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The tyrphostin agent AG490 prevents and reverses type 1 diabetes in NOD mice.

Davoodi-Semiromi A, Wasserfall CH, Xia CQ, Cooper-DeHoff RM, Wabitsch M, Clare-Salzler M, Atkinson M - PLoS ONE (2012)

Bottom Line: However, the therapeutic effects of AG490 on the development of T1D are unknown.AG490 significantly inhibited the development of T1D (p = 0.02, p = 0.005; at two different time points).The use of such agents, given their extensive safety profiles, provides a strong foundation for their translation to humans with or at increased risk for the disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, United States of America. dsemiromi@cop.ufl.edu

ABSTRACT

Background: Recent studies in the NOD (non-obese diabetic) mouse model of type 1 diabetes (T1D) support the notion that tyrosine kinase inhibitors have the potential for modulating disease development. However, the therapeutic effects of AG490 on the development of T1D are unknown.

Materials and methods: Female NOD mice were treated with AG490 (i.p, 1 mg/mouse) or DMSO starting at either 4 or 8 week of age, for five consecutive week, then once per week for 5 additional week. Analyses for the development and/or reversal of diabetes, insulitis, adoptive transfer, and other mechanistic studies were performed.

Results: AG490 significantly inhibited the development of T1D (p = 0.02, p = 0.005; at two different time points). Monotherapy of newly diagnosed diabetic NOD mice with AG490 markedly resulted in disease remission in treated animals (n = 23) in comparision to the absolute inability (0%; 0/10, p = 0.003, Log-rank test) of DMSO and sustained eugluycemia was maintained for several months following drug withdrawal. Interestingly, adoptive transfer of splenocytes from AG490 treated NOD mice failed to transfer diabetes to recipient NOD.Scid mice. CD4 T-cells as well as bone marrow derived dendritic cells (BMDCs) from AG490 treated mice, showed higher expression of Foxp3 (p<0.004) and lower expression of co-stimulatory molecules, respectively. Screening of the mouse immune response gene arrary indicates that expression of costimulaotry molecule Ctla4 was upregulated in CD4+ T-cell in NOD mice treated with AG490, suggesting that AG490 is not a negative regulator of the immune system.

Conclusion: The use of such agents, given their extensive safety profiles, provides a strong foundation for their translation to humans with or at increased risk for the disease.

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Related in: MedlinePlus

AG490 prevents development of autoimmune diabetes.Prediabetic female NOD mice at 4 (UT: n = 11; DMSO: n = 13; and AG490 treated mice: n = 15 mice/group) (A), or at 8 week of age, (n = 10 per group) (B) were treated with AG490 or DMSO (i.p) for 5 consecutive week, three time per week followed by once a week for 5 more week [Kaplan-Meier test (*p = 0.02, 1A) and (**p = 0.005, 1B, at week 30)]. Our data also indicate that significant differences (p<0.01) was observed between the AG490 and DMSO treated mice for up week 52; when treatment was started at week 4. Body weight of NOD mice treated with AG490 (C) or DMSO (D) in mice when treatment initiated from 4 weeks of age is shown. [This figure is intended to be in color online and black and white in print.]
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pone-0036079-g001: AG490 prevents development of autoimmune diabetes.Prediabetic female NOD mice at 4 (UT: n = 11; DMSO: n = 13; and AG490 treated mice: n = 15 mice/group) (A), or at 8 week of age, (n = 10 per group) (B) were treated with AG490 or DMSO (i.p) for 5 consecutive week, three time per week followed by once a week for 5 more week [Kaplan-Meier test (*p = 0.02, 1A) and (**p = 0.005, 1B, at week 30)]. Our data also indicate that significant differences (p<0.01) was observed between the AG490 and DMSO treated mice for up week 52; when treatment was started at week 4. Body weight of NOD mice treated with AG490 (C) or DMSO (D) in mice when treatment initiated from 4 weeks of age is shown. [This figure is intended to be in color online and black and white in print.]

Mentions: Prediabetic female NOD mice were treated with AG490 (i.p, 1 mg/mouse) and control mice received the same volume of vehicle (DMSO, solvent of AG490, and sterile PBS) three times/week for 5 consecutive week and once a week for five more week starting at 4 (preinsulitis) or 8 week of age (established insulitis). Our data suggests that AG490 prevents development of autoimmune diabetes in NOD mice when applied at 4 or 8 week of age (p = 0.02 and p = 0.005, respectively at week 30) (figure 1A & B). Blood glucose and body weights (figure 1C and D) were monitored in both groups as early as 6 week of age and continued for the entire period of investigation. There was no statistically significant differences in terms of body weights between AG490 and DMSO treated mice suggesting administration of AG490 at the given dose is safe in mice. Additionally, we also did not observe any adverse effect of AG490 treated mice by gross examination suggesting that efficacy and safety of multiple injections of AG490. This data suggests that AG490 is an efficient and safe drug in prevention of diabetes in NOD mice.


The tyrphostin agent AG490 prevents and reverses type 1 diabetes in NOD mice.

Davoodi-Semiromi A, Wasserfall CH, Xia CQ, Cooper-DeHoff RM, Wabitsch M, Clare-Salzler M, Atkinson M - PLoS ONE (2012)

AG490 prevents development of autoimmune diabetes.Prediabetic female NOD mice at 4 (UT: n = 11; DMSO: n = 13; and AG490 treated mice: n = 15 mice/group) (A), or at 8 week of age, (n = 10 per group) (B) were treated with AG490 or DMSO (i.p) for 5 consecutive week, three time per week followed by once a week for 5 more week [Kaplan-Meier test (*p = 0.02, 1A) and (**p = 0.005, 1B, at week 30)]. Our data also indicate that significant differences (p<0.01) was observed between the AG490 and DMSO treated mice for up week 52; when treatment was started at week 4. Body weight of NOD mice treated with AG490 (C) or DMSO (D) in mice when treatment initiated from 4 weeks of age is shown. [This figure is intended to be in color online and black and white in print.]
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3351395&req=5

pone-0036079-g001: AG490 prevents development of autoimmune diabetes.Prediabetic female NOD mice at 4 (UT: n = 11; DMSO: n = 13; and AG490 treated mice: n = 15 mice/group) (A), or at 8 week of age, (n = 10 per group) (B) were treated with AG490 or DMSO (i.p) for 5 consecutive week, three time per week followed by once a week for 5 more week [Kaplan-Meier test (*p = 0.02, 1A) and (**p = 0.005, 1B, at week 30)]. Our data also indicate that significant differences (p<0.01) was observed between the AG490 and DMSO treated mice for up week 52; when treatment was started at week 4. Body weight of NOD mice treated with AG490 (C) or DMSO (D) in mice when treatment initiated from 4 weeks of age is shown. [This figure is intended to be in color online and black and white in print.]
Mentions: Prediabetic female NOD mice were treated with AG490 (i.p, 1 mg/mouse) and control mice received the same volume of vehicle (DMSO, solvent of AG490, and sterile PBS) three times/week for 5 consecutive week and once a week for five more week starting at 4 (preinsulitis) or 8 week of age (established insulitis). Our data suggests that AG490 prevents development of autoimmune diabetes in NOD mice when applied at 4 or 8 week of age (p = 0.02 and p = 0.005, respectively at week 30) (figure 1A & B). Blood glucose and body weights (figure 1C and D) were monitored in both groups as early as 6 week of age and continued for the entire period of investigation. There was no statistically significant differences in terms of body weights between AG490 and DMSO treated mice suggesting administration of AG490 at the given dose is safe in mice. Additionally, we also did not observe any adverse effect of AG490 treated mice by gross examination suggesting that efficacy and safety of multiple injections of AG490. This data suggests that AG490 is an efficient and safe drug in prevention of diabetes in NOD mice.

Bottom Line: However, the therapeutic effects of AG490 on the development of T1D are unknown.AG490 significantly inhibited the development of T1D (p = 0.02, p = 0.005; at two different time points).The use of such agents, given their extensive safety profiles, provides a strong foundation for their translation to humans with or at increased risk for the disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacotherapy & Translational Research, College of Pharmacy, University of Florida, Gainesville, Florida, United States of America. dsemiromi@cop.ufl.edu

ABSTRACT

Background: Recent studies in the NOD (non-obese diabetic) mouse model of type 1 diabetes (T1D) support the notion that tyrosine kinase inhibitors have the potential for modulating disease development. However, the therapeutic effects of AG490 on the development of T1D are unknown.

Materials and methods: Female NOD mice were treated with AG490 (i.p, 1 mg/mouse) or DMSO starting at either 4 or 8 week of age, for five consecutive week, then once per week for 5 additional week. Analyses for the development and/or reversal of diabetes, insulitis, adoptive transfer, and other mechanistic studies were performed.

Results: AG490 significantly inhibited the development of T1D (p = 0.02, p = 0.005; at two different time points). Monotherapy of newly diagnosed diabetic NOD mice with AG490 markedly resulted in disease remission in treated animals (n = 23) in comparision to the absolute inability (0%; 0/10, p = 0.003, Log-rank test) of DMSO and sustained eugluycemia was maintained for several months following drug withdrawal. Interestingly, adoptive transfer of splenocytes from AG490 treated NOD mice failed to transfer diabetes to recipient NOD.Scid mice. CD4 T-cells as well as bone marrow derived dendritic cells (BMDCs) from AG490 treated mice, showed higher expression of Foxp3 (p<0.004) and lower expression of co-stimulatory molecules, respectively. Screening of the mouse immune response gene arrary indicates that expression of costimulaotry molecule Ctla4 was upregulated in CD4+ T-cell in NOD mice treated with AG490, suggesting that AG490 is not a negative regulator of the immune system.

Conclusion: The use of such agents, given their extensive safety profiles, provides a strong foundation for their translation to humans with or at increased risk for the disease.

Show MeSH
Related in: MedlinePlus