title: Regulation of experimental autoimmune uveoretinitis by anti-delta-like ligand 4 monoclonal antibody.
abstract: OBJECTIVE
  To investigate the involvement of δ-like ligand (Dll)4 in the development of experimental autoimmune uveoretinitis (EAU) in B10.RIII mice.
  
  
  METHODS
  B10.RIII mice were immunized with interphotoreceptor retinoid binding protein (IRBP) peptide 161-180 in complete Freund's adjuvant together with intraperitoneal injection of Bordetella pertussis toxin. mRNA expressions of Notch receptors and their ligands in the eye were evaluated. To investigate the involvement of Dll in EAU, anti-Dll1, anti-Dll4, or control antibody (Ab) was intraperitoneally injected during both the induction and the effector phases or only the effector phase. Alternatively, mice were intraperitoneally injected with γ-secretase inhibitor (GSI) or the control vehicle during the induction phase. Fourteen days after immunization, the eyes and spleens were harvested. The eyes were used for histologic and/or cytokine mRNA expression analysis, whereas the spleens were used for flow cytometric analysis, and antigen-recall proliferation and cytokine assays.
  
  
  RESULTS
  Expression of Notch1, 2, 4, and Dll4 in the eye were upregulated by EAU induction. Anti-Dll4 Ab treatment during both the induction and effector phases, but not only the effector phase, significantly reduced the severity of EAU. IFN-γ, IL-12p35, IL-17A, and TGF-β mRNA expression in the eye were significantly attenuated by treatment with anti-Dll4 Ab. Splenocytes from anti-Dll4 Ab-treated mice showed significantly less proliferation and IL-17 production on antigen stimulation. Also, the severity of EAU was significantly reduced by γ-secretase inhibitor treatment during the induction phase. CONCLUSIONS; Dll4-mediated Notch signaling during the sensitization is critical for the development of EAU. This can be a novel prophylactic target for autoimmune uveitis.
authors: Department of Ophthalmology, Science Research Center, Kochi Medical School, Nankoku-city, Japan.
authors: Waka
authors: W
authors: Ishida
authors: Ken
authors: K
authors: Fukuda
authors: Shuji
authors: S
authors: Sakamoto
authors: Noriko
authors: N
authors: Koyama
authors: Akemi
authors: A
authors: Koyanagi
authors: Hideo
authors: H
authors: Yagita
authors: Atsuki
authors: A
authors: Fukushima
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000494:pharmacology; D005434:Flow Cytometry; D007274:Injections, Intraperitoneal; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D010446:Peptide Fragments / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D051881:Receptor, Notch1 / Q000235:genetics; D051883:Receptor, Notch2 / Q000235:genetics; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D012173:Retinitis / Q000378:metabolism*; D012177:Retinol-Binding Proteins / Q000494:pharmacology; D014605:Uveitis / Q000378:metabolism*; D000099214:Retinol-Binding Proteins, Interstitial
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053829:Amyloid Precursor Protein Secretases; D000911:Antibodies, Monoclonal; D002135:Calcium-Binding Proteins; D016207:Cytokines; D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial; C519665:DLL4 protein, mouse; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; C073572:Notch4 protein, mouse