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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 accelerates corneal allograft rejection.Normal corneas of C57BL/6 mice were transplanted orthotopically into normal eyes of BALB/c mice. After the grafting procedure, recipients were intraperitoneally injected with 0.2 mg of anti-Tim-3 mAb, anti-Gal-9 mAb (RG9-1 or RG9-35), or control rat IgG three times a week for 8 weeks. Graft survival was clinically assessed and compared. Survival of allografts treated with anti-Tim-3 or anti-Gal-9 mAb was significantly shorter than that in control allografts (n = 9–10 in each group).
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pone-0063620-g002: Blockade of Tim-3 or Gal-9 accelerates corneal allograft rejection.Normal corneas of C57BL/6 mice were transplanted orthotopically into normal eyes of BALB/c mice. After the grafting procedure, recipients were intraperitoneally injected with 0.2 mg of anti-Tim-3 mAb, anti-Gal-9 mAb (RG9-1 or RG9-35), or control rat IgG three times a week for 8 weeks. Graft survival was clinically assessed and compared. Survival of allografts treated with anti-Tim-3 or anti-Gal-9 mAb was significantly shorter than that in control allografts (n = 9–10 in each group).

Mentions: Normal corneas of C57BL/6 mice were transplanted orthotopically into normal eyes of BALB/c mice. In all recipients, 0.2 mg of anti-Tim-3 monoclonal antibody (mAb), anti-Gal-9 mAb, or control rat IgG was administered intraperitoneally 3 times a week for 8 weeks after grafting. Graft survival was clinically assessed and compared. Approximately 50% of allografts survived >8 weeks in the control IgG-treated recipients (Fig. 2). We have previously reported that approximately 50% of corneal allografts from C57BL/6 donors survive in untreated BALB/c recipients [29]. Therefore, administration of the control IgG did not affect corneal allograft survival. In contrast, all allografts were rejected within 50 days when recipients were treated with anti-Gal-9 mAbs, and 90% allografts were rejected after treatment with anti-Tim-3 mAb. Survival of allografts in anti-Tim-3 or anti-Gal-9 mAb-treated mice was significantly shorter than that in control IgG-treated mice (anti-Tim-3, p = 0.005; anti-Gal-9(RG9-1), p = 0.0003; anti-Gal-9(RG9-35), p<0.0001) (Fig. 2).


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 accelerates corneal allograft rejection.Normal corneas of C57BL/6 mice were transplanted orthotopically into normal eyes of BALB/c mice. After the grafting procedure, recipients were intraperitoneally injected with 0.2 mg of anti-Tim-3 mAb, anti-Gal-9 mAb (RG9-1 or RG9-35), or control rat IgG three times a week for 8 weeks. Graft survival was clinically assessed and compared. Survival of allografts treated with anti-Tim-3 or anti-Gal-9 mAb was significantly shorter than that in control allografts (n = 9–10 in each group).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3646846&req=5

pone-0063620-g002: Blockade of Tim-3 or Gal-9 accelerates corneal allograft rejection.Normal corneas of C57BL/6 mice were transplanted orthotopically into normal eyes of BALB/c mice. After the grafting procedure, recipients were intraperitoneally injected with 0.2 mg of anti-Tim-3 mAb, anti-Gal-9 mAb (RG9-1 or RG9-35), or control rat IgG three times a week for 8 weeks. Graft survival was clinically assessed and compared. Survival of allografts treated with anti-Tim-3 or anti-Gal-9 mAb was significantly shorter than that in control allografts (n = 9–10 in each group).
Mentions: Normal corneas of C57BL/6 mice were transplanted orthotopically into normal eyes of BALB/c mice. In all recipients, 0.2 mg of anti-Tim-3 monoclonal antibody (mAb), anti-Gal-9 mAb, or control rat IgG was administered intraperitoneally 3 times a week for 8 weeks after grafting. Graft survival was clinically assessed and compared. Approximately 50% of allografts survived >8 weeks in the control IgG-treated recipients (Fig. 2). We have previously reported that approximately 50% of corneal allografts from C57BL/6 donors survive in untreated BALB/c recipients [29]. Therefore, administration of the control IgG did not affect corneal allograft survival. In contrast, all allografts were rejected within 50 days when recipients were treated with anti-Gal-9 mAbs, and 90% allografts were rejected after treatment with anti-Tim-3 mAb. Survival of allografts in anti-Tim-3 or anti-Gal-9 mAb-treated mice was significantly shorter than that in control IgG-treated mice (anti-Tim-3, p = 0.005; anti-Gal-9(RG9-1), p = 0.0003; anti-Gal-9(RG9-35), p<0.0001) (Fig. 2).

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