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

• Published in: European journal of immunology 2010-05, Vol.40 (5), p.1369-1374
• Main Authors: Kim, James I, Sonawane, Samsher B, Lee, Major K, Lee, Seoung-Hoon, Duff, Patrick E, Moore, Daniel J, O'Connor, Matthew R, Lian, Moh-Moh, Deng, Shaoping, Choi, Yongwon, Yeh, Heidi, Caton, Andrew J, Markmann, James F
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Antigen-Presenting Cells - drug effects; Antigen-Presenting Cells - immunology; Binding, Competitive; CD40 Ligand; CD40L protein; Fc receptors; Fusion protein; GITR; Glucocorticoid-Induced TNFR-Related Protein; Glucocorticoids; Graft rejection; Graft Survival - drug effects; Histocompatibility Antigens Class I; Humans; Immune Tolerance - drug effects; Immunological tolerance; Immunoregulation; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Inflammation; Ligands; Lymphocytes T; Major histocompatibility complex; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Minor Histocompatibility Antigens; Plastic surgery; Receptors, Nerve Growth Factor - genetics; Receptors, Nerve Growth Factor - immunology; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - immunology; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - pharmacology; Recombinant Fusion Proteins - therapeutic use; Skin & tissue grafts; Skin Transplantation - immunology; T-Lymphocytes, Regulatory - immunology; Tolerance; Transplant; Transplantation, Homologous - immunology; Transplants & implants; Treg; Tumor Necrosis Factor Inhibitors; Tumor necrosis factor receptors; Tumor Necrosis Factors - immunology
• ISSN: 0014-2980; 1521-4141
• 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.