Interphotoreceptor Retinoid Binding Protein Peptide-induced Uveitis in B10.RIII Mice: Characterization of Disease Parameters and Immunomodulation

Hankey, Deborah J.R.; Lightman, Susan; Baker, David

doi:10.1006/exer.2000.0957

Cited by 26 publications

(33 citation statements)

References 25 publications

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“…sTNFr-Ig suppresses EAU in rats (8), mice (30), and in humans (10). In these experiments, sTNFr-Ig was added to TNFRp55 Ϫ/Ϫ and WT BM-M 1 h before cytokine stimulation.…”

Section: Ifn-␥-induced Nitrite Production Requires a Signal Through Tmentioning

confidence: 99%

A Selective Role for the TNF p55 Receptor in Autocrine Signaling following IFN-γ Stimulation in Experimental Autoimmune Uveoretinitis

Calder

Nicholson

Dick

2005

The Journal of Immunology

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IFN-γ stimulates macrophage activation and NO production, which leads to destruction of the retina in experimental autoimmune uveoretinitis. In this study, we investigate the mechanism of disease resistance in TNF p55 receptor-deficient animals. We show that although T cell priming is relatively unaffected, macrophages lacking the TNF p55 receptor fail to produce NO following IFN-γ stimulation because of a requirement for autocrine TNF-α signaling through the TNF p55 receptor. In contrast to the impaired activation of NO synthesis, MHC class II up-regulation was indistinguishable in wild-type and TNFRp55−/− mice stimulated with IFN-γ. These defects could be overcome by stimulating macrophages with LPS. Together, these results show that selected aspects of IFN-γ activation are controlled by autocrine secretion of TNF-α, but that this control is lost in the presence of signals generated by pathogen-associated molecular patterns recognizing receptors.

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“…sTNFr-Ig suppresses EAU in rats (8), mice (30), and in humans (10). In these experiments, sTNFr-Ig was added to TNFRp55 Ϫ/Ϫ and WT BM-M 1 h before cytokine stimulation.…”

Section: Ifn-␥-induced Nitrite Production Requires a Signal Through Tmentioning

confidence: 99%

A Selective Role for the TNF p55 Receptor in Autocrine Signaling following IFN-γ Stimulation in Experimental Autoimmune Uveoretinitis

Calder

Nicholson

Dick

2005

The Journal of Immunology

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“…Male B10.RIII (7INS) mice (5-7 wk old; Harlan Olac) were injected s.c. with 25 g of human interphotoreceptor retinoid binding protein (IRBP) 161-180 peptide emulsified in IFA supplemented with 60 g/ml Mycobacterium (29). Eyes were scored daily for clinical signs of EAU (Table I).…”

Section: Induction and Assessment Of Eaumentioning

confidence: 99%

“…Alternatively, following a loading dose of 100 mg/kg lovastatin, a further group of animals was given twice daily injections of 20 mg/kg lovastatin. Vehicle or lovastatin was first administered on day 5 postimmunization, and then daily until day 12 when maximal cellular infiltration and structural damage has been reported to occur (29). In two separate groups of animals, parenteral lovastatin treatment (20 mg/kg) was supplemented with a daily injection of squalene (2 mg/kg) or a twice-daily injection of mevalanolactone (2 mg/kg).…”

Section: Treatment Of Eaumentioning

confidence: 99%

Suppression of Autoimmune Retinal Disease by Lovastatin Does Not Require Th2 Cytokine Induction

Gegg

Harry

Hankey

et al. 2005

The Journal of Immunology

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Intraocular inflammatory diseases are a common cause of severe visual impairment and blindness. In an acute mouse model of autoimmune retinal disease, we demonstrate that treatment with the HMG-CoA reductase inhibitor, lovastatin, suppresses clinical ocular pathology, retinal vascular leakage and leukocytic infiltration into the retina. Efficacy was reversed by co-administration of mevalonolactone, the downstream product of HMG-CoA reductase, but not by squalene which is distal to isoprenoid pyrophosphate metabolites within the cholesterol biosynthetic pathway. Lovastatin treatment over 7 days, which resulted in plasma lovastatin hydroxyacid concentrations of 0.098 ± 0.03μM, did not result in splenocyte production of Th2 cytokines but did cause a small reduction in antigen-induced T cell proliferation and a decrease in the production of IFN-γ and IL-10. Thus, contrary to expected outcome we demonstrate that it is possible to dissociate the therapeutic effect of statins from their activity on the Th1/Th2 balance. Statins inhibit isoprenoid pyrophosphate synthesis, precursors required for the prenylation and posttranslational activation of Rho GTPase, a key molecule in the endothelial ICAM-1 mediated pathway that facilitates lymphocyte migration. Consistent with inhibition of leukocyte infiltration in vivo, lovastatin treatment of retinal endothelial cell monolayers in vitro leads to inhibition of lymphocyte transmigration which may, in part, account for drug efficacy. Unlike lovastatin, atorvastatin treatment failed to attenuate retinal inflammatory disease despite showing significant clinical benefit in experimental autoimmune encephalomyelitis. These data highlight the potential differential activity of statins in different inflammatory conditions and their possible therapeutic use for the treatment of human posterior uveitis.

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“…To determine whether autoreactive CD8 T cells were induced by the uveitogenic peptide IRBP161-180 (Silver et al, 1995,Hankey et al, 2001; (Shao et al, 2005b) in the EAUsusceptible B10RIII mouse, we immunized B10RIII mice with IRBP161-180, then, at 13 days post-immunization (p.i. ), prepared T cells from the pooled draining lymph nodes and spleens using nylon wool.…”

Section: Detection Of Cd8 ± Irbp161-180-specific T Cells In the Immunmentioning

confidence: 99%

“…However, we have recently demonstrated that, in both the Lewis rat (Shao et al, 2004) and B6 mouse (Shao et al, 2005a); (Peng et al, 2007), many CD8 autoreactive T cells are activated and actively participate in disease pathogenesis. To determine whether this observation applies to other EAU models, we tested the B10RIII mouse, which is the mouse strain most susceptible to EAU (Hankey et al, 2001,Karabekian et al, 2005. Since our previous studies demonstrated that CD4 and CD8 IRBP-specific T cells in the B6 mouse both responded to the same antigenic epitope (Shao et al, 2005a), we were also interested in testing whether this was also true in the B10RIII mouse.…”

Section: Introductionmentioning

confidence: 99%

Sequence 168 to 177 of interphotoreceptor retinoid-binding protein (IRBP) is an antigenic epitope for autoreactive CD8 T cells in the B10RIII mouse

Song

et al. 2008

Journal of Neuroimmunology

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We previously demonstrated that a significant proportion of interphotoreceptor retinoid-binding protein (IRBP)-specific uveitogenic T cells in the C57BL/6 mouse and Lewis rat express CD8. The aims of this study were to determine whether some of the IRBP-specific T cells in the B10RIII mouse also express CD8 and whether CD8 and CD4 IRBP-specific T cells in the B10RIII mouse recognize a different or the same antigenic epitope. Our results show that autoreactive CD8 T cells were abundant in B10RIII mice immunized with the uveitogenic peptide IRBP161-180. Using multimers of recombinant H-2D r molecules, we also showed that the binding of the H-2D r fusion protein to IRBP161-180-expanded CD8 T cells was dependent on the peptide complexed with the recombinant molecules. The use of a panel of truncated peptides showed that the truncated 10-mer peptide, IRBP168-177, retained the ability to bind to, and stimulate, IRBP161-180-specific CD8 T cells after complexing with a dimeric MHC class I (H-2D r ) molecule. Finally, adoptive transfer of IRBP161-180-specific T cells stimulated with IRBP168-177 consistently induced mild, but significant, EAU in naïve B10RIII mice.

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Interphotoreceptor Retinoid Binding Protein Peptide-induced Uveitis in B10.RIII Mice: Characterization of Disease Parameters and Immunomodulation

Cited by 26 publications

References 25 publications

A Selective Role for the TNF p55 Receptor in Autocrine Signaling following IFN-γ Stimulation in Experimental Autoimmune Uveoretinitis

A Selective Role for the TNF p55 Receptor in Autocrine Signaling following IFN-γ Stimulation in Experimental Autoimmune Uveoretinitis

Suppression of Autoimmune Retinal Disease by Lovastatin Does Not Require Th2 Cytokine Induction

Sequence 168 to 177 of interphotoreceptor retinoid-binding protein (IRBP) is an antigenic epitope for autoreactive CD8 T cells in the B10RIII mouse

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