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- Title
Blockade of GITR-GITRL interaction maintains Treg function to prolong allograft survival.
- 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.
- 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
European Journal of Immunology, 2010, Vol 40, Issue 5, p1369
- ISSN
0014-2980
- Publication type
Article
- DOI
10.1002/eji.200940046