatment with either anti-IL-17 or IL-25 had no effect on diabetes development in young (<5 weeks) NOD mice, either intervention prevented diabetes when treatment was started at 10 weeks of age (P < 0.001). Insulitis scoring and immunofluorescence staining revealed that both anti-IL-17 and IL-25 significantly reduced peri-islet T-cell infiltrates. Both treatments also decreased GAD65 autoantibody levels. Analysis of pancreatic lymph nodes revealed that both treatments increased the frequency of regulatory T-cells. Further investigation demonstrated that IL-25 therapy was superior to anti-IL-17 during mature diabetes because it promoted a period of remission from new-onset diabetes in 90% of treated animals. Similarly, IL-25 delayed recurrent autoimmunity after syngeneic islet transplantation, whereas anti-IL-17 was of no benefit. GAD65-specific ELISpot and CD4-positive adoptive transfer studies showed that IL-25 treatment resulted in a T-cell-mediated dominant protective effect against autoimmunity.

Conclusions: These studies suggest that Th17 cells are involved in the pathogenesis of autoimmune diabetes. Further development of Th17-targeted therapeutic agents may be of benefit in this disease.

Show MeSH
Related in: MedlinePlus