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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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EAE outcome in animals treated with PD-1 pathway blockade. The disease scores for control and anti–PD-1–treated animals >40 d of follow up are shown, for WT mice with early therapy (a) and delayed therapy (b), and for CD28-deficient mice (d). There is a highly significant difference in disease severity between the early therapy and control groups (P = 0.0053 for WT and P = 0.0074 for CD28-deficient mice by two-tailed Mann-Whitney U test). No difference was found with delayed therapy. PD-L2 blockade also augmented disease (P = 0.03 compared with control by two-tailed Mann-Whitney U test) whereas PD-L1 blockade had no effect (c).
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fig2: EAE outcome in animals treated with PD-1 pathway blockade. The disease scores for control and anti–PD-1–treated animals >40 d of follow up are shown, for WT mice with early therapy (a) and delayed therapy (b), and for CD28-deficient mice (d). There is a highly significant difference in disease severity between the early therapy and control groups (P = 0.0053 for WT and P = 0.0074 for CD28-deficient mice by two-tailed Mann-Whitney U test). No difference was found with delayed therapy. PD-L2 blockade also augmented disease (P = 0.03 compared with control by two-tailed Mann-Whitney U test) whereas PD-L1 blockade had no effect (c).

Mentions: Animals with EAE were killed at different time points up to 1 mo from the time of immunization. Sections of their spinal cords were stained for PD-1 and its ligands PD-L1 and PD-L2. Staining revealed an increased level of PD-1 expression on infiltrating cells beginning in the second week, peaking at the third week, and persisting for the 4 wk studied (Fig. 1 a). Expression of PD-L1 increased over a similar time period, although we found no PD-L2 staining in the brains until day 30 when only minimal staining was observed (Fig. 1 a). This time course of expression of both PD-1 and PD-L1 closely follows that of clinical disease in mice with EAE: peaking in the second to third weeks (Fig. 2 a). Furthermore, using dual color staining we demonstrated PD-L1 but not PD-L2 expression on resident astrocytes (colocalized with anti-GFAP mAb) and microglial cells (colocalized with lectin IB4), in brains of animals with EAE at 20 and 30 d, respectively (Fig. 1 b).


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)

EAE outcome in animals treated with PD-1 pathway blockade. The disease scores for control and anti–PD-1–treated animals >40 d of follow up are shown, for WT mice with early therapy (a) and delayed therapy (b), and for CD28-deficient mice (d). There is a highly significant difference in disease severity between the early therapy and control groups (P = 0.0053 for WT and P = 0.0074 for CD28-deficient mice by two-tailed Mann-Whitney U test). No difference was found with delayed therapy. PD-L2 blockade also augmented disease (P = 0.03 compared with control by two-tailed Mann-Whitney U test) whereas PD-L1 blockade had no effect (c).
© Copyright Policy
Related In: Results  -  Collection

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

fig2: EAE outcome in animals treated with PD-1 pathway blockade. The disease scores for control and anti–PD-1–treated animals >40 d of follow up are shown, for WT mice with early therapy (a) and delayed therapy (b), and for CD28-deficient mice (d). There is a highly significant difference in disease severity between the early therapy and control groups (P = 0.0053 for WT and P = 0.0074 for CD28-deficient mice by two-tailed Mann-Whitney U test). No difference was found with delayed therapy. PD-L2 blockade also augmented disease (P = 0.03 compared with control by two-tailed Mann-Whitney U test) whereas PD-L1 blockade had no effect (c).
Mentions: Animals with EAE were killed at different time points up to 1 mo from the time of immunization. Sections of their spinal cords were stained for PD-1 and its ligands PD-L1 and PD-L2. Staining revealed an increased level of PD-1 expression on infiltrating cells beginning in the second week, peaking at the third week, and persisting for the 4 wk studied (Fig. 1 a). Expression of PD-L1 increased over a similar time period, although we found no PD-L2 staining in the brains until day 30 when only minimal staining was observed (Fig. 1 a). This time course of expression of both PD-1 and PD-L1 closely follows that of clinical disease in mice with EAE: peaking in the second to third weeks (Fig. 2 a). Furthermore, using dual color staining we demonstrated PD-L1 but not PD-L2 expression on resident astrocytes (colocalized with anti-GFAP mAb) and microglial cells (colocalized with lectin IB4), in brains of animals with EAE at 20 and 30 d, respectively (Fig. 1 b).

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