title: Key role of the GITR/GITRLigand pathway in the development of murine autoimmune diabetes: a potential therapeutic target.
abstract: BACKGROUND
  The cross-talk between pathogenic T lymphocytes and regulatory T cells (Tregs) plays a major role in the progression of autoimmune diseases. Our objective is to identify molecules and/or pathways involved in this interaction and representing potential targets for innovative therapies. Glucocorticoid-induced tumor necrosis factor receptor (GITR) and its ligand are key players in the T effector/Treg interaction. GITR is expressed at low levels on resting T cells and is significantly up-regulated upon activation. Constitutive high expression of GITR is detected only on Tregs. GITR interacts with its ligand mainly expressed on antigen presenting cells and endothelial cells. It has been suggested that GITR triggering activates effector T lymphocytes while inhibiting Tregs thus contributing to the amplification of immune responses. In this study, we examined the role of GITR/GITRLigand interaction in the progression of autoimmune diabetes.
  
  
  RESULTS
  Treatment of 10-day-old non-obese diabetic (NOD) mice, which spontaneously develop diabetes, with an agonistic GITR-specific antibody induced a significant acceleration of disease onset (80% at 12 weeks of age). This activity was not due to a decline in the numbers or functional capacity of CD4(+)CD25(+)Foxp3(+) Tregs but rather to a major activation of 'diabetogenic' T cells. This conclusion was supported by results showing that anti-GITR antibody exacerbates diabetes also in CD28(-/-) NOD mice, which lack Tregs. In addition, treatment of NOD mice, infused with the diabetogenic CD4(+)BDC2.5 T cell clone, with GITR-specific antibody substantially increased their migration, proliferation and activation within the pancreatic islets and draining lymph nodes. As a mirror image, blockade of the GITR/GITRLigand pathway using a neutralizing GITRLigand-specific antibody significantly protected from diabetes even at late stages of disease progression. Experiments using the BDC2.5 T cell transfer model suggested that the GITRLigand antibody acted by limiting the homing and proliferation of pathogenic T cells in pancreatic lymph nodes.
  
  
  CONCLUSIONS
  GITR triggering plays an important costimulatory role on diabetogenic T cells contributing to the development of autoimmune responses. Therefore, blockade of the GITR/GITRLigand pathway appears as a novel promising clinically oriented strategy as GITRLigand-specific antibody applied at an advanced stage of disease progression can prevent overt diabetes.
authors: Université Paris Descartes, Paris, France. sylvaine.you@inserm.fr
authors: Sylvaine
authors: S
authors: You
authors: Lynn
authors: L
authors: Poulton
authors: Steve
authors: S
authors: Cobbold
authors: Chih-Pin
authors: CP
authors: Liu
authors: Michael
authors: M
authors: Rosenzweig
authors: Douglas
authors: D
authors: Ringler
authors: Wen-Hui
authors: WH
authors: Lee
authors: Berta
authors: B
authors: Segovia
authors: Jean-François
authors: JF
authors: Bach
authors: Herman
authors: H
authors: Waldmann
authors: Lucienne
authors: L
authors: Chatenoud
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D008024:Ligands; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000166:cytology; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein; D008024:Ligands; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors