Inducible co-stimulatory molecule ligand is protective during the induction and effector phases of crescentic glomerulonephritis.
The inducible co-stimulatory molecule (ICOS)/ICOS ligand (ICOSL) co-stimulatory pathway is critical in T cell activation, differentiation, and effector function. Its role was investigated in a model of Th1-driven crescentic glomerulonephritis (GN). GN was induced by sensitizing mice to sheep globulin (day 0) and challenging them with sheep anti-mouse glomerular basement membrane antibody (Ab; day 10). Disease and immune responses were assessed on day 20. For testing the role of ICOSL in the induction of GN, control or anti-ICOSL mAb were administered from days 0 to 8. For examining the role of ICOSL in the effector phase of GN, treatment lasted from days 10 to 18. Blockade of ICOSL during the induction of GN increased glomerular accumulation of CD4+ T cells and macrophages and augmented renal injury. These results correlated with attenuated splenocyte production of protective Th2 cytokines IL-4 and IL-10 and decreased apoptosis of splenic CD4+ T cells. ICOSL was upregulated within glomeruli of mice with GN. Inhibition of ICOSL during the effector phase of GN enhanced glomerular T cell and macrophage accumulation and augmented disease, without affecting the systemic immune response (cytokine production, T cell apoptosis/proliferation, Ab levels). Increased presence of leukocytes in glomeruli of mice that received anti-ICOSL mAb was associated with enhanced cellular proliferation and upregulation of P-selectin and intercellular adhesion molecule-1 within glomeruli. These studies demonstrate that ICOSL is protective during the induction of GN by augmenting Th2 responses and CD4+ T cell apoptosis. They also show that ICOSL is upregulated in nephritic glomeruli, where it locally reduces accumulation of T cells and macrophages and attenuates renal injury.
Odobasic
Dragana
D
Department of Medicine, Monash University, Monash Medical Centre, Level 5 Block E, 246 Clayton Road, Clayton, Victoria 3168, Australia.
Kitching
A Richard
AR
Semple
Timothy J
TJ
Holdsworth
Stephen R
SR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018925:Chemokines / Q000378:metabolism; D005916:Globulins / Q000008:administration & dosage / Q000276:immunology; D005921:Glomerulonephritis / Q000209:etiology* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D060945:Inducible T-Cell Co-Stimulator Ligand; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology; D008024:Ligands; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D019707:Receptors, Chemokine / Q000378:metabolism; D012756:Sheep; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D000911:Antibodies, Monoclonal; D018925:Chemokines; D005916:Globulins; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D008024:Ligands; D011506:Proteins; D019707:Receptors, Chemokine