Neutralizing TNF-alpha activity modulates T-cell phenotype and function in experimental autoimmune uveoretinitis.
Inhibiting TNF-alpha activity prevents tissue destruction without inhibiting retinal T cell infiltration in experimental autoimmune uveoretinitis (EAU) in Lewis rats. To further determine the role of TNF-alpha in autoimmune uveitis we characterized T cells isolated from retinae after treatment with a TNF-alpha antagonist. TNF-alpha activity was neutralized in vivo with a p55 TNF-alpha receptor-Ig fusion protein (sTNFr-Ig), administered 8 and 10 days after induction of EAU with heterologous retinal antigens. Retinal T-cell phenotype expression was examined by flow cytometry with respect to OX22 status (CD45RBlow or CD45RBhigh), activation (OX40 and CD25 expression) and rate of T-cell apoptosis (Annexin V+PI- expression). Lymphocyte reactivity was assessed by proliferation responses and cytokine production to retinal antigens. Despite greater than 40% of CD4+ T cells being activated at the height of disease, the proportion of OX22low expression was reduced and T cells exhibited reduced IFN-gamma and elevated IL-4 production. Retinal T cells maintained antigen-specific proliferation and demonstrated a low apoptotic rate. Although in both animal groups, comparable numbers of T cells were isolated, neutralizing TNF activity suppressed Th1 effector mechanisms protecting against target organ damage.
Department of Ophthalmology, University of Aberdeen, UK. a.dick@abdn.ac.uk
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Dick
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L
Duncan
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G
Hale
H
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Waldmann
J
J
Isaacs
D000818:Animals; D000867:Anterior Chamber / Q000473:pathology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology*; D015415:Biomarkers; D002455:Cell Division; D002465:Cell Movement; D005260:Female; D018796:Immunoconjugates / Q000627:therapeutic use; D007074:Immunoglobulin G; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D009500:Neutralization Tests; D010641:Phenotype; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D012173:Retinitis / Q000188:drug therapy / Q000209:etiology / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D014605:Uveitis / Q000188:drug therapy / Q000209:etiology / Q000276:immunology*
D015415:Biomarkers; D018796:Immunoconjugates; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007371:Interferon-gamma