Blockade of GITR-GITRL interaction maintains Treg function to prolong allograft survival.

Kim JI, Sonawane SB, Lee MK, Lee SH, Duff PE, Moore DJ, O'Connor MR, Lian MM, Deng S, Choi Y, Yeh H, Caton AJ, Markmann JF
Eur J Immunol. 2010 40 (5): 1369-74

PMID: 20148423 · PMCID: PMC2935584 · DOI:10.1002/eji.200940046

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.

MeSH Terms (25)

Adoptive Transfer Animals Antibodies, Monoclonal Antigen-Presenting Cells Binding, Competitive CD40 Ligand Glucocorticoid-Induced TNFR-Related Protein Graft Survival Histocompatibility Antigens Class I Humans Immune Tolerance Immunosuppressive Agents Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Transgenic Minor Histocompatibility Antigens Receptors, Nerve Growth Factor Receptors, Tumor Necrosis Factor Recombinant Fusion Proteins Skin Transplantation T-Lymphocytes, Regulatory Transplantation, Homologous Tumor Necrosis Factor Inhibitors Tumor Necrosis Factors

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