Activation of OX40 prolongs and exacerbates autoimmune experimental uveitis

Xiumei Wu, James (Jim) Rosenbaum, Grazyna Adamus, Gary L. Zhang, Jie Duan, Andrew Weinberg, Zili Zhang

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Purpose. T cells are essential for the development of autoimmune uveitis. Although the costimulatory molecule OX40 promotes T-cell function and expansion, it is unclear whether OX40 is implicated in ocular inflammation. The purpose of this study was to examine the role of OX40 in uveitis. Methods. Experimental autoimmune uveitis (EAU) was induced in B10.RIII mice by subcutaneous injection of interphotoreceptor retinoid-binding protein peptide 161-180 (IRBP 161-180). Some mice received an intravenous administration of OX40-activating antibody on days 0 and 4 after IRBP161-180 sensitization or on days 10 and 14 of uveitis onset. The severity of EAU was evaluated by histology at different time points. In addition, ocular inflammatory cytokine expression was determined by real time-PCR, and peripheral activated CD4 +CD44 +CD62L - T cells and IL-7Rα expression were analyzed by flow cytometry. The activated CD4 +CD44 + lymphocytes were rechallenged with IRBP 161-180 in vitro to assess their antigen recall response. Results. The authors demonstrated a marked OX40 expression by infiltrating lymphocytes in enucleated human eyes with end-stage inflammation. In addition, the administration of OX40-activating antibody prolonged and exacerbated the disease course of EAU. Moreover, activation of OX40 not only increased CD4 +CD44 +CD62L - lymphocyte number, it upregulated IL-7Rα expression in the activated T-cell population. Lastly, these cells exhibited a stronger interferon-γ response to IRBP 161-180 restimulation in vitro. Conclusions. The results reveal a pathogenic role of OX40 in uveitis. Furthermore, the upregulation of IL-7R in CD4 +CD44 + lymphocytes suggests that the activation of OX40 promotes the generation or expansion of uveitogenic memory T cells.

Original languageEnglish (US)
Pages (from-to)8520-8526
Number of pages7
JournalInvestigative Ophthalmology and Visual Science
Volume52
Issue number11
DOIs
StatePublished - Oct 2011

Fingerprint

Uveitis
T-Lymphocytes
Peptides
Lymphocytes
Inflammation
Antibodies
Lymphocyte Count
Subcutaneous Injections
Lymphocyte Activation
Intravenous Administration
Interferons
Real-Time Polymerase Chain Reaction
Histology
Flow Cytometry
Up-Regulation
Cytokines
Antigens
Population
interstitial retinol-binding protein

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience
  • Medicine(all)

Cite this

Activation of OX40 prolongs and exacerbates autoimmune experimental uveitis. / Wu, Xiumei; Rosenbaum, James (Jim); Adamus, Grazyna; Zhang, Gary L.; Duan, Jie; Weinberg, Andrew; Zhang, Zili.

In: Investigative Ophthalmology and Visual Science, Vol. 52, No. 11, 10.2011, p. 8520-8526.

Research output: Contribution to journalArticle

Wu, Xiumei ; Rosenbaum, James (Jim) ; Adamus, Grazyna ; Zhang, Gary L. ; Duan, Jie ; Weinberg, Andrew ; Zhang, Zili. / Activation of OX40 prolongs and exacerbates autoimmune experimental uveitis. In: Investigative Ophthalmology and Visual Science. 2011 ; Vol. 52, No. 11. pp. 8520-8526.
@article{f4ebf15afb234b498c1c60bdd2a667d6,
title = "Activation of OX40 prolongs and exacerbates autoimmune experimental uveitis",
abstract = "Purpose. T cells are essential for the development of autoimmune uveitis. Although the costimulatory molecule OX40 promotes T-cell function and expansion, it is unclear whether OX40 is implicated in ocular inflammation. The purpose of this study was to examine the role of OX40 in uveitis. Methods. Experimental autoimmune uveitis (EAU) was induced in B10.RIII mice by subcutaneous injection of interphotoreceptor retinoid-binding protein peptide 161-180 (IRBP 161-180). Some mice received an intravenous administration of OX40-activating antibody on days 0 and 4 after IRBP161-180 sensitization or on days 10 and 14 of uveitis onset. The severity of EAU was evaluated by histology at different time points. In addition, ocular inflammatory cytokine expression was determined by real time-PCR, and peripheral activated CD4 +CD44 +CD62L - T cells and IL-7Rα expression were analyzed by flow cytometry. The activated CD4 +CD44 + lymphocytes were rechallenged with IRBP 161-180 in vitro to assess their antigen recall response. Results. The authors demonstrated a marked OX40 expression by infiltrating lymphocytes in enucleated human eyes with end-stage inflammation. In addition, the administration of OX40-activating antibody prolonged and exacerbated the disease course of EAU. Moreover, activation of OX40 not only increased CD4 +CD44 +CD62L - lymphocyte number, it upregulated IL-7Rα expression in the activated T-cell population. Lastly, these cells exhibited a stronger interferon-γ response to IRBP 161-180 restimulation in vitro. Conclusions. The results reveal a pathogenic role of OX40 in uveitis. Furthermore, the upregulation of IL-7R in CD4 +CD44 + lymphocytes suggests that the activation of OX40 promotes the generation or expansion of uveitogenic memory T cells.",
author = "Xiumei Wu and Rosenbaum, {James (Jim)} and Grazyna Adamus and Zhang, {Gary L.} and Jie Duan and Andrew Weinberg and Zili Zhang",
year = "2011",
month = "10",
doi = "10.1167/iovs.11-7664",
language = "English (US)",
volume = "52",
pages = "8520--8526",
journal = "Investigative Ophthalmology and Visual Science",
issn = "0146-0404",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "11",

}

TY - JOUR

T1 - Activation of OX40 prolongs and exacerbates autoimmune experimental uveitis

AU - Wu, Xiumei

AU - Rosenbaum, James (Jim)

AU - Adamus, Grazyna

AU - Zhang, Gary L.

AU - Duan, Jie

AU - Weinberg, Andrew

AU - Zhang, Zili

PY - 2011/10

Y1 - 2011/10

N2 - Purpose. T cells are essential for the development of autoimmune uveitis. Although the costimulatory molecule OX40 promotes T-cell function and expansion, it is unclear whether OX40 is implicated in ocular inflammation. The purpose of this study was to examine the role of OX40 in uveitis. Methods. Experimental autoimmune uveitis (EAU) was induced in B10.RIII mice by subcutaneous injection of interphotoreceptor retinoid-binding protein peptide 161-180 (IRBP 161-180). Some mice received an intravenous administration of OX40-activating antibody on days 0 and 4 after IRBP161-180 sensitization or on days 10 and 14 of uveitis onset. The severity of EAU was evaluated by histology at different time points. In addition, ocular inflammatory cytokine expression was determined by real time-PCR, and peripheral activated CD4 +CD44 +CD62L - T cells and IL-7Rα expression were analyzed by flow cytometry. The activated CD4 +CD44 + lymphocytes were rechallenged with IRBP 161-180 in vitro to assess their antigen recall response. Results. The authors demonstrated a marked OX40 expression by infiltrating lymphocytes in enucleated human eyes with end-stage inflammation. In addition, the administration of OX40-activating antibody prolonged and exacerbated the disease course of EAU. Moreover, activation of OX40 not only increased CD4 +CD44 +CD62L - lymphocyte number, it upregulated IL-7Rα expression in the activated T-cell population. Lastly, these cells exhibited a stronger interferon-γ response to IRBP 161-180 restimulation in vitro. Conclusions. The results reveal a pathogenic role of OX40 in uveitis. Furthermore, the upregulation of IL-7R in CD4 +CD44 + lymphocytes suggests that the activation of OX40 promotes the generation or expansion of uveitogenic memory T cells.

AB - Purpose. T cells are essential for the development of autoimmune uveitis. Although the costimulatory molecule OX40 promotes T-cell function and expansion, it is unclear whether OX40 is implicated in ocular inflammation. The purpose of this study was to examine the role of OX40 in uveitis. Methods. Experimental autoimmune uveitis (EAU) was induced in B10.RIII mice by subcutaneous injection of interphotoreceptor retinoid-binding protein peptide 161-180 (IRBP 161-180). Some mice received an intravenous administration of OX40-activating antibody on days 0 and 4 after IRBP161-180 sensitization or on days 10 and 14 of uveitis onset. The severity of EAU was evaluated by histology at different time points. In addition, ocular inflammatory cytokine expression was determined by real time-PCR, and peripheral activated CD4 +CD44 +CD62L - T cells and IL-7Rα expression were analyzed by flow cytometry. The activated CD4 +CD44 + lymphocytes were rechallenged with IRBP 161-180 in vitro to assess their antigen recall response. Results. The authors demonstrated a marked OX40 expression by infiltrating lymphocytes in enucleated human eyes with end-stage inflammation. In addition, the administration of OX40-activating antibody prolonged and exacerbated the disease course of EAU. Moreover, activation of OX40 not only increased CD4 +CD44 +CD62L - lymphocyte number, it upregulated IL-7Rα expression in the activated T-cell population. Lastly, these cells exhibited a stronger interferon-γ response to IRBP 161-180 restimulation in vitro. Conclusions. The results reveal a pathogenic role of OX40 in uveitis. Furthermore, the upregulation of IL-7R in CD4 +CD44 + lymphocytes suggests that the activation of OX40 promotes the generation or expansion of uveitogenic memory T cells.

UR - http://www.scopus.com/inward/record.url?scp=84862833568&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84862833568&partnerID=8YFLogxK

U2 - 10.1167/iovs.11-7664

DO - 10.1167/iovs.11-7664

M3 - Article

C2 - 21948545

AN - SCOPUS:84862833568

VL - 52

SP - 8520

EP - 8526

JO - Investigative Ophthalmology and Visual Science

JF - Investigative Ophthalmology and Visual Science

SN - 0146-0404

IS - 11

ER -