[Translational research with experimental autoimmune uveoretinitis (EAU)].
Experimental autoimmune uveoretinitis (EAU) induced by immunization with retinal antigen (Santigen or interphotoreceptor retinoid-binding protein; IRBP) serves as an animal model of human uveoretinitis. As the first stage, we demonstrated the similarities between EAU and ocular inflammation in Behçet's disease by investigating anti-retinal antibodies, leukocyte migration inhibition by retinal antigen, immunogenic antigens, aberrant functions of neutrophils, and dominant Th1 lymphocyte reaction. From these findings, we verified that EAU, which is not associated with the systemic disorders observed in Behçet's disease, is an appropriate model for translational research targeting ocular inflammation. In the second stage, we set 3 therapeutic strategies for uveitis in Behçet's disease to be conducted in the translational research: (1) intraocular administration of an immunosuppressive drug; (2) inhibition of Th1 lymphocytes; and (3) activation of immunoregulatory cells. In strategy 1, our studies indicated that intravitreal injection of 10 microg of tacrolimus (FK 506) was not harmful to the retina and was predominantly effective in suppressing ongoing EAU in rats. In strategy 2, two approaches were adopted to prevent differentiation of Thl cells. One is anti-cytokine antibody therapy using anti-IL-12 monoclonal antibodies(mAb). The other is blockade of co-stimulatory signals, especially the ICOS-B7RP-1 pathway. Administration of anti-IL-12 mAb at the time of IRBP immunization completely inhibited development of EAU, and antagonistic anti B7RP-1 mAb suppressed the severity of EAU even when administered after development of EAU. In strategy 3, adoptive transfer of antigen presenting cells treated with a neuropeptide (vasoactive intestinal peptide or calcitonin gene-related peptide) or CD 4+ CD 25+ regulatory T cells suppressed EAU. We look forward to the day when therapies that are being developed in our translational research using EAU will become available for treating intraocular inflammation in Behçet's disease.
Usui
Masahiko
M
Department of Ophthalmology, Tokyo Medical University.
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000945:Antigens, Differentiation, T-Lymphocyte; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D001528:Behcet Syndrome; D018106:CD28 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D004195:Disease Models, Animal; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D018664:Interleukin-12 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit; D009479:Neuropeptides; D051381:Rats; D012173:Retinitis / Q000276:immunology / Q000628:therapy*; D016559:Tacrolimus / Q000008:administration & dosage; D018417:Th1 Cells / Q000276:immunology; D014605:Uveitis / Q000276:immunology / Q000628:therapy*
D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D053645:Interleukin-2 Receptor alpha Subunit; D009479:Neuropeptides; D018664:Interleukin-12; D016559:Tacrolimus