Blockade of GITR-GITRL interaction maintains Treg function to prolong allograft survival.
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.
Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA. jmarkmann@partners.org
James I
JI
Kim
Samsher B
SB
Sonawane
Major K
MK
Lee
Seoung-Hoon
SH
Lee
Patrick E
PE
Duff
Daniel J
DJ
Moore
Matthew R
MR
O'Connor
Moh-Moh
MM
Lian
Shaoping
S
Deng
Yongwon
Y
Choi
Heidi
H
Yeh
Andrew J
AJ
Caton
James F
JF
Markmann
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology; D001667:Binding, Competitive; D023201:CD40 Ligand; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006085:Graft Survival / Q000187:drug effects*; D015395:Histocompatibility Antigens Class I; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016038:Skin Transplantation / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology*; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors / Q000276:immunology
D000911:Antibodies, Monoclonal; D053450:Glucocorticoid-Induced TNFR-Related Protein; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D015778:Minor Histocompatibility Antigens; C490628:Mr1 protein, mouse; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D000079424:Tumor Necrosis Factor Inhibitors; D048069:Tumor Necrosis Factors; D023201:CD40 Ligand