Inhibition of experimental autoimmune uveoretinitis by systemic and subconjunctival adenovirus-mediated transfer of the viral IL-10 gene.
Pathological ocular manifestations result from a dysregulation in the balance between proinflammatory type 1 cytokines and regulatory type 2 cytokines. Interleukin-10 (IL-10) is an anti-inflammatory cytokine with potent immunosuppressive effects. We have examined the efficiency of viral IL-10 adenovirus (Ad-vIL-10)-mediated gene transfer on experimental autoimmune uveoretinitis (EAU) induced in mice and rats by purified retinal autoantigens, respectively, interphotoreceptor binding protein (IRBP) and S-antigen (S-Ag). B10-A mice that received a single unilateral injection of Ad-vIL-10 in the retro-orbital sinus venosus performed 1 day before immunization with IRBP in the footpads showed high levels of circulating vIL-10 in their sera and a significant reduction in pathological ocular manifestations. Lower levels of IFN-gamma and IL-2 were found in cellular supernatants from IRBP-stimulated splenic cells in these treated mice. The local effect on ocular disease of vIL-10 was neutralized completely by injection of a monoclonal anti-vIL-10 antibody, demonstrating the specificity of the treatment. To determine whether the transfer of the vIL-10 gene within the periocular tissues of the eye could prevent acute EAU, a subconjunctival injection of Ad-vIL-10 was performed in Lewis rats simultaneously with S-antigen in the footpads. This injection determined in situ vIL-10 expression with very low circulating vIL-10 and led to a significant reduction of EAU without affecting the systemic immune response. The present results suggest that Ad-mediated gene transfer resulting in systemic and local expression of vIL-10 provide a promising approach for the treatment of uveitis.
De Kozak
Y
Y
INSERM U450, Development, Ageing and Pathology of the Retina, Paris, France.
Thillaye-Goldenberg
B
B
Naud
M-C
MC
Da Costa
A Vianna
AV
Auriault
C
C
Verwaerde
C
C
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D002478:Cells, Cultured; D003228:Conjunctiva; D005123:Eye / Q000737:chemistry / Q000378:metabolism; D005136:Eye Proteins; D005260:Female; D005814:Genes, Viral; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D049452:Green Fluorescent Proteins; D007074:Immunoglobulin G / Q000097:blood; D007267:Injections; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000097:blood / Q000235:genetics*; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D008297:Male; D051379:Mice; D051381:Rats; D011917:Rats, Inbred Lew; D012173:Retinitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D012177:Retinol-Binding Proteins / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014605:Uveitis / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics; D000099214:Retinol-Binding Proteins, Interstitial
D005136:Eye Proteins; D049452:Green Fluorescent Proteins; D007074:Immunoglobulin G; D016753:Interleukin-10; D008164:Luminescent Proteins; D012177:Retinol-Binding Proteins; D001616:beta-Galactosidase; D000099214:Retinol-Binding Proteins, Interstitial