PURPOSE: To evaluate the immunotherapeutic efficacy of recombinant T cell receptor ligands (RTLs) specific for arrestin immunity in treatment of experimental autoimmune uveitis (EAU) in humanized leukocyte antigen (HLA-DR3) transgenic (Tg) mice. METHODS: We generated de novo recombinant human DR3-derived RTLs bearing covalently tethered arrestin peptides 291-310 (RTL351) or 305-324 (RTL352). EAU was induced by immunization of HLA-DR3 mice with arrestin or arrestin peptide and treated with RTLs by subcutaneous delivery. T cell proliferation and cytokine expression was measured in RTL-treated and control mice. RESULTS: RTL351 prevented the migration of cells outside of the spleen and the recruitment of inflammatory cells into the eye, and provided full protection against inflammation from EAU induced with arrestin or arrestin peptides. RTL351 significantly inhibited T cell proliferation and secretion of inflammatory cytokines interleukin 2 (IL-2), interferon γ (IFN-γ), IL-6, and IL-17 and chemokines (macrophage inflammatory proteins [MIP-1a] and regulated and normal T cell expressed and secreted [RANTES]), which is in agreement with the suppression of intraocular inflammation. RTL350 ("empty," no peptide) and RTL352 were not effective. CONCLUSIONS: Immunotherapy with a single RTL351 successfully prevented and treated arrestin-induced EAU in HLA-DR3 mice and provided proof of concept for therapy of autoimmune uveitis in human patients. The beneficial effects of RTL351 should be attributed to a significant decrease in Th1/Th17 mediated inflammation. TRANSLATIONAL RELEVANCE: Successful therapies for autoimmune uveitis must specifically inhibit pathogenic inflammation without inducing generalized immunosuppression. RTLs can offer such an option. The single retina-specific RTLs may have a value as potential immunotherapeutic drug for human autoimmune uveitis because they effectively prevent disease induced by multiple T cell specificities.
PURPOSE: To evaluate the immunotherapeutic efficacy of recombinant T cell receptor ligands (RTLs) specific for arrestin immunity in treatment of experimental autoimmune uveitis (EAU) in humanized leukocyte antigen (HLA-DR3) transgenic (Tg) mice. METHODS: We generated de novo recombinant human DR3-derived RTLs bearing covalently tethered arrestin peptides 291-310 (RTL351) or 305-324 (RTL352). EAU was induced by immunization of HLA-DR3 mice with arrestin or arrestin peptide and treated with RTLs by subcutaneous delivery. T cell proliferation and cytokine expression was measured in RTL-treated and control mice. RESULTS: RTL351 prevented the migration of cells outside of the spleen and the recruitment of inflammatory cells into the eye, and provided full protection against inflammation from EAU induced with arrestin or arrestin peptides. RTL351 significantly inhibited T cell proliferation and secretion of inflammatory cytokines interleukin 2 (IL-2), interferon γ (IFN-γ), IL-6, and IL-17 and chemokines (macrophage inflammatory proteins [MIP-1a] and regulated and normal T cell expressed and secreted [RANTES]), which is in agreement with the suppression of intraocular inflammation. RTL350 ("empty," no peptide) and RTL352 were not effective. CONCLUSIONS: Immunotherapy with a single RTL351 successfully prevented and treated arrestin-induced EAU in HLA-DR3 mice and provided proof of concept for therapy of autoimmune uveitis in human patients. The beneficial effects of RTL351 should be attributed to a significant decrease in Th1/Th17 mediated inflammation. TRANSLATIONAL RELEVANCE: Successful therapies for autoimmune uveitis must specifically inhibit pathogenic inflammation without inducing generalized immunosuppression. RTLs can offer such an option. The single retina-specific RTLs may have a value as potential immunotherapeutic drug for human autoimmune uveitis because they effectively prevent disease induced by multiple T cell specificities.
Authors: Hiroe Sato; Felix A Woodhead; Tariq Ahmad; Jan C Grutters; Paolo Spagnolo; Jules M M van den Bosch; Lisa A Maier; Lee S Newman; Sonoko Nagai; Takateru Izumi; Athol U Wells; Roland M du Bois; Kenneth I Welsh Journal: Hum Mol Genet Date: 2010-08-03 Impact factor: 6.150
Authors: C Alaez; M del Pilar Mora; L Arellanes; S Cano; E Perez-Luque; M N Vazquez; A Olivo; A Burguete; A Hernandez; M Pedroza; C Gorodezky Journal: Hum Immunol Date: 1999-09 Impact factor: 2.850
Authors: Giuseppina Pennesi; Mary J Mattapallil; Shu-Hui Sun; Dody Avichezer; Phyllis B Silver; Zaruhi Karabekian; Chella S David; Paul A Hargrave; J Hugh McDowell; W Clay Smith; Barbara Wiggert; Larry A Donoso; Chi-Chao Chan; Rachel R Caspi Journal: J Clin Invest Date: 2003-04 Impact factor: 14.808
Authors: M Cuccia Belvedere; M Martinetti; F de Paoli; D Mazzacane; C Redaelli; A Tafi; G Morone Journal: Dis Markers Date: 1986-10 Impact factor: 3.434