Abstract
Involvement of Treg in transplant tolerance has been demonstrated in multiple models. During the active process of graft rejection, these regulatory cells are themselves regulated and inactivated, a process termed counter-regulation. We hypothesize that ligation of the costimulatory molecule glucocorticoid-induced TNF receptor-related protein (GITR) on Treg inhibits their ability to promote graft survival, and by blocking GITR ligation graft survival can be prolonged. To this aim, we have designed a soluble GITR fusion protein (GITR-Fc), which binds GITR ligand and inhibits activation of GITR. Here, we show that GITR-Fc prolonged mouse skin graft survival, and this prolongation is dependent on Treg. In a full MHC-mismatched skin graft setting, GITR-Fc significantly improved graft survival when used in combination with MR1, anti-CD40L, while GITR-Fc alone did not demonstrate graft prolongation. These results demonstrate that disruption of binding of GITR with GITR ligand may be an important strategy in prolonging allograft survival.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adoptive Transfer
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Animals
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Antibodies, Monoclonal / administration & dosage
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal / therapeutic use
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Antigen-Presenting Cells / drug effects
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Antigen-Presenting Cells / immunology
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Binding, Competitive
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CD40 Ligand
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Glucocorticoid-Induced TNFR-Related Protein
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Graft Survival / drug effects*
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Histocompatibility Antigens Class I
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Humans
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Immune Tolerance / drug effects
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Immunosuppressive Agents / administration & dosage
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Immunosuppressive Agents / pharmacology
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Immunosuppressive Agents / therapeutic use*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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Minor Histocompatibility Antigens
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Receptors, Nerve Growth Factor / genetics
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Receptors, Nerve Growth Factor / immunology*
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Receptors, Tumor Necrosis Factor / genetics
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Receptors, Tumor Necrosis Factor / immunology*
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Recombinant Fusion Proteins / administration & dosage
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Recombinant Fusion Proteins / pharmacology
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Recombinant Fusion Proteins / therapeutic use
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Skin Transplantation / immunology*
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T-Lymphocytes, Regulatory / immunology*
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Transplantation, Homologous / immunology*
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Tumor Necrosis Factor Inhibitors*
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Tumor Necrosis Factors / immunology
Substances
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Antibodies, Monoclonal
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Glucocorticoid-Induced TNFR-Related Protein
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Histocompatibility Antigens Class I
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Immunosuppressive Agents
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Minor Histocompatibility Antigens
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Mr1 protein, mouse
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Receptors, Nerve Growth Factor
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Receptors, Tumor Necrosis Factor
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Recombinant Fusion Proteins
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Tnfrsf18 protein, mouse
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Tnfsf18 protein, mouse
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Tumor Necrosis Factor Inhibitors
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Tumor Necrosis Factors
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CD40 Ligand