Involvement of inducible costimulator-B7 homologous protein costimulatory pathway in murine lupus nephritis.
Inducible costimulator (ICOS)-B7 homologous protein (B7h) is a new member of the CD28-B7 family of costimulatory molecules that regulates T cell-dependent humoral immune responses. In this study, we examined the involvement of this costimulatory pathway in the development and progression of lupus in NZB/W F(1) mice. Expression of ICOS on T cells was enhanced with disease progression, whereas B7h expression on B cells was down-regulated. Administration of anti-B7h mAb before the onset of renal disease significantly delayed the onset of proteinuria and prolonged survival. Blockade of B7h effectively inhibited all subclasses of IgG autoantibody production and accumulation of both Th1 and Th2 cells. Hypercellularity and deposition of IgG and C3 in glomeruli were significantly reduced. B7h blockade after the onset of proteinuria prevented the disease progression and improved the renal pathology. Our results demonstrated the involvement of the ICOS-B7h costimulatory pathway in the pathogenesis of lupus nephritis, and the blockade of this pathway may be beneficial for the treatment of human systemic lupus erythematosus.
Iwai
Hideyuki
H
Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo, Japan. iwi.rheu@tmd.ac.jp
Abe
Masaaki
M
Hirose
Sachiko
S
Tsushima
Fumihiko
F
Tezuka
Katsunari
K
Akiba
Hisaya
H
Yagita
Hideo
H
Okumura
Ko
K
Kohsaka
Hitoshi
H
Miyasaka
Nobuyuki
N
Azuma
Miyuki
M
D019264:Adoptive Transfer; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D003433:Crosses, Genetic; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004334:Drug Administration Schedule; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007274:Injections, Intraperitoneal; D008024:Ligands; D008181:Lupus Nephritis / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D016131:Lymphocyte Subsets / Q000145:classification / Q000166:cytology / Q000276:immunology; D051379:Mice; D008814:Mice, Inbred NZB; D016513:Mice, SCID; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D014176:Protein Biosynthesis; D011506:Proteins / Q000276:immunology / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; 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; D008024:Ligands; D011506:Proteins; D010047:Ovalbumin