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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

Increased frequency of IFN-γ–producing GAD-specific splenocytes in NOD mice treated with anti–PD- or anti–PD-L1 mAb. ELISPOT responses are expressed as number of IFN-γ spots per million splenocytes from anti–PD-1 mAb, anti–PD-L1 mAb, and control IgG–treated 4-wk-old female NOD mice.
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fig4: Increased frequency of IFN-γ–producing GAD-specific splenocytes in NOD mice treated with anti–PD- or anti–PD-L1 mAb. ELISPOT responses are expressed as number of IFN-γ spots per million splenocytes from anti–PD-1 mAb, anti–PD-L1 mAb, and control IgG–treated 4-wk-old female NOD mice.

Mentions: To address these two possibilities, we quantified the frequencies of IFN-γ–producing GAD-reactive T cells and assessed the state of activation of T cells in mice receiving anti–PD-1 mAb, anti–PD-L1 mAb, or control IgG. Using ELISPOT analysis we found increased frequency of IFN-γ–producing GAD-reactive splenocytes in 4- or 10-wk-old mice from anti–PD-1 or anti–PD-L1 mAb-treated group, compared with age-matched control IgG–treated mice (Fig. 4). Flow cytometry analysis showed that the percentages of CD4+ CD25+ and CD4 or CD8 T cells expressing a CD62Llow CD44high memory/effector phenotype were similar in the anti–PD-L1, anti–PD-1, and control groups (not depicted). Therefore, taken together, it appears that PD-1–PD-L1 blockade resulted in expansion of activated GAD-reactive cells. This is consistent with the results of Salama et al. (22), who used antigen-specific transgenic T cells and demonstrated a critical role of PD-1 in regulating autoimmune encephalomyelitis in the C57BL/6 mouse model. Interestingly, blockade of PD-L1 resulted in greater insulitis, overt diabetes, and higher frequencies of GAD-reactive T cells than PD-1 blockade. These data are in keeping with a recent report indicating that PD-L1 may mediate apoptosis of activated T cells through ligation of a receptor distinct from PD-1 (16).


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)

Increased frequency of IFN-γ–producing GAD-specific splenocytes in NOD mice treated with anti–PD- or anti–PD-L1 mAb. ELISPOT responses are expressed as number of IFN-γ spots per million splenocytes from anti–PD-1 mAb, anti–PD-L1 mAb, and control IgG–treated 4-wk-old female NOD mice.
© Copyright Policy
Related In: Results  -  Collection

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

fig4: Increased frequency of IFN-γ–producing GAD-specific splenocytes in NOD mice treated with anti–PD- or anti–PD-L1 mAb. ELISPOT responses are expressed as number of IFN-γ spots per million splenocytes from anti–PD-1 mAb, anti–PD-L1 mAb, and control IgG–treated 4-wk-old female NOD mice.
Mentions: To address these two possibilities, we quantified the frequencies of IFN-γ–producing GAD-reactive T cells and assessed the state of activation of T cells in mice receiving anti–PD-1 mAb, anti–PD-L1 mAb, or control IgG. Using ELISPOT analysis we found increased frequency of IFN-γ–producing GAD-reactive splenocytes in 4- or 10-wk-old mice from anti–PD-1 or anti–PD-L1 mAb-treated group, compared with age-matched control IgG–treated mice (Fig. 4). Flow cytometry analysis showed that the percentages of CD4+ CD25+ and CD4 or CD8 T cells expressing a CD62Llow CD44high memory/effector phenotype were similar in the anti–PD-L1, anti–PD-1, and control groups (not depicted). Therefore, taken together, it appears that PD-1–PD-L1 blockade resulted in expansion of activated GAD-reactive cells. This is consistent with the results of Salama et al. (22), who used antigen-specific transgenic T cells and demonstrated a critical role of PD-1 in regulating autoimmune encephalomyelitis in the C57BL/6 mouse model. Interestingly, blockade of PD-L1 resulted in greater insulitis, overt diabetes, and higher frequencies of GAD-reactive T cells than PD-1 blockade. These data are in keeping with a recent report indicating that PD-L1 may mediate apoptosis of activated T cells through ligation of a receptor distinct from PD-1 (16).

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