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Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis.

Salama AD, Chitnis T, Imitola J, Ansari MJ, Akiba H, Tushima F, Azuma M, Yagita H, Sayegh MH, Khoury SJ - J. Exp. Med. (2003)

Bottom Line: Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon gamma-producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody.In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production.Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunogenetics and Transplantation, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon gamma-producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.

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Immunohistology of the CNS in animals treated with PD-1 blockade. Spinal cord sections from WT and CD28-deficient animals treated with anti–PD-1 or control antibody were obtained on day 14 after immunization and stained with anti-CD4, anti-CD8, and anti-F4/80. There is a visible increase in the number of CD4+ and CD8+ T cells as well as the macrophages (F4/80+ cells) in the anti–PD-1–treated mice, compared with controls in both the WT and CD28-deficient animals, more apparent in the former (×200).
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fig4: Immunohistology of the CNS in animals treated with PD-1 blockade. Spinal cord sections from WT and CD28-deficient animals treated with anti–PD-1 or control antibody were obtained on day 14 after immunization and stained with anti-CD4, anti-CD8, and anti-F4/80. There is a visible increase in the number of CD4+ and CD8+ T cells as well as the macrophages (F4/80+ cells) in the anti–PD-1–treated mice, compared with controls in both the WT and CD28-deficient animals, more apparent in the former (×200).

Mentions: Histological examination of spinal cord sections from mice treated with anti–PD-1 or control IgG on day 14 after immunization mirrored the clinical course (Fig. 4) . Compared with the control mice, both WT and CD28-deficient mice treated with anti–PD-1 mAb exhibited increased cellular infiltration into the CNS of CD4+ and CD8+ lymphocytes and F4/80+ macrophages. Interestingly, there was an excess of CD8+ cells in the CNS of mice treated with anti–PD-1 mAb, suggesting that the PD-1 pathway preferentially regulates encephalitogenic CD8+ cells, in keeping with previous reports demonstrating greater sensitivity of CD8+ cells to PD-1–mediated suppression (12).


Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis.

Salama AD, Chitnis T, Imitola J, Ansari MJ, Akiba H, Tushima F, Azuma M, Yagita H, Sayegh MH, Khoury SJ - J. Exp. Med. (2003)

Immunohistology of the CNS in animals treated with PD-1 blockade. Spinal cord sections from WT and CD28-deficient animals treated with anti–PD-1 or control antibody were obtained on day 14 after immunization and stained with anti-CD4, anti-CD8, and anti-F4/80. There is a visible increase in the number of CD4+ and CD8+ T cells as well as the macrophages (F4/80+ cells) in the anti–PD-1–treated mice, compared with controls in both the WT and CD28-deficient animals, more apparent in the former (×200).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196082&req=5

fig4: Immunohistology of the CNS in animals treated with PD-1 blockade. Spinal cord sections from WT and CD28-deficient animals treated with anti–PD-1 or control antibody were obtained on day 14 after immunization and stained with anti-CD4, anti-CD8, and anti-F4/80. There is a visible increase in the number of CD4+ and CD8+ T cells as well as the macrophages (F4/80+ cells) in the anti–PD-1–treated mice, compared with controls in both the WT and CD28-deficient animals, more apparent in the former (×200).
Mentions: Histological examination of spinal cord sections from mice treated with anti–PD-1 or control IgG on day 14 after immunization mirrored the clinical course (Fig. 4) . Compared with the control mice, both WT and CD28-deficient mice treated with anti–PD-1 mAb exhibited increased cellular infiltration into the CNS of CD4+ and CD8+ lymphocytes and F4/80+ macrophages. Interestingly, there was an excess of CD8+ cells in the CNS of mice treated with anti–PD-1 mAb, suggesting that the PD-1 pathway preferentially regulates encephalitogenic CD8+ cells, in keeping with previous reports demonstrating greater sensitivity of CD8+ cells to PD-1–mediated suppression (12).

Bottom Line: Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon gamma-producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody.In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production.Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Immunogenetics and Transplantation, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.

ABSTRACT
Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon gamma-producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.

Show MeSH
Related in: MedlinePlus