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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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T cell and antibody responses to MOG in animals treated with PD-1 blockade. ELISPOT analysis from one representative experiment, demonstrating the frequency of MOG-specific IFN-γ–producing T cells at different concentrations of antigen for WT (a) and CD28-deficient animals (b). In the WT group, anti–PD-1–treated animals (solid bars) had a higher frequency of MOG-specific IFN-γ–producing T cells at all antigen concentrations compared with controls (hatched bars, *, P = 0.017 by one-way ANOVA). In the CD28-deficient mice, a significant difference was also seen at higher antigen concentrations (*, P = 0.0254 by one-way ANOVA). (c) DTH measurement assessed by an increase in footpad skin thickness after intradermal injection with 50 μg antigen. DTH response was significantly greater in the anti–PD-1–treated animals than controls (*, P = 0.0245 by two-tailed Mann-Whitney U test). (d) Serum level of anti-MOG antibodies obtained on day 14 after immunization were greater in anti–PD-1–treated animals than controls in both WT and CD28-deficient animals (*, P = 0.0476; **, P = 0.0009 by two-tailed Mann-Whitney U test).
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fig3: T cell and antibody responses to MOG in animals treated with PD-1 blockade. ELISPOT analysis from one representative experiment, demonstrating the frequency of MOG-specific IFN-γ–producing T cells at different concentrations of antigen for WT (a) and CD28-deficient animals (b). In the WT group, anti–PD-1–treated animals (solid bars) had a higher frequency of MOG-specific IFN-γ–producing T cells at all antigen concentrations compared with controls (hatched bars, *, P = 0.017 by one-way ANOVA). In the CD28-deficient mice, a significant difference was also seen at higher antigen concentrations (*, P = 0.0254 by one-way ANOVA). (c) DTH measurement assessed by an increase in footpad skin thickness after intradermal injection with 50 μg antigen. DTH response was significantly greater in the anti–PD-1–treated animals than controls (*, P = 0.0245 by two-tailed Mann-Whitney U test). (d) Serum level of anti-MOG antibodies obtained on day 14 after immunization were greater in anti–PD-1–treated animals than controls in both WT and CD28-deficient animals (*, P = 0.0476; **, P = 0.0009 by two-tailed Mann-Whitney U test).

Mentions: 14 d after MOG immunization, splenocytes were isolated from animals in each of the treatment groups and were assayed by ELISPOT for IFN-γ production in response to MOG peptide. When compared with the control animals, those treated with PD-1 blockade had a higher frequency of IFN-γ–producing MOG-reactive T cells in both WT (Fig. 3 a; P = 0.017 by one-way analysis of variance [ANOVA]) and CD28-deficient animals (Fig. 3 b; P = 0.0254 by one-way ANOVA). Moreover, in WT mice there was a significant increase in DTH reaction in the animals treated with anti–PD-1 mAb compared with controls (Fig. 3 c; P = 0.0245 by two-tailed Mann-Whitney U test).


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)

T cell and antibody responses to MOG in animals treated with PD-1 blockade. ELISPOT analysis from one representative experiment, demonstrating the frequency of MOG-specific IFN-γ–producing T cells at different concentrations of antigen for WT (a) and CD28-deficient animals (b). In the WT group, anti–PD-1–treated animals (solid bars) had a higher frequency of MOG-specific IFN-γ–producing T cells at all antigen concentrations compared with controls (hatched bars, *, P = 0.017 by one-way ANOVA). In the CD28-deficient mice, a significant difference was also seen at higher antigen concentrations (*, P = 0.0254 by one-way ANOVA). (c) DTH measurement assessed by an increase in footpad skin thickness after intradermal injection with 50 μg antigen. DTH response was significantly greater in the anti–PD-1–treated animals than controls (*, P = 0.0245 by two-tailed Mann-Whitney U test). (d) Serum level of anti-MOG antibodies obtained on day 14 after immunization were greater in anti–PD-1–treated animals than controls in both WT and CD28-deficient animals (*, P = 0.0476; **, P = 0.0009 by two-tailed Mann-Whitney U test).
© Copyright Policy
Related In: Results  -  Collection

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

fig3: T cell and antibody responses to MOG in animals treated with PD-1 blockade. ELISPOT analysis from one representative experiment, demonstrating the frequency of MOG-specific IFN-γ–producing T cells at different concentrations of antigen for WT (a) and CD28-deficient animals (b). In the WT group, anti–PD-1–treated animals (solid bars) had a higher frequency of MOG-specific IFN-γ–producing T cells at all antigen concentrations compared with controls (hatched bars, *, P = 0.017 by one-way ANOVA). In the CD28-deficient mice, a significant difference was also seen at higher antigen concentrations (*, P = 0.0254 by one-way ANOVA). (c) DTH measurement assessed by an increase in footpad skin thickness after intradermal injection with 50 μg antigen. DTH response was significantly greater in the anti–PD-1–treated animals than controls (*, P = 0.0245 by two-tailed Mann-Whitney U test). (d) Serum level of anti-MOG antibodies obtained on day 14 after immunization were greater in anti–PD-1–treated animals than controls in both WT and CD28-deficient animals (*, P = 0.0476; **, P = 0.0009 by two-tailed Mann-Whitney U test).
Mentions: 14 d after MOG immunization, splenocytes were isolated from animals in each of the treatment groups and were assayed by ELISPOT for IFN-γ production in response to MOG peptide. When compared with the control animals, those treated with PD-1 blockade had a higher frequency of IFN-γ–producing MOG-reactive T cells in both WT (Fig. 3 a; P = 0.017 by one-way analysis of variance [ANOVA]) and CD28-deficient animals (Fig. 3 b; P = 0.0254 by one-way ANOVA). Moreover, in WT mice there was a significant increase in DTH reaction in the animals treated with anti–PD-1 mAb compared with controls (Fig. 3 c; P = 0.0245 by two-tailed Mann-Whitney U test).

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