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Hideo Yagita - One of the best experts on this subject based on the ideXlab platform.
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expression and function of the ox40 OX40L costimulatory pair during herpes stromal keratitis
Journal of Leukocyte Biology, 2007Co-Authors: Andrew J. Lepisto, Andrew D. Weinberg, Hideo Yagita, Robert L. HendricksAbstract:Herpes stromal keratitis (HSK) is an immunopathological disease regulated by Th1 CD4 T cells, which require APC and costimulation within the infected cornea to mediate disease. Recent studies suggest the OX40:OX40 ligand (OX40L) interaction enhances effector cell cytokine secretion at inflammatory sites. OX40 + cells were detected in HSV-1-infected mouse corneas as early as 3 days postinfection (dpi), prior to the onset of HSK, and their frequency increased through 15 dpi, when all mice exhibited severe HSK. OX40L + cells were first detected at 7 dpi, coincident with the initiation of HSK. It is interesting that the OX40L + cells did not coexpress MHC Class II or the dendritic cell (DC) marker CD11 e . Our findings demonstrate rapid infiltration of activated (OX40 + ) CD4 + T cells into HSV-1-infected corneas and expression of OX40L on MHC Class II-negative cells but surprisingly, not on MHC Class II + CD11c + DC, which are present in the infected corneas and required for HSK. Moreover, neither local nor systemic treatment of mice with a blocking antibody to OX40L or with a blocking fusion protein altered the course of HSK significantly, possibly as a result of a lack of OX40L expression on functional APC.
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interruption of the tnfrsf4 tnfsf4 ox40 OX40L pathway attenuates atherogenesis in low density lipoprotein receptor deficient mice
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: Eva J.a. Van Wanrooij, Gijs H.m. Van Puijvelde, Paula De Vos, Hideo Yagita, Theo J.c. Van Berkel, Johan KuiperAbstract:Objective— Atherosclerosis is a chronic (auto-)inflammatory disease and T cell activation is an important factor in this process. Tnfrsf4 (OX40) and Tnfsf4 (OX40 ligand) are members of the tumor necrosis factor (TNF) and TNF receptor family and OX40/OX40L mediated signaling is important in co-activation of T cells and facilitates B-T cell interaction. In this study we assessed the role of the OX40/OX40L pathway in atherosclerosis and the effect of interruption of the OX40/OX40L pathway on lesion development. Methods and Results— We treated low-density lipoprotein receptor-deficient (LDLr −/− ) mice with an anti-OX40L antibody which lead to a 53% decrease in atherosclerotic lesion formation. Treatment resulted in inhibition of Th2 mediated isotype switching by decreasing interleukin (IL)-4 secretion and subsequent low IgG1 serum levels against oxLDL, whereas protective anti-oxLDL specific IgM titers were increased in treated mice compared with control. Conclusions— We conclude that blocking the OX-40/OX40L interaction reduced atherogenesis by inhibition of IL-4 mediated Th2 induced isotype switching and subsequent increased levels of anti-oxLDL IgM.
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Expression and function of the OX40/OX40L costimulatory pair during herpes stromal keratitis.
Journal of leukocyte biology, 2006Co-Authors: Andrew J. Lepisto, Andrew D. Weinberg, Hideo Yagita, Robert L. HendricksAbstract:Herpes stromal keratitis (HSK) is an immunopathological disease regulated by Th1 CD4 T cells, which require APC and costimulation within the infected cornea to mediate disease. Recent studies suggest the OX40:OX40 ligand (OX40L) interaction enhances effector cell cytokine secretion at inflammatory sites. OX40 + cells were detected in HSV-1-infected mouse corneas as early as 3 days postinfection (dpi), prior to the onset of HSK, and their frequency increased through 15 dpi, when all mice exhibited severe HSK. OX40L + cells were first detected at 7 dpi, coincident with the initiation of HSK. It is interesting that the OX40L + cells did not coexpress MHC Class II or the dendritic cell (DC) marker CD11 e . Our findings demonstrate rapid infiltration of activated (OX40 + ) CD4 + T cells into HSV-1-infected corneas and expression of OX40L on MHC Class II-negative cells but surprisingly, not on MHC Class II + CD11c + DC, which are present in the infected corneas and required for HSK. Moreover, neither local nor systemic treatment of mice with a blocking antibody to OX40L or with a blocking fusion protein altered the course of HSK significantly, possibly as a result of a lack of OX40L expression on functional APC.
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Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) Pathway Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice
Arteriosclerosis thrombosis and vascular biology, 2006Co-Authors: Eva J.a. Van Wanrooij, Gijs H.m. Van Puijvelde, Paula De Vos, Hideo Yagita, Theo J.c. Van Berkel, Johan KuiperAbstract:Objective— Atherosclerosis is a chronic (auto-)inflammatory disease and T cell activation is an important factor in this process. Tnfrsf4 (OX40) and Tnfsf4 (OX40 ligand) are members of the tumor necrosis factor (TNF) and TNF receptor family and OX40/OX40L mediated signaling is important in co-activation of T cells and facilitates B-T cell interaction. In this study we assessed the role of the OX40/OX40L pathway in atherosclerosis and the effect of interruption of the OX40/OX40L pathway on lesion development. Methods and Results— We treated low-density lipoprotein receptor-deficient (LDLr −/− ) mice with an anti-OX40L antibody which lead to a 53% decrease in atherosclerotic lesion formation. Treatment resulted in inhibition of Th2 mediated isotype switching by decreasing interleukin (IL)-4 secretion and subsequent low IgG1 serum levels against oxLDL, whereas protective anti-oxLDL specific IgM titers were increased in treated mice compared with control. Conclusions— We conclude that blocking the OX-40/OX40L interaction reduced atherogenesis by inhibition of IL-4 mediated Th2 induced isotype switching and subsequent increased levels of anti-oxLDL IgM.
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therapeutic effect of anti OX40L and anti tnf α mabs in a murine model of chronic colitis
American Journal of Physiology-gastrointestinal and Liver Physiology, 2003Co-Authors: Teruji Totsuka, Hideo Yagita, Takanori Kanai, Koji Uraushihara, Ryouichi Iiyama, Motomi Yamazaki, Hisaya Akiba, Ko Okumura, Mamoru WatanabeAbstract:Interaction of OX40 (CD134) on T cells with its ligand (OX40L) on antigen-presenting cells has been implicated in pathogenic T cell activation. This study was performed to explore the involvement o...
Johan Kuiper - One of the best experts on this subject based on the ideXlab platform.
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interruption of the tnfrsf4 tnfsf4 ox40 OX40L pathway attenuates atherogenesis in low density lipoprotein receptor deficient mice
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: Eva J.a. Van Wanrooij, Gijs H.m. Van Puijvelde, Paula De Vos, Hideo Yagita, Theo J.c. Van Berkel, Johan KuiperAbstract:Objective— Atherosclerosis is a chronic (auto-)inflammatory disease and T cell activation is an important factor in this process. Tnfrsf4 (OX40) and Tnfsf4 (OX40 ligand) are members of the tumor necrosis factor (TNF) and TNF receptor family and OX40/OX40L mediated signaling is important in co-activation of T cells and facilitates B-T cell interaction. In this study we assessed the role of the OX40/OX40L pathway in atherosclerosis and the effect of interruption of the OX40/OX40L pathway on lesion development. Methods and Results— We treated low-density lipoprotein receptor-deficient (LDLr −/− ) mice with an anti-OX40L antibody which lead to a 53% decrease in atherosclerotic lesion formation. Treatment resulted in inhibition of Th2 mediated isotype switching by decreasing interleukin (IL)-4 secretion and subsequent low IgG1 serum levels against oxLDL, whereas protective anti-oxLDL specific IgM titers were increased in treated mice compared with control. Conclusions— We conclude that blocking the OX-40/OX40L interaction reduced atherogenesis by inhibition of IL-4 mediated Th2 induced isotype switching and subsequent increased levels of anti-oxLDL IgM.
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Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) Pathway Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice
Arteriosclerosis thrombosis and vascular biology, 2006Co-Authors: Eva J.a. Van Wanrooij, Gijs H.m. Van Puijvelde, Paula De Vos, Hideo Yagita, Theo J.c. Van Berkel, Johan KuiperAbstract:Objective— Atherosclerosis is a chronic (auto-)inflammatory disease and T cell activation is an important factor in this process. Tnfrsf4 (OX40) and Tnfsf4 (OX40 ligand) are members of the tumor necrosis factor (TNF) and TNF receptor family and OX40/OX40L mediated signaling is important in co-activation of T cells and facilitates B-T cell interaction. In this study we assessed the role of the OX40/OX40L pathway in atherosclerosis and the effect of interruption of the OX40/OX40L pathway on lesion development. Methods and Results— We treated low-density lipoprotein receptor-deficient (LDLr −/− ) mice with an anti-OX40L antibody which lead to a 53% decrease in atherosclerotic lesion formation. Treatment resulted in inhibition of Th2 mediated isotype switching by decreasing interleukin (IL)-4 secretion and subsequent low IgG1 serum levels against oxLDL, whereas protective anti-oxLDL specific IgM titers were increased in treated mice compared with control. Conclusions— We conclude that blocking the OX-40/OX40L interaction reduced atherogenesis by inhibition of IL-4 mediated Th2 induced isotype switching and subsequent increased levels of anti-oxLDL IgM.
Xueguang Zhang - One of the best experts on this subject based on the ideXlab platform.
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Enhancement of the Soluble Form of OX40 and OX40L Costimulatory Molecules but Reduction of the Membrane Form in Type 1 Diabetes (T1D)
Journal of immunology research, 2019Co-Authors: Sisi Ding, Lili Sun, Xin Chang, Ziyi Huang, Bin Zhou, Chen Fang, Cuiping Liu, Xueguang ZhangAbstract:This study analyzed the expression of membrane OX40 and OX40L (mOX40 and mOX40L) and levels of soluble OX40 and OX40L (sOX40 and sOX40L) in T1D patients to determine their clinical significance. Peripheral blood (PB) was collected from patients with T1D and healthy control participants. Expression of mOX40 and mOX40L on immune cells was detected by flow cytometry. Levels of sOX40 and sOX40L in sera were measured by ELISA. We demonstrated for the first time enhanced sOX40 and sOX40L expression and reduced mOX40 and mOX40L levels in T1D patients which correlated with the clinical characteristics and inflammatory factors. These results suggest that OX40/OX40L signal may be promising biomarkers and associated with the pathogenesis of T1D.
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Enhancement of CD4+ T cell response and survival via coexpressed OX40/OX40L in Graves' disease
Molecular and cellular endocrinology, 2016Co-Authors: Qin Wang, Cuiping Liu, Yongjing Chen, Fang Xie, Bi-min Shi, Xue-kun Zhang, Xueguang ZhangAbstract:OX40/OX40L pathway plays a very important role in the antigen priming T cells and effector T cells. In the present study, we aimed to examine the involvement of OX40/OX40L pathway in the activation of autoreactive T cells in patients with Grave's disease (GD). We found that OX40 and OX40L were constitutively coexpressed on peripheral CD4(+) T cells from GD patients using flow cytometry analysis. The levels of OX40 and OX40L coexpression on CD4(+) T cells were shown to be correlated with TRAbs. Cell proliferation assay showed that blocking OX40/OX40L signal inhibited T cell proliferation and survival, which suggested that OX40/OX40L could enhance CD4(+) T cell proliferation and maintain their long-term survival in GD by self-enhancing loop of T cell activation independent of APCs. Confocal microscopy and coimmunoprecipitation analysis further revealed that OX40 and OX40L formed a functional complex, which may facilitate signal transduction from OX40L to OX40 and contribute to the pathogenesis of GD.
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Expressions and clinical significance of OX40 and OX40L in peripheral blood of patients with primary Sjogren's syndrome
Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology, 2013Co-Authors: Ran-ran Zhu, Cuiping Liu, Juean Jiang, Ting Wang, Xueguang ZhangAbstract:Objective To investigate the expressions of costimulatory molecules OX40 and OX40L on peripheral blood mononuclear cells( PBMC) and their relationship with clinical characteristics of patients with primary Sjgren's syndrome( pSS). Methods Peripheral blood samples were collected from 51 pSS patients and 36 healthy subjects( HC). The expressions of OX40 and OX40L on PBMC were detected by immunofluorescence and flow cytometry. In addition,we observed the changes in the levels of OX40 and OX40L after treatment in 11 patients with primary pSS and searched for the relationship between their expression levels and patients' clinical manifestations. Results The expression of OX40 on CD4+T cells in pSS patients was significantly higher than that in the HC group( 8. 65% ± 3. 51% vs 5. 68% ± 1. 68%,P 0. 01). However,there was no significant difference in OX40 expression on CD8+T cells between patient group and HC group. In comparison with HC group,the expression of OX40L on CD14+monocytes( 6. 76% ± 3. 60% vs 3. 15% ± 1. 89%,P 0. 01) and CD19+B cells( 4. 69% ± 2. 40% vs 2. 76% ± 1. 33%,P 0. 01) significantly increased in pSS patients. Moreover,OX40 expression on CD4+T cells and OX40L expression on monocytes and B cells rose significantly in active pSS patients compared with those in inactive patients. The expression levels of OX40 and OX40L were higher in pSS patients with multiple system damage than in patients with simple exocrine gland injury. In addition,immunosuppressive therapy significantly reduced the expressions of OX40 and OX40L. Conclusion The expressions of OX40 and OX40L on peripheral lymphocytes was upregulated in pSS patients. The high levels of OX40 and OX40L expression were significantly correlated with clinical outcome and therapeutic response,suggesting that OX40 /OX40L pathway may play a critical role in pSS pathogenesis.
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costimulatory molecule ox40 OX40L expression in ductal carcinoma in situ and invasive ductal carcinoma of breast an immunohistochemistry based pilot study
Pathology Research and Practice, 2010Co-Authors: Fang Xie, Qin Wang, Yongjing Chen, Hui Mao, Wang Zeng, Xueguang ZhangAbstract:Abstract OX40, a membrane-bound member of the tumor-necrosis-factor-receptor (TNFR) superfamily, plays an important role in proliferation, survival and infiltration of activated T cells via binding to OX40L. Recent studies indicate that OX40/OX40L system mediates the adhesion and infiltration of adult T cell leukemia (ATL). Previously, we detected OX40 expression in breast carcinoma cell lines and tissues. The correlation of expression of OX40 and OX40L and clinical features in breast carcinogenesis, however, has not been well characterized. The expression of OX40 and OX40L in 107 invasive ductal carcinomas (IDCa), 9 ductal carcinomas in situ (DCIS), and 31 fibroadenomas from breast tissues and its relationship with the clinical features were determined using immunohistochemistry (peroxidase-conjugated polymer method, ChemMate™ Envision™ Detection kit). The positive immunostaining rates for OX40 in IDCa, DCIS and fibroadenomas from breast tissues were 85.0%, 66.7% and 38.7% respectively, showing a significant difference in OX40 expression among IDCa, DCIS and fibroadenoma of breast ( z = 5.206, P = 0.001). Increased staining intensity of OX40 was associated with TNM stages ( z = 2.112, P = 0.017). Meanwhile, a relation of OX40 expression with lymph node metastatic status in IDCa was found ( P = 0.041). The expression of OX40L did not show any obvious difference among IDCa, DCIS and fibroadenomas from breast tissues. OX40L expression was also not related to histopathological parameters in IDCa except for progesterone receptor (PR) being positive ( P = 0.005). However, a high coincidental positive rate for OX40 and OX40L was observed in biopsy samples with IDCa ( P = 0.017, Kappa = 0.231). The present results suggest that high OX40 expression may be associated with malignant transformation, progression, invasion and metastasis in breast cancer biology.
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Preparation and characterization of two novel functional monoclonal antibodies against human OX40L
Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology, 2007Co-Authors: Qin Wang, Yongjing Chen, Fang Xie, Gaoqin Liu, Yi-xiang Mao, Xueguang ZhangAbstract:AIM To prepare novel anti-OX40L functional monoclonal antibodies and characterize their distinct biological functions. METHODS Routine immunization of BALB/c mice by a tansfected cell line L929/OX40L expressing high level of OX40L as antigens. Then fuse the immunized spleen with Sp2/0, a kind of myloma, and screen the positive clones by FCS with L929/OX40L as a positive control.After acquisition of the hybidomas secreting anti-OX40L mAb, investigation of their biological activities by Western blot, rapid isotyping analysis, karyotype analysis, competitive inhibition test, indirect immunofluorescence and MTT incorporation assay were followed. RESULTS Obtain two stable hybridomas, 4D6 and 5C2, which could continuously secret specific anti-OX40L monoclonal antibodies. The following biological activity studies showed that these monoclonal antibodies could both recognize the natural OX40L expressed on the mature DC, especially the OX40L on the several leukemia cell lines, such as Jurkat, SHI-1, U937 etc. Furthermore, they could also suppress the proliferation of SHI-1 in vitro. CONCLUSION Two hybridomas secreting anti-OX40L monoclonal antibodies continuously and steadily have been established. These monoclonal antibodies could specifically recognize human OX40L and effect the proliferation of leukemia cell line SHI-1 through OX40/OX40L costimulatory signals.
Andrew D. Weinberg - One of the best experts on this subject based on the ideXlab platform.
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OX40 (CD134) and OX40L.
Advances in experimental medicine and biology, 2009Co-Authors: Michael J. Gough, Andrew D. WeinbergAbstract:The interaction between OX40 and OX40L plays an important role in antigen-specific T-cell expansion and survival. While OX40 is expressed predominantly on T-lymphocytes early after antigen activation, OX40L is expressed on activated antigen presenting cells and endothelial cells within acute inflammatory environments. We discuss here how ligation of OX40 by OX40L leads to enhanced T-cell survival, along with local inflammatory responses that appear critical for both effective T-cell mediated responses and chronic immune pathologies. We describe how interventions that block or mimic the OX40-OX40L interaction can be applied to treat autoimmune diseases or enhance anti-tumor immune responses. The clinically relevant properties of these agents emphasize the importance of this particular TNFSF-TNFSF in health and disease.
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development and characterization of recombinant human fc OX40L fusion protein linked via a coiled coil trimerization domain
Molecular Immunology, 2007Co-Authors: Nicholas P Morris, Carmen Peters, Ryan Montler, Brendan D Curti, Walter J Urba, Andrew D. WeinbergAbstract:OX40 (CD134) is a potent costimulatory molecule found on the surface of activated CD4(+) and CD8(+) T cells. Immunotherapy with OX40 agonists administered in vivo has demonstrated efficacy in several murine tumor models. A phase I clinical trial is currently underway in patients with advanced cancer using a mouse anti-CD134 monoclonal antibody. Therapy with this antibody will likely be limited to one cycle because patients develop neutralizing human anti-mouse antibody (HAMA). Therefore, we developed a humanized OX40 agonist that links the extracellular domain of human OX40L to the Fc domain of human IgG(1) via a trimerizing isoleucine zipper domain (ILZ). Physical characterization by velocity sedimentation revealed that this novel construct, hFcILZOX40L, was assembled into hexamers in which the Fc domains formed three disulfide-bonded dimers and the ILZ-OX40L domains formed two trimers. Trimerization of the ILZ domain was necessary to achieve appropriate assembly. In vitro biologic activity of the hFcILZOX40L hexamer was equivalent to the activity of agonist antibodies in plate-bound assays and was superior when the agonists were tested as soluble agents. Our ultimate goal is to use this recombinant molecule in a future clinical trial, and we feel that the OX40L hexamer will have equivalent or superior agonist activity in vivo when compared to an anti-OX40 antibody.
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expression and function of the ox40 OX40L costimulatory pair during herpes stromal keratitis
Journal of Leukocyte Biology, 2007Co-Authors: Andrew J. Lepisto, Andrew D. Weinberg, Hideo Yagita, Robert L. HendricksAbstract:Herpes stromal keratitis (HSK) is an immunopathological disease regulated by Th1 CD4 T cells, which require APC and costimulation within the infected cornea to mediate disease. Recent studies suggest the OX40:OX40 ligand (OX40L) interaction enhances effector cell cytokine secretion at inflammatory sites. OX40 + cells were detected in HSV-1-infected mouse corneas as early as 3 days postinfection (dpi), prior to the onset of HSK, and their frequency increased through 15 dpi, when all mice exhibited severe HSK. OX40L + cells were first detected at 7 dpi, coincident with the initiation of HSK. It is interesting that the OX40L + cells did not coexpress MHC Class II or the dendritic cell (DC) marker CD11 e . Our findings demonstrate rapid infiltration of activated (OX40 + ) CD4 + T cells into HSV-1-infected corneas and expression of OX40L on MHC Class II-negative cells but surprisingly, not on MHC Class II + CD11c + DC, which are present in the infected corneas and required for HSK. Moreover, neither local nor systemic treatment of mice with a blocking antibody to OX40L or with a blocking fusion protein altered the course of HSK significantly, possibly as a result of a lack of OX40L expression on functional APC.
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Targeting OX40 and OX40L for the treatment of autoimmunity and cancer.
Critical reviews in immunology, 2007Co-Authors: William L. Redmond, Andrew D. WeinbergAbstract:The optimal activation of naive T cells requires TCR-mediated recognition of cognate peptide-MHC complexes on antigen presenting cells in the presence of costimulatory signals. Although signals provided via CD28-B7 interactions are important for enhancing the initial T-cell response, other costimulatory signals are required for sustaining the response and promoting both T-cell differentiation and survival. In particular, engagement of OX40 (CD134) by its natural ligand OX40L (CD134L) or OX40 agonists has been shown to provide key signals that can augment CD4 and CD8 T-cell responses. Importantly, numerous studies have highlighted the ability of OX40-specific agonists or antagonists to enhance antitumor immunity or ameliorate autoimmune disease, respectively. On the basis of these studies, the development of OX40- and OX40L-specific reagents has been pursued for clinical use. Given the emerging role of OX40 and OX40L as novel therapeutic targets, this review will focus on the cellular and molecular mechanisms of OX40-mediated T-cell costimulation with a special emphasis on the role of OX40-OX40L interactions in the etiology and treatment of autoimmunity and cancer.
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Expression and function of the OX40/OX40L costimulatory pair during herpes stromal keratitis.
Journal of leukocyte biology, 2006Co-Authors: Andrew J. Lepisto, Andrew D. Weinberg, Hideo Yagita, Robert L. HendricksAbstract:Herpes stromal keratitis (HSK) is an immunopathological disease regulated by Th1 CD4 T cells, which require APC and costimulation within the infected cornea to mediate disease. Recent studies suggest the OX40:OX40 ligand (OX40L) interaction enhances effector cell cytokine secretion at inflammatory sites. OX40 + cells were detected in HSV-1-infected mouse corneas as early as 3 days postinfection (dpi), prior to the onset of HSK, and their frequency increased through 15 dpi, when all mice exhibited severe HSK. OX40L + cells were first detected at 7 dpi, coincident with the initiation of HSK. It is interesting that the OX40L + cells did not coexpress MHC Class II or the dendritic cell (DC) marker CD11 e . Our findings demonstrate rapid infiltration of activated (OX40 + ) CD4 + T cells into HSV-1-infected corneas and expression of OX40L on MHC Class II-negative cells but surprisingly, not on MHC Class II + CD11c + DC, which are present in the infected corneas and required for HSK. Moreover, neither local nor systemic treatment of mice with a blocking antibody to OX40L or with a blocking fusion protein altered the course of HSK significantly, possibly as a result of a lack of OX40L expression on functional APC.
Eva J.a. Van Wanrooij - One of the best experts on this subject based on the ideXlab platform.
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interruption of the tnfrsf4 tnfsf4 ox40 OX40L pathway attenuates atherogenesis in low density lipoprotein receptor deficient mice
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: Eva J.a. Van Wanrooij, Gijs H.m. Van Puijvelde, Paula De Vos, Hideo Yagita, Theo J.c. Van Berkel, Johan KuiperAbstract:Objective— Atherosclerosis is a chronic (auto-)inflammatory disease and T cell activation is an important factor in this process. Tnfrsf4 (OX40) and Tnfsf4 (OX40 ligand) are members of the tumor necrosis factor (TNF) and TNF receptor family and OX40/OX40L mediated signaling is important in co-activation of T cells and facilitates B-T cell interaction. In this study we assessed the role of the OX40/OX40L pathway in atherosclerosis and the effect of interruption of the OX40/OX40L pathway on lesion development. Methods and Results— We treated low-density lipoprotein receptor-deficient (LDLr −/− ) mice with an anti-OX40L antibody which lead to a 53% decrease in atherosclerotic lesion formation. Treatment resulted in inhibition of Th2 mediated isotype switching by decreasing interleukin (IL)-4 secretion and subsequent low IgG1 serum levels against oxLDL, whereas protective anti-oxLDL specific IgM titers were increased in treated mice compared with control. Conclusions— We conclude that blocking the OX-40/OX40L interaction reduced atherogenesis by inhibition of IL-4 mediated Th2 induced isotype switching and subsequent increased levels of anti-oxLDL IgM.
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Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) Pathway Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice
Arteriosclerosis thrombosis and vascular biology, 2006Co-Authors: Eva J.a. Van Wanrooij, Gijs H.m. Van Puijvelde, Paula De Vos, Hideo Yagita, Theo J.c. Van Berkel, Johan KuiperAbstract:Objective— Atherosclerosis is a chronic (auto-)inflammatory disease and T cell activation is an important factor in this process. Tnfrsf4 (OX40) and Tnfsf4 (OX40 ligand) are members of the tumor necrosis factor (TNF) and TNF receptor family and OX40/OX40L mediated signaling is important in co-activation of T cells and facilitates B-T cell interaction. In this study we assessed the role of the OX40/OX40L pathway in atherosclerosis and the effect of interruption of the OX40/OX40L pathway on lesion development. Methods and Results— We treated low-density lipoprotein receptor-deficient (LDLr −/− ) mice with an anti-OX40L antibody which lead to a 53% decrease in atherosclerotic lesion formation. Treatment resulted in inhibition of Th2 mediated isotype switching by decreasing interleukin (IL)-4 secretion and subsequent low IgG1 serum levels against oxLDL, whereas protective anti-oxLDL specific IgM titers were increased in treated mice compared with control. Conclusions— We conclude that blocking the OX-40/OX40L interaction reduced atherogenesis by inhibition of IL-4 mediated Th2 induced isotype switching and subsequent increased levels of anti-oxLDL IgM.
