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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.

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Related in: MedlinePlus

Inhibition of Th17 cells with either neutralizing anti–IL-17 or IL-25 has no effect when treatment is initiated during the initiation stage of autoimmune diabetes, but treatment significantly reduces the incidence of diabetes when it occurs during the effector stage. The impact of a neutralizing anti–IL-17 antibody as well as the Th17-inhibitory cytokine IL-25 was investigated during two phases of diabetes development in NOD mice. Treatment was initiated at either 5 weeks of age, which represents the initiation stage of autoimmunity, as characterized by mild insulitis, or at 10 weeks of age, when the effector phase of autoimmunity is occurring, and the majority of NODs will have invasive insulitis. Anti–IL-17 treatment (100 μg i.p. on days 0, 2, 4, 6, 8, and 10) did not alter the course of diabetes when it was initiated at 5 weeks of age (A), whereas treatment initiation at 10 weeks of age (B) resulted in a significant increase in the number of nondiabetic animals (P = 0.001 by log-rank). Similar results were obtained with recombinant IL-25, which had no effect when treatment was started at 5 weeks of age (C) but significantly increased diabetes-free survival at 10 weeks of age (D) (P = 0.001 by log-rank).
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Figure 1: Inhibition of Th17 cells with either neutralizing anti–IL-17 or IL-25 has no effect when treatment is initiated during the initiation stage of autoimmune diabetes, but treatment significantly reduces the incidence of diabetes when it occurs during the effector stage. The impact of a neutralizing anti–IL-17 antibody as well as the Th17-inhibitory cytokine IL-25 was investigated during two phases of diabetes development in NOD mice. Treatment was initiated at either 5 weeks of age, which represents the initiation stage of autoimmunity, as characterized by mild insulitis, or at 10 weeks of age, when the effector phase of autoimmunity is occurring, and the majority of NODs will have invasive insulitis. Anti–IL-17 treatment (100 μg i.p. on days 0, 2, 4, 6, 8, and 10) did not alter the course of diabetes when it was initiated at 5 weeks of age (A), whereas treatment initiation at 10 weeks of age (B) resulted in a significant increase in the number of nondiabetic animals (P = 0.001 by log-rank). Similar results were obtained with recombinant IL-25, which had no effect when treatment was started at 5 weeks of age (C) but significantly increased diabetes-free survival at 10 weeks of age (D) (P = 0.001 by log-rank).

Mentions: To explore the potential contribution of Th17 cells to the natural development of type 1 diabetes, either neutralizing anti–IL-17 antibodies or IL-25 were administered to 5-week-old NOD females to investigate the role of this population in the initiation phase of autoimmunity and to 10-week-old NOD females to investigate the role of Th17 cells during the effector phase of autoimmunity. Dosing regimens for anti–IL-17 (100 μg i.p. days on alternating days for 2 weeks) and IL-25 (1 μg s.c. each day for 25 days) were based on results obtained in the EAE model, which effectively controlled antigen-specific Th17 cells (15,18). As shown inFig. 1A, IL-17 neutralization did not alter diabetes progression when treatment was initiated at 5 weeks of age, and a similar result was obtained using IL-25 beginning at 5 weeks of age (Fig. 1C). In contrast, both anti–IL-17 (Fig. 1B) and IL-25 (Fig. 1D) prevented diabetes development in the majority of treated animals by 6 months of age when treatment was initiated at 10 weeks of age (P = 0.001 by log-rank test for each group vs. controls; n = 10 per group). These data suggest that Th17 cells are involved in the natural progression of type 1 diabetes, particularly during the effector phase of disease development.


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)

Inhibition of Th17 cells with either neutralizing anti–IL-17 or IL-25 has no effect when treatment is initiated during the initiation stage of autoimmune diabetes, but treatment significantly reduces the incidence of diabetes when it occurs during the effector stage. The impact of a neutralizing anti–IL-17 antibody as well as the Th17-inhibitory cytokine IL-25 was investigated during two phases of diabetes development in NOD mice. Treatment was initiated at either 5 weeks of age, which represents the initiation stage of autoimmunity, as characterized by mild insulitis, or at 10 weeks of age, when the effector phase of autoimmunity is occurring, and the majority of NODs will have invasive insulitis. Anti–IL-17 treatment (100 μg i.p. on days 0, 2, 4, 6, 8, and 10) did not alter the course of diabetes when it was initiated at 5 weeks of age (A), whereas treatment initiation at 10 weeks of age (B) resulted in a significant increase in the number of nondiabetic animals (P = 0.001 by log-rank). Similar results were obtained with recombinant IL-25, which had no effect when treatment was started at 5 weeks of age (C) but significantly increased diabetes-free survival at 10 weeks of age (D) (P = 0.001 by log-rank).
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Related In: Results  -  Collection

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Figure 1: Inhibition of Th17 cells with either neutralizing anti–IL-17 or IL-25 has no effect when treatment is initiated during the initiation stage of autoimmune diabetes, but treatment significantly reduces the incidence of diabetes when it occurs during the effector stage. The impact of a neutralizing anti–IL-17 antibody as well as the Th17-inhibitory cytokine IL-25 was investigated during two phases of diabetes development in NOD mice. Treatment was initiated at either 5 weeks of age, which represents the initiation stage of autoimmunity, as characterized by mild insulitis, or at 10 weeks of age, when the effector phase of autoimmunity is occurring, and the majority of NODs will have invasive insulitis. Anti–IL-17 treatment (100 μg i.p. on days 0, 2, 4, 6, 8, and 10) did not alter the course of diabetes when it was initiated at 5 weeks of age (A), whereas treatment initiation at 10 weeks of age (B) resulted in a significant increase in the number of nondiabetic animals (P = 0.001 by log-rank). Similar results were obtained with recombinant IL-25, which had no effect when treatment was started at 5 weeks of age (C) but significantly increased diabetes-free survival at 10 weeks of age (D) (P = 0.001 by log-rank).
Mentions: To explore the potential contribution of Th17 cells to the natural development of type 1 diabetes, either neutralizing anti–IL-17 antibodies or IL-25 were administered to 5-week-old NOD females to investigate the role of this population in the initiation phase of autoimmunity and to 10-week-old NOD females to investigate the role of Th17 cells during the effector phase of autoimmunity. Dosing regimens for anti–IL-17 (100 μg i.p. days on alternating days for 2 weeks) and IL-25 (1 μg s.c. each day for 25 days) were based on results obtained in the EAE model, which effectively controlled antigen-specific Th17 cells (15,18). As shown inFig. 1A, IL-17 neutralization did not alter diabetes progression when treatment was initiated at 5 weeks of age, and a similar result was obtained using IL-25 beginning at 5 weeks of age (Fig. 1C). In contrast, both anti–IL-17 (Fig. 1B) and IL-25 (Fig. 1D) prevented diabetes development in the majority of treated animals by 6 months of age when treatment was initiated at 10 weeks of age (P = 0.001 by log-rank test for each group vs. controls; n = 10 per group). These data suggest that Th17 cells are involved in the natural progression of type 1 diabetes, particularly during the effector phase of disease development.

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