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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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PD-L1 expression is down-regulated on stimulated splenocytes of older NOD mice. Expression of PD-L1 on CD3+ (A and B) or CD3− (C and D) splenocytes of female NOD (A and C) or BALB/c (B and D) mice of various ages before and after stimulation with immobilized anti-CD3 mAb for 72 h. *, P < 0.01 and **, P < 0.05 versus stimulated CD3+ cells from 9-wk-old female NOD mice.
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fig6: PD-L1 expression is down-regulated on stimulated splenocytes of older NOD mice. Expression of PD-L1 on CD3+ (A and B) or CD3− (C and D) splenocytes of female NOD (A and C) or BALB/c (B and D) mice of various ages before and after stimulation with immobilized anti-CD3 mAb for 72 h. *, P < 0.01 and **, P < 0.05 versus stimulated CD3+ cells from 9-wk-old female NOD mice.

Mentions: In the case of NOD mice, this inhibitory pathway ultimately fails resulting in diabetes as the mice age. This may in part relate to decreased levels of expression of PD-L1 or PD-1 in aging mice. Indeed, we found that anti-CD3–activated splenocytes from female NOD mice had decreasing percentages of cells expressing PD-L1 (Fig. 6, A–D) and decreasing mean fluorescence intensity of PD-L1 expression (not depicted) on both CD3+ and CD3− cells with increasing age, compared with age-matched control BALB/c mice. We found no change in PD-1 expression with age (not depicted).


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-L1 expression is down-regulated on stimulated splenocytes of older NOD mice. Expression of PD-L1 on CD3+ (A and B) or CD3− (C and D) splenocytes of female NOD (A and C) or BALB/c (B and D) mice of various ages before and after stimulation with immobilized anti-CD3 mAb for 72 h. *, P < 0.01 and **, P < 0.05 versus stimulated CD3+ cells from 9-wk-old female NOD mice.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: PD-L1 expression is down-regulated on stimulated splenocytes of older NOD mice. Expression of PD-L1 on CD3+ (A and B) or CD3− (C and D) splenocytes of female NOD (A and C) or BALB/c (B and D) mice of various ages before and after stimulation with immobilized anti-CD3 mAb for 72 h. *, P < 0.01 and **, P < 0.05 versus stimulated CD3+ cells from 9-wk-old female NOD mice.
Mentions: In the case of NOD mice, this inhibitory pathway ultimately fails resulting in diabetes as the mice age. This may in part relate to decreased levels of expression of PD-L1 or PD-1 in aging mice. Indeed, we found that anti-CD3–activated splenocytes from female NOD mice had decreasing percentages of cells expressing PD-L1 (Fig. 6, A–D) and decreasing mean fluorescence intensity of PD-L1 expression (not depicted) on both CD3+ and CD3− cells with increasing age, compared with age-matched control BALB/c mice. We found no change in PD-1 expression with age (not depicted).

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