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

Area of Science:

• Immunology
• Transplantation Biology
• Cellular Immunology

Background:

• Regulatory T cells (Treg) are crucial for transplant tolerance.
• During graft rejection, Treg function is suppressed through counter-regulation.
• The costimulatory molecule GITR (glucocorticoid-induced TNF receptor-related protein) is implicated in Treg regulation.

Purpose of the Study:

• To investigate the role of GITR ligation in Treg function during graft rejection.
• To determine if blocking GITR-ligand interaction can prolong allograft survival.
• To assess the efficacy of a soluble GITR fusion protein (GITR-Fc) in enhancing transplant tolerance.

Main Methods:

• Development of a soluble GITR fusion protein (GITR-Fc) to inhibit GITR-ligand binding.
• Administration of GITR-Fc in a mouse skin transplantation model.
• Evaluation of graft survival and the role of Treg in mediating the observed effects.
• Combination therapy using GITR-Fc with MR1 and anti-CD40L.

Main Results:

• GITR-Fc administration prolonged mouse skin allograft survival.
• The graft-prolonging effect of GITR-Fc was dependent on the presence of Treg.
• GITR-Fc showed enhanced efficacy in prolonging graft survival when combined with MR1 and anti-CD40L.
• GITR-Fc alone did not significantly prolong survival in a fully MHC-mismatched setting.

Conclusions:

• Disrupting the GITR-GITR ligand interaction is a viable strategy to inhibit Treg inactivation.
• Targeting GITR offers a potential therapeutic approach for prolonging allograft survival.
• Combination therapy involving GITR blockade may be more effective in overcoming active graft rejection.