Limits...
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.

Show MeSH

Related in: MedlinePlus

PD-1–PD-L1 and CTLA-4 blockade accelerates insulitis in prediabetic female NOD mice. (A) Islets from control IgG–treated mouse at 5 wk of age. (B–D) Inflamed islets from anti–CTLA-4, anti–PD-1, or anti–PD-L1 mAb-treated mice, respectively, at 5 wk of age (all stained with hematoxylin and eosin; ×400).
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2196083&req=5

fig3: PD-1–PD-L1 and CTLA-4 blockade accelerates insulitis in prediabetic female NOD mice. (A) Islets from control IgG–treated mouse at 5 wk of age. (B–D) Inflamed islets from anti–CTLA-4, anti–PD-1, or anti–PD-L1 mAb-treated mice, respectively, at 5 wk of age (all stained with hematoxylin and eosin; ×400).

Mentions: We then examined the pathology of pancreata of young (4–5-wk-old) diabetic mice from the experimental group in which treatment was started at 1 wk of age for evidence of insulitis to compare the effect of PD-1 or PD-L1 blockade with control mice (which normally exhibit minimal insulitis at this age) and with that of CTLA-4 blockade (the only experimental age group where CTLA-4 blockade induced disease). Pathologically, there was marked destructive insulitis in the young diabetic animals after either CTLA-4, PD-1, or PD-L1 blockade, whereas the control animals had minimal inflammation of the islets at that time (Fig. 3, A–D). Insulitis scores were significantly higher in the PD-1 (mean score 1.249 ± 0.2349) and PD-L1 (mean score 2.275 ± 0.1987) blockade groups compared with the control group (mean score 0.03634 ± 0.01987, P < 0.001 for both anti–PD-1 and anti–PD-L1 vs. controls; Fig. 2 F).


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 and CTLA-4 blockade accelerates insulitis in prediabetic female NOD mice. (A) Islets from control IgG–treated mouse at 5 wk of age. (B–D) Inflamed islets from anti–CTLA-4, anti–PD-1, or anti–PD-L1 mAb-treated mice, respectively, at 5 wk of age (all stained with hematoxylin and eosin; ×400).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196083&req=5

fig3: PD-1–PD-L1 and CTLA-4 blockade accelerates insulitis in prediabetic female NOD mice. (A) Islets from control IgG–treated mouse at 5 wk of age. (B–D) Inflamed islets from anti–CTLA-4, anti–PD-1, or anti–PD-L1 mAb-treated mice, respectively, at 5 wk of age (all stained with hematoxylin and eosin; ×400).
Mentions: We then examined the pathology of pancreata of young (4–5-wk-old) diabetic mice from the experimental group in which treatment was started at 1 wk of age for evidence of insulitis to compare the effect of PD-1 or PD-L1 blockade with control mice (which normally exhibit minimal insulitis at this age) and with that of CTLA-4 blockade (the only experimental age group where CTLA-4 blockade induced disease). Pathologically, there was marked destructive insulitis in the young diabetic animals after either CTLA-4, PD-1, or PD-L1 blockade, whereas the control animals had minimal inflammation of the islets at that time (Fig. 3, A–D). Insulitis scores were significantly higher in the PD-1 (mean score 1.249 ± 0.2349) and PD-L1 (mean score 2.275 ± 0.1987) blockade groups compared with the control group (mean score 0.03634 ± 0.01987, P < 0.001 for both anti–PD-1 and anti–PD-L1 vs. controls; Fig. 2 F).

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