Delivering PD-1 inhibitory signal concomitant with blocking ICOS co-stimulation suppresses lupus-like syndrome in autoimmune BXSB mice.
BXSB mice spontaneously develop an autoimmune syndrome characterized by hypergammaglobulinemia, autoantibody production, and the development of fatal glomerulonephritis that closely resembles systemic lupus erythematosus (SLE) in humans. While blocking positive T cell co-stimulation has shown effectiveness in preventing the onset of murine lupus, deliberate delivering negative co-stimulation to halt unwanted T and B cell activation has not been tested. We developed a recombinant adenovirus containing the full-length mouse PD-L1 gene (Ad.PD-L1) to engage the immunoinhibitory receptor PD-1 on activated lymphocytes to prevent lupus nephritis in BXSB mice. This strategy was further reinforced by concomitant injection of anti-ICOSL(B7h) mAb to block ICOS-mediated co-stimulation. The combined therapy dramatically delayed the onset of proteinuria, effectively inhibited IgG autoantibody production, and significantly reduced hypercellularity and deposition of IgG in glomeruli, resulting in almost complete amelioration of lupus nephritis in these animals. Our results indicate the therapeutic potential of simultaneous stimulation of PD-1-mediated pathway and blockade of ICOS-B7h co-stimulation in the prevention of human lupus nephritis.
Ding
Hanlu
H
Department of Nephrology, Southwestern Hospital, The Third Military Medical University, Chongqing 400038, P.R. China.
Wu
Xiongfei
X
Wu
Jun
J
Yagita
Hideo
H
He
Yani
Y
Zhang
Jianguo
J
Ren
Jiangwen
J
Gao
Wenda
W
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000502:physiology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology* / Q000502:physiology; D004247:DNA / Q000276:immunology; D004847:Epithelial Cells / Q000378:metabolism; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D007074:Immunoglobulin G / Q000096:biosynthesis; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D061026:Programmed Cell Death 1 Receptor; D011506:Proteins / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013577:Syndrome
D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; C556692:ICOS protein, human; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D007074:Immunoglobulin G; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011506:Proteins; D004247:DNA