Activation of OX40 prolongs and exacerbates autoimmune experimental uveitis.
نویسندگان
چکیده
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 IRBP(161-180) 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.
منابع مشابه
Roscovitine Suppresses CD4+ T Cells and T Cell-Mediated Experimental Uveitis
BACKGROUND T cells are essential for the development of uveitis and other autoimmune diseases. After initial activation, CD4+ lymphocytes express the co-stimulatory molecule OX40 that plays an important role in T cell proliferation. Cyclin dependent kinase 2 (CdK2) plays a pivotal role in the cell cycle transition from G1 to S phase. In addition, recent research has implicated CdK2 in T cell ac...
متن کاملSuppression of complement regulatory proteins (CRPs) exacerbates experimental autoimmune anterior uveitis (EAAU).
This study was undertaken to explore the role of complement regulatory proteins (CRPs) in experimental autoimmune anterior uveitis (EAAU). We observed that the levels of CRPs, Crry and CD59, in the eyes of Lewis rats increased during EAAU and remained elevated when the disease resolved. The in vivo role of these CRPs in EAAU was explored using neutralizing mAbs, antisense oligodeoxynucleotides ...
متن کاملLow Dose Rapamycin Exacerbates Autoimmune Experimental Uveitis
BACKGROUND Rapamycin, a potent immune modulator, is used to treat transplant rejection and some autoimmune diseases. Uveitis is a potentially severe inflammatory eye disease, and 2 clinical trials of treating uveitis with rapamycin are under way. Unexpectedly, recent research has demonstrated that low dose rapamycin enhances the memory T cell population and function. However, it is unclear how ...
متن کاملDeletion in the Retina Confers Protection Irf8 in T Cells Exacerbates Uveitis, Whereas Factor in Autoimmune Uveitis: Loss of IRF8 Dual Function of the IRF8 Transcription
متن کامل
ساخت گیرنده کایمریک لنفوسیت T دارای کمک محرک OX40 علیه سلول‌های سرطان سینه
Background and Objective: Chimeric antigen T cell receptors provide a good approach for adoptive immunotherapy of cancer. In this new kind of chimeric T cell receptor, nanobodies are replaced as variable fragment of T cell receptor. Nanobodies (VHH) are the smallest fragments of antibodies that have great homology to human VH and low immunogenic potential. VHH-hing-CD28-CD3و construct was made ...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Investigative ophthalmology & visual science
دوره 52 11 شماره
صفحات -
تاریخ انتشار 2011