title: The long-term immunosuppressive effects of disulfide-linked HLA-G dimer in mice with collagen-induced arthritis.
abstract: HLA-G, a natural immunosuppressant present in the human placenta during pregnancy, prevents fetal destruction by the maternal immune system. The immunosuppressive effect of HLA-G is mediated by the immune cell inhibitory receptors, LILRB1 and LILRB2. HLA-G forms disulfide-linked dimers by natural oxidation, and the dimer associates with LILRB1/B2 much more strongly than the monomer. Furthermore, the dimer formation remarkably enhanced the LILRB-mediated signaling. In this report, we studied the in vivo immunosuppressive effect of the HLA-G dimer, using the collagen-induced arthritis model mouse. Mice were treated with the HLA-G monomer or dimer intracutaneously at the left foot joint, once or for 5 days, and the clinical severity was evaluated daily in a double-blind study. The HLA-G monomer and dimer both produced excellent anti-inflammatory effects with a single, local administration. Notably, as compared to the monomer, the dimer exhibited significant immunosuppressive effects at lower concentrations, which persisted for about two months. In accordance with this result, a binding study revealed that the HLA-G dimer binds PIR-B, the mouse homolog of the LILRBs, with higher affinity and avidity than the monomer. The HLA-G dimer is expected to be quite useful as an anti-rheumatoid arthritis agent, in small amounts with minimal side effects.
authors.affiliation: Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. k-kimiko@pharm.hokudai.ac.jp
authors.forename: Kimiko
authors.initials: K
authors.lastname: Kuroki
authors.forename: Kaoru
authors.initials: K
authors.lastname: Hirose
authors.forename: Yuki
authors.initials: Y
authors.lastname: Okabe
authors.forename: Yuko
authors.initials: Y
authors.lastname: Fukunaga
authors.forename: Ami
authors.initials: A
authors.lastname: Takahashi
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Shiroishi
authors.forename: Mizuho
authors.initials: M
authors.lastname: Kajikawa
authors.forename: Shigekazu
authors.initials: S
authors.lastname: Tabata
authors.forename: Seiko
authors.initials: S
authors.lastname: Nakamura
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takai
authors.forename: Satoru
authors.initials: S
authors.lastname: Koyanagi
authors.forename: Shigehiro
authors.initials: S
authors.lastname: Ohdo
authors.forename: Katsumi
authors.initials: K
authors.lastname: Maenaka
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D024043:Collagen Type II; D004220:Disulfides / Q000737:chemistry; D059951:HLA-G Antigens / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*; D007267:Injections; D007596:Joints / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011485:Protein Binding; D055503:Protein Multimerization; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000276:immunology; D012720:Severity of Illness Index
chemical_list: D024043:Collagen Type II; D004220:Disulfides; D059951:HLA-G Antigens; D007166:Immunosuppressive Agents; C105949:Pirb protein, mouse; D011971:Receptors, Immunologic