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The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice.

Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ, Auchincloss H, Sayegh MH - J. Exp. Med. (2003)

Bottom Line: Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance.By contrast, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade induced disease only in neonates.Insulitis scores were significantly higher and frequency of interferon gamma-producing GAD-reactive splenocytes was increased after PD-1-PD-L1 pathway blockade compared with controls.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Boston, MA 02115, USA.

ABSTRACT
Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1-PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon gamma-producing GAD-reactive splenocytes was increased after PD-1-PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1-PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

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Related in: MedlinePlus

PD-1–PD-L1 blockade accelerates autoimmune diabetes in NOD mice. All p-values are for comparisons with respective controls. (A) Diabetes-free survival after PD-1–PD-L1 blockade in 10-wk-old female NOD mice: anti–PD-1 (•; n = 17; P < 0.0001), anti–PD-L1 (▪; n = 17; P < 0.0001), anti–PD-L2 (▾; n = 7; P = 0.1904), anti–CTLA-4 (▴; n = 6; P = NS), and control antibody (♦; n = 12) treatment. (B) Diabetes-free survival after PD-1–PD-L1 blockade in 4-wk-old female NOD mice: anti–PD-1 (•; n = 15; P < 0.0184), anti–PD-L1 (▪; n = 18; P < 0.0001), anti–PD-L2 (▾; n = 7; P = NS), anti–CTLA-4 (▴; n = 10; P = NS), and control antibody (♦; n = 12) treatment. (C) Diabetes-free survival after PD-1–PD-L1 blockade in 1-wk-old female NOD mice: anti–PD-1 (•; n = 18; P = 0.0071), anti–PD-L1 (▪; n = 18; P = 0.0018), anti–PD-L2 (▾; n = 11; P = NS), anti–CTLA-4 (▴; n = 11; P = 0.0016), and control antibody (♦; n = 10) treatment. (D) Diabetes-free survival after PD-1–PD-L1 blockade in 10-wk-old male NOD mice: anti–PD-1 (•; n = 5; P = 0.0126), anti–PD-L1 (▪; n = 5; P = 0.0126), and control antibody (♦; n = 5) treatment. In 10-wk-old female NOR mice: anti–PD-1 (▾; n = 5; P = NS) and anti–PD-L1 (▴; n = 5; P = NS) treatment. (E) Diabetes-free survival after PD-1–PD-L1 blockade in 4-wk-old male NOD mice: anti–PD-1 (•; n = 5; P = NS), anti–PD-L1 (▪; n = 6; P = 0.038), control Ig (♦; n = 5) treatment. In 4-wk-old female NOR mice: anti–PD-1 (▾; n = 5; P = NS) and anti–PD-L1 (▴; n = 6; P = NS) treatment. (F) Insulitis scores in 4–5-wk-old female NOD mice treated with anti–PD-1 (▪; mean score 1.249 ± 0.2349; P < 0.001), anti–PD-L1 (•; mean score 2.275 ± 0.1987; P < 0.001), and control IgG (♦; mean score 0.03634 ± 0.01987).
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fig2: PD-1–PD-L1 blockade accelerates autoimmune diabetes in NOD mice. All p-values are for comparisons with respective controls. (A) Diabetes-free survival after PD-1–PD-L1 blockade in 10-wk-old female NOD mice: anti–PD-1 (•; n = 17; P < 0.0001), anti–PD-L1 (▪; n = 17; P < 0.0001), anti–PD-L2 (▾; n = 7; P = 0.1904), anti–CTLA-4 (▴; n = 6; P = NS), and control antibody (♦; n = 12) treatment. (B) Diabetes-free survival after PD-1–PD-L1 blockade in 4-wk-old female NOD mice: anti–PD-1 (•; n = 15; P < 0.0184), anti–PD-L1 (▪; n = 18; P < 0.0001), anti–PD-L2 (▾; n = 7; P = NS), anti–CTLA-4 (▴; n = 10; P = NS), and control antibody (♦; n = 12) treatment. (C) Diabetes-free survival after PD-1–PD-L1 blockade in 1-wk-old female NOD mice: anti–PD-1 (•; n = 18; P = 0.0071), anti–PD-L1 (▪; n = 18; P = 0.0018), anti–PD-L2 (▾; n = 11; P = NS), anti–CTLA-4 (▴; n = 11; P = 0.0016), and control antibody (♦; n = 10) treatment. (D) Diabetes-free survival after PD-1–PD-L1 blockade in 10-wk-old male NOD mice: anti–PD-1 (•; n = 5; P = 0.0126), anti–PD-L1 (▪; n = 5; P = 0.0126), and control antibody (♦; n = 5) treatment. In 10-wk-old female NOR mice: anti–PD-1 (▾; n = 5; P = NS) and anti–PD-L1 (▴; n = 5; P = NS) treatment. (E) Diabetes-free survival after PD-1–PD-L1 blockade in 4-wk-old male NOD mice: anti–PD-1 (•; n = 5; P = NS), anti–PD-L1 (▪; n = 6; P = 0.038), control Ig (♦; n = 5) treatment. In 4-wk-old female NOR mice: anti–PD-1 (▾; n = 5; P = NS) and anti–PD-L1 (▴; n = 6; P = NS) treatment. (F) Insulitis scores in 4–5-wk-old female NOD mice treated with anti–PD-1 (▪; mean score 1.249 ± 0.2349; P < 0.001), anti–PD-L1 (•; mean score 2.275 ± 0.1987; P < 0.001), and control IgG (♦; mean score 0.03634 ± 0.01987).

Mentions: To explore the involvement of PD-1 and its ligands in the development of diabetes, we administered blocking mAbs against PD-1, PD-L1, and PD-L2 into prediabetic female NOD mice of various ages. In 10-wk-old female NOD mice, PD-L1 blockade by anti–PD-L1 mAb precipitated diabetes in 82.4% of the animals 6 d after initiation of therapy with nearly a quarter developing diabetes after a single injection of the antibody. Anti–PD-1 mAb had a similar effect (76.5% of mice developed diabetes). In contrast, only one mouse in the anti–PD-L2 mAb-treated group developed diabetes (not statistically significant over controls) and none in the anti–CTLA-4 mAb-treated group for the duration of follow up. The incidence of diabetes in our colony of unmanipulated NOD female mice is 20% at 10 wk of age, and >70% by 20 wk of age. However, in keeping with previous reports, control IgG–treated animals had slightly delayed onset of overt diabetes (20), demonstrating that the accelerated onset in our treated cohort was a true biological effect related to PD-1–PD-L1 blockade (Fig. 2 A). In 4-wk-old female NOD mice, anti–PD-L1 mAb treatment induced diabetes in 86.2% of mice by 20 d after initiation of treatment with the first cases appearing around day 10. Anti–PD-1 mAb had a less pronounced effect with over a third (41.4%) developing diabetes by day 15, and none of the animals developed diabetes in the anti–PD-L2 mAb-treated group. Again, anti–CTLA-4 mAb and control IgG did not result in diabetes for the duration of follow up (Fig. 2 B). By contrast, in 1-wk-old female NOD mice, anti–CTLA-4 mAb treatment was able to induce diabetes in 54.5% of mice by 28 d after initiation of treatment with the first cases appearing around day 21. PD-1–PD-L1 blockade was able to induce diabetes in 47.6% of mice in the anti–PD-1 group and 57.1% in the anti–PD-L1 group (not statistically significant vs. CTLA-4) and this effect was not seen until day 28, more than 1 wk after the first cases seen with anti–CTLA-4 antibody treatment (Fig. 2 C).


The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice.

Ansari MJ, Salama AD, Chitnis T, Smith RN, Yagita H, Akiba H, Yamazaki T, Azuma M, Iwai H, Khoury SJ, Auchincloss H, Sayegh MH - J. Exp. Med. (2003)

PD-1–PD-L1 blockade accelerates autoimmune diabetes in NOD mice. All p-values are for comparisons with respective controls. (A) Diabetes-free survival after PD-1–PD-L1 blockade in 10-wk-old female NOD mice: anti–PD-1 (•; n = 17; P < 0.0001), anti–PD-L1 (▪; n = 17; P < 0.0001), anti–PD-L2 (▾; n = 7; P = 0.1904), anti–CTLA-4 (▴; n = 6; P = NS), and control antibody (♦; n = 12) treatment. (B) Diabetes-free survival after PD-1–PD-L1 blockade in 4-wk-old female NOD mice: anti–PD-1 (•; n = 15; P < 0.0184), anti–PD-L1 (▪; n = 18; P < 0.0001), anti–PD-L2 (▾; n = 7; P = NS), anti–CTLA-4 (▴; n = 10; P = NS), and control antibody (♦; n = 12) treatment. (C) Diabetes-free survival after PD-1–PD-L1 blockade in 1-wk-old female NOD mice: anti–PD-1 (•; n = 18; P = 0.0071), anti–PD-L1 (▪; n = 18; P = 0.0018), anti–PD-L2 (▾; n = 11; P = NS), anti–CTLA-4 (▴; n = 11; P = 0.0016), and control antibody (♦; n = 10) treatment. (D) Diabetes-free survival after PD-1–PD-L1 blockade in 10-wk-old male NOD mice: anti–PD-1 (•; n = 5; P = 0.0126), anti–PD-L1 (▪; n = 5; P = 0.0126), and control antibody (♦; n = 5) treatment. In 10-wk-old female NOR mice: anti–PD-1 (▾; n = 5; P = NS) and anti–PD-L1 (▴; n = 5; P = NS) treatment. (E) Diabetes-free survival after PD-1–PD-L1 blockade in 4-wk-old male NOD mice: anti–PD-1 (•; n = 5; P = NS), anti–PD-L1 (▪; n = 6; P = 0.038), control Ig (♦; n = 5) treatment. In 4-wk-old female NOR mice: anti–PD-1 (▾; n = 5; P = NS) and anti–PD-L1 (▴; n = 6; P = NS) treatment. (F) Insulitis scores in 4–5-wk-old female NOD mice treated with anti–PD-1 (▪; mean score 1.249 ± 0.2349; P < 0.001), anti–PD-L1 (•; mean score 2.275 ± 0.1987; P < 0.001), and control IgG (♦; mean score 0.03634 ± 0.01987).
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Related In: Results  -  Collection

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fig2: PD-1–PD-L1 blockade accelerates autoimmune diabetes in NOD mice. All p-values are for comparisons with respective controls. (A) Diabetes-free survival after PD-1–PD-L1 blockade in 10-wk-old female NOD mice: anti–PD-1 (•; n = 17; P < 0.0001), anti–PD-L1 (▪; n = 17; P < 0.0001), anti–PD-L2 (▾; n = 7; P = 0.1904), anti–CTLA-4 (▴; n = 6; P = NS), and control antibody (♦; n = 12) treatment. (B) Diabetes-free survival after PD-1–PD-L1 blockade in 4-wk-old female NOD mice: anti–PD-1 (•; n = 15; P < 0.0184), anti–PD-L1 (▪; n = 18; P < 0.0001), anti–PD-L2 (▾; n = 7; P = NS), anti–CTLA-4 (▴; n = 10; P = NS), and control antibody (♦; n = 12) treatment. (C) Diabetes-free survival after PD-1–PD-L1 blockade in 1-wk-old female NOD mice: anti–PD-1 (•; n = 18; P = 0.0071), anti–PD-L1 (▪; n = 18; P = 0.0018), anti–PD-L2 (▾; n = 11; P = NS), anti–CTLA-4 (▴; n = 11; P = 0.0016), and control antibody (♦; n = 10) treatment. (D) Diabetes-free survival after PD-1–PD-L1 blockade in 10-wk-old male NOD mice: anti–PD-1 (•; n = 5; P = 0.0126), anti–PD-L1 (▪; n = 5; P = 0.0126), and control antibody (♦; n = 5) treatment. In 10-wk-old female NOR mice: anti–PD-1 (▾; n = 5; P = NS) and anti–PD-L1 (▴; n = 5; P = NS) treatment. (E) Diabetes-free survival after PD-1–PD-L1 blockade in 4-wk-old male NOD mice: anti–PD-1 (•; n = 5; P = NS), anti–PD-L1 (▪; n = 6; P = 0.038), control Ig (♦; n = 5) treatment. In 4-wk-old female NOR mice: anti–PD-1 (▾; n = 5; P = NS) and anti–PD-L1 (▴; n = 6; P = NS) treatment. (F) Insulitis scores in 4–5-wk-old female NOD mice treated with anti–PD-1 (▪; mean score 1.249 ± 0.2349; P < 0.001), anti–PD-L1 (•; mean score 2.275 ± 0.1987; P < 0.001), and control IgG (♦; mean score 0.03634 ± 0.01987).
Mentions: To explore the involvement of PD-1 and its ligands in the development of diabetes, we administered blocking mAbs against PD-1, PD-L1, and PD-L2 into prediabetic female NOD mice of various ages. In 10-wk-old female NOD mice, PD-L1 blockade by anti–PD-L1 mAb precipitated diabetes in 82.4% of the animals 6 d after initiation of therapy with nearly a quarter developing diabetes after a single injection of the antibody. Anti–PD-1 mAb had a similar effect (76.5% of mice developed diabetes). In contrast, only one mouse in the anti–PD-L2 mAb-treated group developed diabetes (not statistically significant over controls) and none in the anti–CTLA-4 mAb-treated group for the duration of follow up. The incidence of diabetes in our colony of unmanipulated NOD female mice is 20% at 10 wk of age, and >70% by 20 wk of age. However, in keeping with previous reports, control IgG–treated animals had slightly delayed onset of overt diabetes (20), demonstrating that the accelerated onset in our treated cohort was a true biological effect related to PD-1–PD-L1 blockade (Fig. 2 A). In 4-wk-old female NOD mice, anti–PD-L1 mAb treatment induced diabetes in 86.2% of mice by 20 d after initiation of treatment with the first cases appearing around day 10. Anti–PD-1 mAb had a less pronounced effect with over a third (41.4%) developing diabetes by day 15, and none of the animals developed diabetes in the anti–PD-L2 mAb-treated group. Again, anti–CTLA-4 mAb and control IgG did not result in diabetes for the duration of follow up (Fig. 2 B). By contrast, in 1-wk-old female NOD mice, anti–CTLA-4 mAb treatment was able to induce diabetes in 54.5% of mice by 28 d after initiation of treatment with the first cases appearing around day 21. PD-1–PD-L1 blockade was able to induce diabetes in 47.6% of mice in the anti–PD-1 group and 57.1% in the anti–PD-L1 group (not statistically significant vs. CTLA-4) and this effect was not seen until day 28, more than 1 wk after the first cases seen with anti–CTLA-4 antibody treatment (Fig. 2 C).

Bottom Line: Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance.By contrast, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade induced disease only in neonates.Insulitis scores were significantly higher and frequency of interferon gamma-producing GAD-reactive splenocytes was increased after PD-1-PD-L1 pathway blockade compared with controls.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Boston, MA 02115, USA.

ABSTRACT
Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1-PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon gamma-producing GAD-reactive splenocytes was increased after PD-1-PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1-PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

Show MeSH
Related in: MedlinePlus