Osteopontin aggravates experimental autoimmune uveoretinitis in mice.
Human endogenous uveitis is a common sight-threatening intraocular inflammatory disease and has been studied extensively using a murine model of experimental autoimmune uveoretinitis (EAU). It is possibly mediated by Th1 immune responses. In the present study, we investigated the role of osteopontin (OPN), a protein with pleiotropic functions that contributes to the development of Th1 cell-mediated immunity. Accompanying EAU progression, OPN was elevated in wild-type (WT) mice that had been immunized with human interphotoreceptor retinoid-binding protein (hIRBP) peptide 1-20. OPN-deficient (OPN-/-) mice showed milder EAU progression in clinical and histopathological scores compared with those of WT mice. The T cells from hIRBP-immunized OPN-/- mice exhibited reduced Ag-specific proliferation and proinflammatory cytokine (TNF-alpha and IFN-gamma) production compared with those of WT T cells. When hIRBP-immunized WT mice were administered M5 Ab reacting to SLAYGLR sequence, a cryptic binding site to integrins within OPN, EAU development was significantly ameliorated. T cells from hIRBP-immunized WT mice showed significantly reduced proliferative responses and proinflammatory cytokine production upon stimulation with hIRBP peptide in the presence of M5 Ab in the culture. Our present results demonstrate that OPN may represent a novel therapeutic target to control uveoretinitis.
Kitamura
Mizuki
M
Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Iwabuchi
Kazuya
K
Kitaichi
Nobuyoshi
N
Kon
Shigeyuki
S
Kitamei
Hirokuni
H
Namba
Kenichi
K
Yoshida
Kazuhiko
K
Denhardt
David T
DT
Rittling
Susan R
SR
Ohno
Shigeaki
S
Uede
Toshimitsu
T
Onoé
Kazunori
K
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D053495:Osteopontin / Q000009:adverse effects* / Q000097:blood / Q000172:deficiency / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D012173:Retinitis / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D012720:Severity of Illness Index; D014605:Uveitis / Q000235:genetics / Q000276:immunology* / Q000628:therapy
D000906:Antibodies; D010446:Peptide Fragments; D053495:Osteopontin