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Galectin-9-mediated protection from allo-specific T cells as a mechanism of immune privilege of corneal allografts.

Shimmura-Tomita M, Wang M, Taniguchi H, Akiba H, Yagita H, Hori J - PLoS ONE (2013)

Bottom Line: The eye is an immune-privileged organ, and corneal transplantation is therefore one of the most successful organ transplantation.T-cell immunoglobulin and mucin domain (Tim)-3 is a regulatory molecule for T-cell function, and galectin (Gal)-9 is a Tim-3 ligand.Blockade of Tim-3 or Gal-9 did not abolish anterior chamber-associated immune deviation.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Nippon Medical School, Tokyo, Japan. machiko@jichi.ac.jp

ABSTRACT
The eye is an immune-privileged organ, and corneal transplantation is therefore one of the most successful organ transplantation. The immunosuppressive intraocular microenvironment is known as one of the mechanisms underlying immune privilege in the eye. T-cell immunoglobulin and mucin domain (Tim)-3 is a regulatory molecule for T-cell function, and galectin (Gal)-9 is a Tim-3 ligand. We investigated the role of this pathway in establishing the immune-privileged status of corneal allografts in mice. Gal-9 is constitutively expressed on the corneal epithelium, endothelium and iris-ciliary body in normal mouse eyes and eyes bearing surviving allografts, and Tim-3 was expressed on CD8 T cells infiltrating the allografts. Allograft survival in recipients treated with anti-Tim-3 monoclonal antibody (mAb) or anti-Gal-9 mAb was significantly shorter than that in control recipients. In vitro, destruction of corneal endothelial cells by allo-reactive T cells was enhanced when the cornea was pretreated with anti-Gal-9 mAb. Blockade of Tim-3 or Gal-9 did not abolish anterior chamber-associated immune deviation. We propose that constitutive expression of Gal-9 plays an immunosuppressive role in corneal allografts. Gal-9 expressed on corneal endothelial cells protects them from destruction by allo-reactive T cells within the cornea.

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Blockade of Tim-3 or Gal-9 does not abolish ACAID.C57BL/6 spleen cells were used as alloantigens and injected into the right AC of BALB/c normal eyes. Two weeks later, C57BL/6 spleen cells were injected subcutaneously to sensitize the mice. After one more week, a challenge was conducted by injecting C57BL/6 spleen cells into the right ear pinnae of each mouse, and specific ear swelling was measured 24 h later as an indication of DH. Treatments with anti-Tim-3 mAb, anti-Gal-9 mAb (RG9-1 or RG9-35), or control rat IgG were performed starting from the day of AC injection and continuing until the day of ear challenge. DH responses were similarly suppressed in anti-Tim-3, anti-Gal-9, and control IgG-treated groups, with no significant differences observed among them. Positive control mice (Posi.C) received subcutaneous immunization and ear challenge without previous AC injection. Negative control mice (Nega.C) received only the ear challenge without AC injection or immunization. Data are presented as the mean ± standard error of five corneas in each group.
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pone-0063620-g006: Blockade of Tim-3 or Gal-9 does not abolish ACAID.C57BL/6 spleen cells were used as alloantigens and injected into the right AC of BALB/c normal eyes. Two weeks later, C57BL/6 spleen cells were injected subcutaneously to sensitize the mice. After one more week, a challenge was conducted by injecting C57BL/6 spleen cells into the right ear pinnae of each mouse, and specific ear swelling was measured 24 h later as an indication of DH. Treatments with anti-Tim-3 mAb, anti-Gal-9 mAb (RG9-1 or RG9-35), or control rat IgG were performed starting from the day of AC injection and continuing until the day of ear challenge. DH responses were similarly suppressed in anti-Tim-3, anti-Gal-9, and control IgG-treated groups, with no significant differences observed among them. Positive control mice (Posi.C) received subcutaneous immunization and ear challenge without previous AC injection. Negative control mice (Nega.C) received only the ear challenge without AC injection or immunization. Data are presented as the mean ± standard error of five corneas in each group.

Mentions: Eye-associated tolerance, termed ACAID, is one of the major mechanisms underlying the immune privilege of the eye and maintains acceptance of corneal allografts [10]. We hypothesized that the vulnerability of corneal allografts noted after blockade of Tim-3/Gal-9 might result from a failure to induce ACAID. We therefore tested the effect of Tim-3/Gal-9 blockade on alloantigen-specific ACAID induction using a simple model. B6 spleen cells were used as alloantigens and injected into the right anterior chamber of normal BALB/c eyes. Two weeks later, B6 spleen cells were injected subcutaneously to sensitize the mice. After one more week, B6 spleen cells were introduced into the ear pinnae to determine the delayed hypersensitivity (DH) response 24 h later. For 3 weeks, treatments with anti-Tim-3 or anti-Gal-9 mAb were applied starting from the day of anterior chamber (AC) injection and continued until the day of ear challenge. The DH response was induced in sensitized mice without prior AC injection (positive controls) as compared with unsensitized naïve mice (negative controls) (Fig. 6). Prior AC injection significantly suppressed the DH response in control IgG-treated mice, indicating the induction of ACAID. Treatments with either anti-Tim-3 or anti-Gal-9 mAb did not significantly affect the induction of ACAID (Fig. 6). These results indicate that Tim-3/Gal-9 interaction is not involved in the induction of ACAID.


Galectin-9-mediated protection from allo-specific T cells as a mechanism of immune privilege of corneal allografts.

Shimmura-Tomita M, Wang M, Taniguchi H, Akiba H, Yagita H, Hori J - PLoS ONE (2013)

Blockade of Tim-3 or Gal-9 does not abolish ACAID.C57BL/6 spleen cells were used as alloantigens and injected into the right AC of BALB/c normal eyes. Two weeks later, C57BL/6 spleen cells were injected subcutaneously to sensitize the mice. After one more week, a challenge was conducted by injecting C57BL/6 spleen cells into the right ear pinnae of each mouse, and specific ear swelling was measured 24 h later as an indication of DH. Treatments with anti-Tim-3 mAb, anti-Gal-9 mAb (RG9-1 or RG9-35), or control rat IgG were performed starting from the day of AC injection and continuing until the day of ear challenge. DH responses were similarly suppressed in anti-Tim-3, anti-Gal-9, and control IgG-treated groups, with no significant differences observed among them. Positive control mice (Posi.C) received subcutaneous immunization and ear challenge without previous AC injection. Negative control mice (Nega.C) received only the ear challenge without AC injection or immunization. Data are presented as the mean ± standard error of five corneas in each group.
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Related In: Results  -  Collection

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pone-0063620-g006: Blockade of Tim-3 or Gal-9 does not abolish ACAID.C57BL/6 spleen cells were used as alloantigens and injected into the right AC of BALB/c normal eyes. Two weeks later, C57BL/6 spleen cells were injected subcutaneously to sensitize the mice. After one more week, a challenge was conducted by injecting C57BL/6 spleen cells into the right ear pinnae of each mouse, and specific ear swelling was measured 24 h later as an indication of DH. Treatments with anti-Tim-3 mAb, anti-Gal-9 mAb (RG9-1 or RG9-35), or control rat IgG were performed starting from the day of AC injection and continuing until the day of ear challenge. DH responses were similarly suppressed in anti-Tim-3, anti-Gal-9, and control IgG-treated groups, with no significant differences observed among them. Positive control mice (Posi.C) received subcutaneous immunization and ear challenge without previous AC injection. Negative control mice (Nega.C) received only the ear challenge without AC injection or immunization. Data are presented as the mean ± standard error of five corneas in each group.
Mentions: Eye-associated tolerance, termed ACAID, is one of the major mechanisms underlying the immune privilege of the eye and maintains acceptance of corneal allografts [10]. We hypothesized that the vulnerability of corneal allografts noted after blockade of Tim-3/Gal-9 might result from a failure to induce ACAID. We therefore tested the effect of Tim-3/Gal-9 blockade on alloantigen-specific ACAID induction using a simple model. B6 spleen cells were used as alloantigens and injected into the right anterior chamber of normal BALB/c eyes. Two weeks later, B6 spleen cells were injected subcutaneously to sensitize the mice. After one more week, B6 spleen cells were introduced into the ear pinnae to determine the delayed hypersensitivity (DH) response 24 h later. For 3 weeks, treatments with anti-Tim-3 or anti-Gal-9 mAb were applied starting from the day of anterior chamber (AC) injection and continued until the day of ear challenge. The DH response was induced in sensitized mice without prior AC injection (positive controls) as compared with unsensitized naïve mice (negative controls) (Fig. 6). Prior AC injection significantly suppressed the DH response in control IgG-treated mice, indicating the induction of ACAID. Treatments with either anti-Tim-3 or anti-Gal-9 mAb did not significantly affect the induction of ACAID (Fig. 6). These results indicate that Tim-3/Gal-9 interaction is not involved in the induction of ACAID.

Bottom Line: The eye is an immune-privileged organ, and corneal transplantation is therefore one of the most successful organ transplantation.T-cell immunoglobulin and mucin domain (Tim)-3 is a regulatory molecule for T-cell function, and galectin (Gal)-9 is a Tim-3 ligand.Blockade of Tim-3 or Gal-9 did not abolish anterior chamber-associated immune deviation.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology, Nippon Medical School, Tokyo, Japan. machiko@jichi.ac.jp

ABSTRACT
The eye is an immune-privileged organ, and corneal transplantation is therefore one of the most successful organ transplantation. The immunosuppressive intraocular microenvironment is known as one of the mechanisms underlying immune privilege in the eye. T-cell immunoglobulin and mucin domain (Tim)-3 is a regulatory molecule for T-cell function, and galectin (Gal)-9 is a Tim-3 ligand. We investigated the role of this pathway in establishing the immune-privileged status of corneal allografts in mice. Gal-9 is constitutively expressed on the corneal epithelium, endothelium and iris-ciliary body in normal mouse eyes and eyes bearing surviving allografts, and Tim-3 was expressed on CD8 T cells infiltrating the allografts. Allograft survival in recipients treated with anti-Tim-3 monoclonal antibody (mAb) or anti-Gal-9 mAb was significantly shorter than that in control recipients. In vitro, destruction of corneal endothelial cells by allo-reactive T cells was enhanced when the cornea was pretreated with anti-Gal-9 mAb. Blockade of Tim-3 or Gal-9 did not abolish anterior chamber-associated immune deviation. We propose that constitutive expression of Gal-9 plays an immunosuppressive role in corneal allografts. Gal-9 expressed on corneal endothelial cells protects them from destruction by allo-reactive T cells within the cornea.

Show MeSH
Related in: MedlinePlus