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Gaetani L, Bellomo G, Di Sabatino E, Sperandei S, Mancini A, Blennow K, Zetterberg H, Parnetti L, Di Filippo M. The Immune Signature of CSF in Multiple Sclerosis with and without Oligoclonal Bands: A Machine Learning Approach to Proximity Extension Assay Analysis. Int J Mol Sci 2023; 25:139. [PMID: 38203309 PMCID: PMC10778830 DOI: 10.3390/ijms25010139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/04/2023] [Accepted: 12/08/2023] [Indexed: 01/12/2024] Open
Abstract
Early diagnosis of multiple sclerosis (MS) relies on clinical evaluation, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) analysis. Reliable biomarkers are needed to differentiate MS from other neurological conditions and to define the underlying pathogenesis. This study aimed to comprehensively profile immune activation biomarkers in the CSF of individuals with MS and explore distinct signatures between MS with and without oligoclonal bands (OCB). A total of 118 subjects, including relapsing-remitting MS with OCB (MS OCB+) (n = 58), without OCB (MS OCB-) (n = 24), and controls with other neurological diseases (OND) (n = 36), were included. CSF samples were analyzed by means of proximity extension assay (PEA) for quantifying 92 immune-related proteins. Neurofilament light chain (NfL), a marker of axonal damage, was also measured. Machine learning techniques were employed to identify biomarker panels differentiating MS with and without OCB from controls. Analyses were performed by splitting the cohort into a training and a validation set. CSF CD5 and IL-12B exhibited the highest discriminatory power in differentiating MS from controls. CSF MIP-1-alpha, CD5, CXCL10, CCL23 and CXCL9 were positively correlated with NfL. Multivariate models were developed to distinguish MS OCB+ and MS OCB- from controls. The model for MS OCB+ included IL-12B, CD5, CX3CL1, FGF-19, CST5, MCP-1 (91% sensitivity and 94% specificity in the training set, 81% sensitivity, and 94% specificity in the validation set). The model for MS OCB- included CX3CL1, CD5, NfL, CCL4 and OPG (87% sensitivity and 80% specificity in the training set, 56% sensitivity and 48% specificity in the validation set). Comprehensive immune profiling of CSF biomarkers in MS revealed distinct pathophysiological signatures associated with OCB status. The identified biomarker panels, enriched in T cell activation markers and immune mediators, hold promise for improved diagnostic accuracy and insights into MS pathogenesis.
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Affiliation(s)
- Lorenzo Gaetani
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (L.G.)
| | - Giovanni Bellomo
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (L.G.)
| | - Elena Di Sabatino
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (L.G.)
| | - Silvia Sperandei
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (L.G.)
| | - Andrea Mancini
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (L.G.)
| | - Kaj Blennow
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, 431 41 Mölndal, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 41 Mölndal, Sweden
| | - Henrik Zetterberg
- Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, 431 41 Mölndal, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, 431 41 Mölndal, Sweden
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK
- UK Dementia Research Institute at UCL, London WC1E 6BT, UK
- Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong 518172, China
- Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA
| | - Lucilla Parnetti
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (L.G.)
| | - Massimiliano Di Filippo
- Section of Neurology, Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy; (L.G.)
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Wang F, Yang M, Luo W, Zhou Q. Characteristics of tumor microenvironment and novel immunotherapeutic strategies for non-small cell lung cancer. JOURNAL OF THE NATIONAL CANCER CENTER 2022; 2:243-262. [PMID: 39036549 PMCID: PMC11256730 DOI: 10.1016/j.jncc.2022.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 10/12/2022] [Accepted: 10/14/2022] [Indexed: 11/08/2022] Open
Abstract
Immune checkpoint inhibitor-based immunotherapy has revolutionized the treatment approach of non-small cell lung cancer (NSCLC). Monoclonal antibodies against programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) are widely used in clinical practice, but other antibodies that can circumvent innate and acquired resistance are bound to undergo preclinical and clinical studies. However, tumor cells can develop and facilitate the tolerogenic nature of the tumor microenvironment (TME), resulting in tumor progression. Therefore, the immune escape mechanisms exploited by growing lung cancer involve a fine interplay between all actors in the TME. A better understanding of the molecular biology of lung cancer and the cellular/molecular mechanisms involved in the crosstalk between lung cancer cells and immune cells in the TME could identify novel therapeutic weapons in the old war against lung cancer. This article discusses the role of TME in the progression of lung cancer and pinpoints possible advances and challenges of immunotherapy for NSCLC.
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Affiliation(s)
- Fen Wang
- Department of Oncology, Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Cancer Institute, Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center, Shenzhen, China
| | - Mingyi Yang
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Weichi Luo
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Qing Zhou
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
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Kang J, Sun T, Zhang Y. Immunotherapeutic progress and application of bispecific antibody in cancer. Front Immunol 2022; 13:1020003. [PMID: 36341333 PMCID: PMC9630604 DOI: 10.3389/fimmu.2022.1020003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 10/05/2022] [Indexed: 08/19/2023] Open
Abstract
Bispecific antibodies (bsAbs) are artificial antibodies with two distinct antigen-binding sites that can bind to different antigens or different epitopes on the same antigen. Based on a variety of technology platforms currently developed, bsAbs can exhibit different formats and mechanisms of action. The upgrading of antibody technology has promoted the development of bsAbs, which has been effectively used in the treatment of tumors. So far, 7 bsAbs have been approved for marketing in the world, and more than 200 bsAbs are in clinical and preclinical research stages. Here, we summarize the development process of bsAbs, application in tumor treatment and look forward to the challenges in future development.
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Affiliation(s)
- Jingyue Kang
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Tonglin Sun
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Yan Zhang
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Division of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Krzyżanowska N, Wojas-Krawczyk K, Milanowski J, Krawczyk P. Future Prospects of Immunotherapy in Non-Small-Cell Lung Cancer Patients: Is There Hope in Other Immune Checkpoints Targeting Molecules? Int J Mol Sci 2022; 23:3087. [PMID: 35328510 PMCID: PMC8950480 DOI: 10.3390/ijms23063087] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 02/04/2023] Open
Abstract
Currently, one of the leading treatments for non-small-cell lung cancer is immunotherapy involving immune checkpoint inhibitors. These monoclonal antibodies restore the anti-tumour immune response altered by negative immune checkpoint interactions. The most commonly used immunotherapeutics in monotherapy are anti-PD-1 and anti-PD-L1 antibodies. The effectiveness of both groups of antibodies has been proven in many clinical trials, which have translated into positive immunotherapeutic registrations for cancer patients worldwide. These antibodies are generally well tolerated, and certain patients achieve durable responses. However, given the resistance of some patients to this form of therapy, along with its other drawbacks, such as adverse events, alternatives are constantly being sought. Specifically, new drugs targeting already known molecules are being tested, and new potential targets are being explored. The aim of this paper is to provide an overview of the latest developments in this area.
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Affiliation(s)
- Natalia Krzyżanowska
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-954 Lublin, Poland; (K.W.-K.); (J.M.); (P.K.)
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Zhan MR, Gao XZ, Wang C, Peng F, Wang XM, Xu HQ, Niu JQ. Elevated soluble 4-1BB is associated with serum markers of hepatitis B virus in patients with chronic hepatitis B. World J Clin Cases 2021; 9:1619-1630. [PMID: 33728305 PMCID: PMC7942032 DOI: 10.12998/wjcc.v9.i7.1619] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 12/13/2020] [Accepted: 12/23/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Previous studies have suggested that the costimulatory molecule 4-1BB plays pivotal roles in regulating immunity during chronic viral infection. However, up to now, there are few studies about 4-1BB in chronic hepatitis B (CHB).
AIM To clarify this issue, we report our comprehensive study results on the expression levels of 4-1BB in patients with CHB.
METHODS From September 2018 to June 2019, a total of 64 patients with CHB were recruited from the Department of Hepatology, The First Hospital of Jilin University. Peripheral blood samples were collected from 52 treatment-naïve and 12 entecavir-treated patients with CHB as well as 37 healthy donors (including 24 healthy adults and 13 healthy children). The levels of soluble 4-1BB (s4-1BB) in plasma were measured by ELISA. 4-1BB mRNA expression in peripheral blood mononuclear cells was detected by real-time quantitative PCR.
RESULTS The s4-1BB levels in the plasma of patients with CHB were significantly higher than those in healthy adults (94.390 ± 7.393 ng/mL vs 8.875 ± 0.914 ng/mL, P < 0.001). In addition, the s4-1BB level in plasma was significantly increased in patients with a higher viral load and a disease flare up. However, there were no significant differences between treatment-naïve and entecavir-treated patients. Interestingly, among treatment-naïve patients with CHB, the levels of s4-1BB in plasma had a significant positive correlation with hepatitis B surface antigen, hepatitis B virus DNA, hepatitis B e antigen, and triglyceride levels (r = 0.748, P < 0.001; r = 0.406, P = 0.004; r = 0.356, P = 0.019 and r = -0.469, P = 0.007, respectively). The 4-1BB mRNA expression was higher in the peripheral blood mononuclear cells of patients with CHB than in the peripheral blood mononuclear cells of healthy adults, but the difference was not statistically significant.
CONCLUSION These results suggest that the levels of s4-1BB may be associated with pathogenesis of hepatitis B virus and therefore may be a promising biomarker for disease progression.
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Affiliation(s)
- Meng-Ru Zhan
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Xiu-Zhu Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
- Phase I Clinical Research Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Chang Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Fei Peng
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Xiao-Mei Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Hong-Qin Xu
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Jun-Qi Niu
- Department of Hepatology, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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You G, Lee Y, Kang YW, Park HW, Park K, Kim H, Kim YM, Kim S, Kim JH, Moon D, Chung H, Son W, Jung UJ, Park E, Lee S, Son YG, Eom J, Won J, Park Y, Jung J, Lee SW. B7-H3×4-1BB bispecific antibody augments antitumor immunity by enhancing terminally differentiated CD8 + tumor-infiltrating lymphocytes. SCIENCE ADVANCES 2021; 7:7/3/eaax3160. [PMID: 33523913 PMCID: PMC7810375 DOI: 10.1126/sciadv.aax3160] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 11/19/2020] [Indexed: 05/17/2023]
Abstract
Cancer immunotherapy with 4-1BB agonists has limited further clinical development because of dose-limiting toxicity. Here, we developed a bispecific antibody (bsAb; B7-H3×4-1BB), targeting human B7-H3 (hB7-H3) and mouse or human 4-1BB, to restrict the 4-1BB stimulation in tumors. B7-H3×m4-1BB elicited a 4-1BB-dependent antitumor response in hB7-H3-overexpressing tumor models without systemic toxicity. BsAb primarily targets CD8 T cells in the tumor and increases their proliferation and cytokine production. Among the CD8 T cell population in the tumor, 4-1BB is solely expressed on PD-1+Tim-3+ "terminally differentiated" subset, and bsAb potentiates these cells for eliminating the tumor. Furthermore, the combination of bsAb and PD-1 blockade synergistically inhibits tumor growth accompanied by further increasing terminally differentiated CD8 T cells. B7-H3×h4-1BB also shows antitumor activity in h4-1BB-expressing mice. Our data suggest that B7-H3×4-1BB is an effective and safe therapeutic agent against B7-H3-positive cancers as monotherapy and combination therapy with PD-1 blockade.
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Affiliation(s)
- Gihoon You
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | | | - Yeon-Woo Kang
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Han Wook Park
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | | | - Hyekang Kim
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Young-Min Kim
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Sora Kim
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Ji-Hae Kim
- Department of Life Sciences, POSTECH, Pohang, Republic of Korea
| | - Dain Moon
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | | | - Wonjun Son
- ABL Bio Inc., Seongnam, Republic of Korea
| | | | | | - Shinai Lee
- ABL Bio Inc., Seongnam, Republic of Korea
| | | | | | | | - Yunji Park
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea
| | - Jaeho Jung
- ABL Bio Inc., Seongnam, Republic of Korea.
| | - Seung-Woo Lee
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea.
- Department of Life Sciences, POSTECH, Pohang, Republic of Korea
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Recombinant Costimulatory Fusion Proteins as Functional Immunomodulators Enhance Antitumor Activity in Murine B16F10 Melanoma. Vaccines (Basel) 2020; 8:vaccines8020223. [PMID: 32423130 PMCID: PMC7349950 DOI: 10.3390/vaccines8020223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 05/04/2020] [Accepted: 05/12/2020] [Indexed: 11/23/2022] Open
Abstract
Blocking inhibitory signaling and engaging stimulatory signaling have emerged as important therapeutic modalities for cancer immunotherapy. This study aimed to investigate immunomodulatory features of three recombinant costimulatory ligand proteins in a mouse model, which are extracellular domains of OX40-ligand (OX40L), 4-1BB-ligand (4-1BBL), or two domains in tandem, fused with the transmembrane domain of diphtheria toxin (DTT), named DTT-COS1, DTT-COS2, and DTT-COS12, respectively. In vitro study showed that DTT-COS1 and DTT-COS12 had immunological activity increasing the ratio of CD8/CD4 T cells. Treatments with DTT-COS1 and DTT-COS12 dramatically generated immune protection against the B16F10 tumor challenge in both prophylactic and therapeutic efficacy. Furthermore, regarding tumor microenvironment (TME) immunomodulation, DTT-COS1 treatment increased the proportion of CD4+ effector T cells (Teff) and decreased the expression of a suppressive cytokine. Meanwhile, DTT-COS12 reduced regulatory T cells (Treg) and improved the level of stimulatory cytokines. In addition, endogenous antibodies against OX40L/4-1BBL were generated, which may help with antitumor responses. Unexpectedly, DTT-COS2 lacked antitumor effects in vitro and in vivo. Importantly, serum analysis of liver-function associated factors and pro-inflammatory cytokines demonstrated that treatments were safe formulations in mice without signs of systemic toxicity. Remarkably, DTT-COS1 and DTT-COS12 are functional immunomodulators for mouse B16F10 melanoma, creating practical preclinical value in cancer immunotherapy.
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Activation-induced surface proteins in the identification of antigen-responsive CD4 T cells. Immunol Lett 2019; 219:1-7. [PMID: 31881234 DOI: 10.1016/j.imlet.2019.12.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 12/09/2019] [Accepted: 12/22/2019] [Indexed: 02/06/2023]
Abstract
Identification of antigen specificity of CD4 T cells is instrumental in understanding adaptive immune responses in health and disease. The high diversity of CD4 T cell repertoire combined with the functional heterogeneity of the compartment poses a challenge to the assessment of CD4 T cell responses. In spite of that, multiple technologies allow direct or indirect interrogation of antigen specificity of CD4 T cells. In the last decade, multiple surface proteins have been established as cytokine-independent surrogates of in vitro CD4 T cell activation, and have found applications in the live identification and isolation of antigen-responsive CD4 T cells. Here we review the current knowledge of the surface proteins that permit identification of viable antigen-responsive CD4 T cells with high specificity, including those capable of identifying specialized CD4 T subsets such as germinal center follicular helper T cells and CD4 regulatory T cells.
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Arya RP, Arankalle VA. Phenotypic analysis of monocytes and CD4 + T cells in hepatitis E patients with or without pregnancy. Hum Immunol 2019; 80:855-862. [PMID: 31285077 DOI: 10.1016/j.humimm.2019.06.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/19/2019] [Accepted: 06/23/2019] [Indexed: 01/16/2023]
Abstract
High mortality in pregnant women is a characteristic of hepatitis E virus (HEV) infection. Role of monocytes/T cells in HEV infection during pregnancy is still unclear. We compared CD14+monocytes and CD4+T cells by flow-cytometry in hepatitis-E patients including 13 pregnant (Antenatal care, ANC), 25 non-ANC patients and respective controls (12 and 20). Non-ANC-patients showed significantly higher frequency of monocytes with increased expression of CD80, CD86 and HLA-DR than control individuals (p < 0.001). Healthy pregnancy was associated with increased frequency of monocytes with higher CD80 expression and lower levels of HLA-DR (p < 0.05) compared to non-ANC controls. ANC-patients exhibited elevated levels of monocytes (p < 0.01) with higher expression of CD80 (p < 0.001) and reduced levels of HLA-DR and CD86 (p < 0.05) when compared with non-ANC patients. TLR2 and TLR4 surface expression on monocytes was higher in non-ANC-patients (p < 0.00) and lower in the ANC-patients (p < 0.01). Healthy-ANCs exhibited lower TLR4 expression on monocytes (p < 0.05). HEV infection did not change the frequency of CD4+ and CD4+CD28+T cells in patients' group (p > 0.05). Compared to respective controls, CD137+ and CD152+CD4+T cells were higher (p < 0.05) in both patients' categories. Higher levels of CD152+CD4+T cells (p < 0.001) was noted in healthy pregnant women. Among patients' groups, the CD4+T cells and their subpopulation were not different (p > 0.05). We found higher and reduced levels of circulating inflammatory cytokines (IL12, TNFα, IL6 and IL8; miliplex-assay) in non-ANC and ANC-patients respectively. In conclusion, on contrary to the classical activation of CD14+monocytes in the non-ANC-patients, impaired response was evident in the ANC-patients while the CD4+T cell populations were similar in the patient groups.
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Affiliation(s)
- Ravi P Arya
- Hepatitis Group, National Institute of Virology, Pune 411021, India; KSBS, IIT Delhi, New Delhi 110016, India
| | - Vidya A Arankalle
- Hepatitis Group, National Institute of Virology, Pune 411021, India; Bharati Vidyapeeth University, Pune 411043, India.
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Copsel S, Wolf D, Komanduri KV, Levy RB. The promise of CD4 +FoxP3 + regulatory T-cell manipulation in vivo: applications for allogeneic hematopoietic stem cell transplantation. Haematologica 2019; 104:1309-1321. [PMID: 31221786 PMCID: PMC6601084 DOI: 10.3324/haematol.2018.198838] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 05/07/2019] [Indexed: 12/12/2022] Open
Abstract
CD4+FoxP3+ regulatory T cells (Tregs) are a non-redundant population critical for the maintenance of self-tolerance. Over the past decade, the use of these cells for therapeutic purposes in transplantation and autoimmune disease has emerged based on their capacity to inhibit immune activation. Basic science discoveries have led to identifying key receptors on Tregs that can regulate their proliferation and function. Notably, the understanding that IL-2 signaling is crucial for Treg homeostasis promoted the hypothesis that in vivo IL-2 treatment could provide a strategy to control the compartment. The use of low-dose IL-2 in vivo was shown to selectively expand Tregs versus other immune cells. Interestingly, a number of other Treg cell surface proteins, including CD28, CD45, IL-33R and TNFRSF members, have been identified which can also induce activation and proliferation of this population. Pre-clinical studies have exploited these observations to prevent and treat mice developing autoimmune diseases and graft-versus-host disease post-allogeneic hematopoietic stem cell transplantation. These findings support the development of translational strategies to expand Tregs in patients. Excitingly, the use of low-dose IL-2 for patients suffering from graft-versus-host disease and autoimmune disease has demonstrated increased Treg levels together with beneficial outcomes. To date, promising pre-clinical and clinical studies have directly targeted Tregs and clearly established the ability to increase their levels and augment their function in vivo. Here we review the evolving field of in vivo Treg manipulation and its application to allogeneic hematopoietic stem cell transplantation.
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Affiliation(s)
| | | | - Krishna V Komanduri
- Department of Microbiology and Immunology.,Sylvester Comprehensive Cancer Center.,Division of Transplantation and Cellular Therapy, Department of Medicine
| | - Robert B Levy
- Department of Microbiology and Immunology .,Division of Transplantation and Cellular Therapy, Department of Medicine.,Department of Ophthalmology, Miller School of Medicine, University of Miami, FL, USA
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Zhang J, Song K, Wang J, Li Y, Liu S, Dai C, Chen L, Wang S, Qin Z. S100A4 blockage alleviates agonistic anti-CD137 antibody-induced liver pathology without disruption of antitumor immunity. Oncoimmunology 2018; 7:e1296996. [PMID: 29632708 PMCID: PMC5889198 DOI: 10.1080/2162402x.2017.1296996] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Revised: 02/11/2017] [Accepted: 02/14/2017] [Indexed: 01/01/2023] Open
Abstract
Liver-related autoimmune toxicities triggered by agonistic anti-CD137 antibodies have greatly limited their use in clinical applications. Here, we found that anti-CD137 monoclonal antibody (mAb) treatment in mice induced the infiltration of a large number of S100A4+ macrophages into the liver. Depletion of these cells or deficiency of S100A4 decreased inflammatory cytokine profiles and drastically reduced the number of liver pathogenic CD8+ T cells. Mechanistically, soluble S100A4 directly activated the Akt pathway and specifically prolonged CD8+ T cell survival. Interestingly, one S100A4 neutralizing mAb selectively alleviated liver abnormalities but did not affect the antitumor immunity induced by anti-CD137 mAb therapy. Thus, our study presents a novel molecular link to the liver pathology induced by an immune stimulatory antibody and proposes that combinational immunotherapies targeting those pathways could potentially elicit optimal antitumor immunity with minimal side effects.
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Affiliation(s)
- Jinhua Zhang
- Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Kun Song
- Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jun Wang
- Department of Immunobiology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA
| | - Yanan Li
- Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Shuangqing Liu
- Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Chengliang Dai
- Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Lieping Chen
- Department of Immunobiology and Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA
| | - Shengdian Wang
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Zhihai Qin
- Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Chinese Academy of Sciences-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.,Medical Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
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Co-stimulation Agonists via CD137, OX40, GITR, and CD27 for Immunotherapy of Cancer. Oncoimmunology 2018. [DOI: 10.1007/978-3-319-62431-0_26] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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13
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Yoo JK, Choo YK, Kwak DH, Lee JM, Lim CY, Lee JH, Park MY, Kim CH. Protective effects of agonistic anti-4-1BB antibody on the development of imiquimod-induced psoriasis-like dermatitis in mice. Immunol Lett 2016; 178:131-9. [PMID: 27592361 DOI: 10.1016/j.imlet.2016.08.012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 08/01/2016] [Accepted: 08/30/2016] [Indexed: 01/06/2023]
Abstract
Agonistic anti-4-1BB antibodies (Abs) play a central role in immunomodulatory conditions that control the pathogenesis of immune-mediated autoimmune and allergic diseases. However, the effects of agonistic anti-4-1BB Abs have not been examined in an experimental mouse model of psoriasis. Therefore, we investigated the protective effects of agonistic anti-4-1BB Abs, using imiquimod (IMQ)-induced psoriasis-like dermatitis in mice, a condition histologically and clinically similar to human psoriasis. We found that administration of agonistic anti-4-1BB Abs (10mg/kg) significantly alleviated the severity of IMQ-induced psoriasis-like skin inflammation in mice, with reduced histologic symptoms, including inflammatory infiltration, parakeratosis, and hyperkeratosis. Subsequent analyses revealed that the production of Th17 cytokines (IL-17A and IL-23) in the serum and skin of IMQ-induced mice was significantly inhibited by agonistic anti-4-1BB Abs (10mg/kg), although Th1 cytokines (TNF-α and IFN-γ) were not. Moreover, administration of agonistic anti-4-1BB Abs (10mg/kg) induced a relative increase of CD4(+)FoxP3(+) regulatory T (Treg) cells in the spleen and draining lymph node (DLN). Taken together, our data provide evidence that agonistic anti-4-1BB Abs possesses immunosuppressive properties in IMQ-induced psoriasis-like skin inflammation, providing insight into the immunomodulatory effect of agonistic anti-4-1BB Abs for psoriasis immunotherapy.
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Affiliation(s)
- Jung Ki Yoo
- Department of Pharmacy, College of Pharmacy, CHA University, 335 Pangyo-ro, Bundang-gu, Seongman-si, Gyeonggi-do 463-400, Republic of Korea
| | - Young-Kug Choo
- Department of Biological science, College of Natural Sciences, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea
| | - Dong Hoon Kwak
- Institute for Glycoscience, Wonkwang University, Iksan, Jeonbuk 570-749, Republic of Korea
| | - Jong Min Lee
- College of Medicine, Dongguk University, Goyang 410-773, Republic of Korea
| | - Chi-Yeon Lim
- Department of Biostatistics, Dongguk University, Goyang 410-773, Republic of Korea
| | - Ju-Hee Lee
- College of Korean Medicine, Dongguk University, Gyeongju 38066, Republic of Korea
| | - Mi-Young Park
- Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul 137-701, Republic of Korea
| | - Chang-Hyun Kim
- College of Medicine, Dongguk University, Goyang 410-773, Republic of Korea.
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Liu J, Blake SJ, Harjunpää H, Fairfax KA, Yong MCR, Allen S, Kohrt HE, Takeda K, Smyth MJ, Teng MWL. Assessing Immune-Related Adverse Events of Efficacious Combination Immunotherapies in Preclinical Models of Cancer. Cancer Res 2016; 76:5288-301. [PMID: 27503925 DOI: 10.1158/0008-5472.can-16-0194] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 07/07/2016] [Indexed: 11/16/2022]
Abstract
New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAE) in humans. However, grade 3/4 irAEs occur in a high proportion, which can lead to discontinuation of treatment and can result in fatalities if not promptly treated. Prolonged T regulatory cell (Treg) depletion in tumor-bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab-treated patients. In contrast, transient Treg depletion or anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily induced following treatment with additional immunomodulatory antibodies. Transient Treg depletion of DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies had a high therapeutic window compared with DT plus anti-CD137. In contrast, DT plus anti-CD137-treated mice developed severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared because of an infiltration of activated proliferating effector T cells in the tissues producing IFNγ and TNF; however, TNF blockade decreased irAEs severity without impacting on tumor growth. Cancer Res; 76(18); 5288-301. ©2016 AACR.
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Affiliation(s)
- Jing Liu
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia
| | - Stephen J Blake
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Heidi Harjunpää
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia
| | - Kirsten A Fairfax
- The Walter and Eliza Hall Institute of Medical Research, Molecular Medicine Division, Melbourne, Australia. The Department of Experimental Medicine, University of Melbourne, Parkville, Victoria, Australia
| | - Michelle C R Yong
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Stacey Allen
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Holbrook E Kohrt
- Division of Oncology, Department of Medicine, Stanford University, Stanford, California
| | - Kazuyoshi Takeda
- Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo, Japan
| | - Mark J Smyth
- Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia
| | - Michele W L Teng
- Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. School of Medicine, University of Queensland, Herston, Queensland, Australia.
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Gacerez AT, Arellano B, Sentman CL. How Chimeric Antigen Receptor Design Affects Adoptive T Cell Therapy. J Cell Physiol 2016; 231:2590-8. [PMID: 27163336 DOI: 10.1002/jcp.25419] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Accepted: 05/09/2016] [Indexed: 01/09/2023]
Abstract
Chimeric antigen receptor (CAR) T cells have been developed to treat tumors and have shown great success against B cell malignancies. Exploiting modular designs and swappable domains, CARs can target an array of cell surface antigens and, upon receptor-ligand interactions, direct signaling cascades, thereby driving T cell effector functions. CARs have been designed using receptors, ligands, or scFv binding domains. Different regions of a CAR have each been found to play a role in determining the overall efficacy of CAR T cells. Therefore, this review provides an overview of CAR construction and common designs. Each CAR region is discussed in the context of its importance to a CAR's function. Additionally, the review explores how various engineering strategies have been applied to CAR T cells in order to regulate CAR T cell function and activity. J. Cell. Physiol. 231: 2590-2598, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Albert T Gacerez
- Department of Microbiology and Immunology, Center for Synthetic Immunity, The Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, New Hampshire
| | - Benjamine Arellano
- Department of Microbiology and Immunology, Center for Synthetic Immunity, The Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, New Hampshire
| | - Charles L Sentman
- Department of Microbiology and Immunology, Center for Synthetic Immunity, The Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, New Hampshire
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Sanchez-Paulete AR, Labiano S, Rodriguez-Ruiz ME, Azpilikueta A, Etxeberria I, Bolaños E, Lang V, Rodriguez M, Aznar MA, Jure-Kunkel M, Melero I. Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy. Eur J Immunol 2016; 46:513-22. [PMID: 26773716 DOI: 10.1002/eji.201445388] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2015] [Revised: 12/29/2015] [Accepted: 01/11/2016] [Indexed: 01/22/2023]
Abstract
CD137 (4-1BB, TNF-receptor superfamily 9) is a surface glycoprotein of the TNFR family which can be induced on a variety of leukocyte subsets. On T and NK cells, CD137 is expressed following activation and, if ligated by its natural ligand (CD137L), conveys polyubiquitination-mediated signals via TNF receptor associated factor 2 that inhibit apoptosis, while enhancing proliferation and effector functions. CD137 thus behaves as a bona fide inducible costimulatory molecule. These functional properties of CD137 can be exploited in cancer immunotherapy by systemic administration of agonist monoclonal antibodies, which increase anticancer CTLs and enhance NK-cell-mediated antibody-dependent cell-mediated cytotoxicity. Reportedly, anti-CD137 mAb and adoptive T-cell therapy strongly synergize, since (i) CD137 expression can be used to select the T cells endowed with the best activities against the tumor, (ii) costimulation of the lymphocyte cultures to be used in adoptive T-cell therapy can be done with CD137 agonist antibodies or CD137L, and (iii) synergistic effects upon coadministration of T cells and antibodies are readily observed in mouse models. Furthermore, the signaling cytoplasmic tail of CD137 is a key component of anti-CD19 chimeric antigen receptors that are used to redirect T cells against leukemia and lymphoma in the clinic. Ongoing phase II clinical trials with agonist antibodies and the presence of CD137 sequence in these successful chimeric antigen receptors highlight the importance of CD137 in oncoimmunology.
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Affiliation(s)
- Alfonso R Sanchez-Paulete
- Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain
| | - Sara Labiano
- Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain
| | - Maria E Rodriguez-Ruiz
- Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.,University Clinic, University of Navarra, Pamplona, Spain
| | - Arantza Azpilikueta
- Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain
| | - Iñaki Etxeberria
- Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain
| | - Elixabet Bolaños
- Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain
| | - Valérie Lang
- Ubiquitylation and Cancer Molecular Biology Laboratory, Foundation for Stem Cell Research, Fundación Inbiomed, San Sebastián, Spain
| | - Manuel Rodriguez
- Advanced Technology Institute in Life Sciences (ITAV), CNRS-USR3505, Toulouse, France.,University of Toulouse III-Paul Sabatier, Toulouse, France.,Institut de Pharmacologie et de Biologie Structurale (IPBS), CNRS-UMR5089, Toulouse, France
| | - M Angela Aznar
- Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | | | - Ignacio Melero
- Division of Immunology and Immunotherapy, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.,Instituto de Investigación Sanitaria de Navarra (IdISNA), Pamplona, Spain.,University Clinic, University of Navarra, Pamplona, Spain
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D'Ambrosio A, Pontecorvo S, Colasanti T, Zamboni S, Francia A, Margutti P. Peripheral blood biomarkers in multiple sclerosis. Autoimmun Rev 2015; 14:1097-110. [PMID: 26226413 DOI: 10.1016/j.autrev.2015.07.014] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 07/23/2015] [Indexed: 10/23/2022]
Abstract
Multiple sclerosis is the most common autoimmune disorder affecting the central nervous system. The heterogeneity of pathophysiological processes in MS contributes to the highly variable course of the disease and unpredictable response to therapies. The major focus of the research on MS is the identification of biomarkers in biological fluids, such as cerebrospinal fluid or blood, to guide patient management reliably. Because of the difficulties in obtaining spinal fluid samples and the necessity for lumbar puncture to make a diagnosis has reduced, the research of blood-based biomarkers may provide increasingly important tools for clinical practice. However, currently there are no clearly established MS blood-based biomarkers. The availability of reliable biomarkers could radically alter the management of MS at critical phases of the disease spectrum, allowing for intervention strategies that may prevent evolution to long-term neurological disability. This article provides an overview of this research field and focuses on recent advances in blood-based biomarker research.
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Affiliation(s)
- Antonella D'Ambrosio
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Simona Pontecorvo
- Multiple Sclerosis Center of Department of Neurology and Psychiatry of "Sapienza" University of Rome, Italy
| | - Tania Colasanti
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Silvia Zamboni
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
| | - Ada Francia
- Multiple Sclerosis Center of Department of Neurology and Psychiatry of "Sapienza" University of Rome, Italy
| | - Paola Margutti
- Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
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18
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Sanmamed MF, Pastor F, Rodriguez A, Perez-Gracia JL, Rodriguez-Ruiz ME, Jure-Kunkel M, Melero I. Agonists of Co-stimulation in Cancer Immunotherapy Directed Against CD137, OX40, GITR, CD27, CD28, and ICOS. Semin Oncol 2015; 42:640-55. [PMID: 26320067 DOI: 10.1053/j.seminoncol.2015.05.014] [Citation(s) in RCA: 161] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
T and natural killer (NK) lymphocytes are considered the main effector players in the immune response against tumors. Full activation of T and NK lymphocytes requires the coordinated participation of several surface receptors that meet their cognate ligands through structured transient cell-to-cell interactions known as immune synapses. In the case of T cells, the main route of stimulation is driven by antigens as recognized in the form of short polypeptides associated with major histocompatibility complex (MHC) antigen-presenting molecules. However, the functional outcome of T-cell stimulation towards clonal expansion and effector function acquisition is contingent on the contact of additional surface receptor-ligand pairs and on the actions of cytokines in the milieu. While some of those interactions are inhibitory, others are activating and are collectively termed co-stimulatory receptors. The best studied belong to either the immunoglobulin superfamily or the tumor necrosis factor-receptor (TNFR) family. Co-stimulatory receptors include surface moieties that are constitutively expressed on resting lymphocytes such as CD28 or CD27 and others whose expression is induced upon recent previous antigen priming, ie, CD137, GITR, OX40, and ICOS. Ligation of these glycoproteins with agonist antibodies actively conveys activating signals to the lymphocyte. Those signals, acting through a potentiation of the cellular immune response, give rise to anti-tumor effects in mouse models. Anti-CD137 antibodies are undergoing clinical trials with evidence of clinical activity and anti-OX40 monoclonal antibodies (mAbs) induce interesting immunomodulation effects in humans. Antibodies anti-CD27 and GITR have recently entered clinical trials. The inherent dangers of these immunomodulation strategies are the precipitation of excessive systemic inflammation or/and invigorating silent autoimmunity. Agonist antibodies, recombinant forms of the natural ligands, and polynucleotide-based aptamers constitute the pharmacologic tools to manipulate such receptors. Preclinical data suggest that the greatest potential of these agents is achieved in combined treatment strategies.
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Affiliation(s)
- Miguel F Sanmamed
- Department of Immunobiology, Yale School of Medicine, New Haven, CT.
| | - Fernando Pastor
- Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Alfonso Rodriguez
- Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | | | | | | | - Ignacio Melero
- Centro de investigación médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain; Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain.
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Adler AJ, Vella AT. Betting on improved cancer immunotherapy by doubling down on CD134 and CD137 co-stimulation. Oncoimmunology 2014; 2:e22837. [PMID: 23482891 PMCID: PMC3583935 DOI: 10.4161/onci.22837] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The ability of T cells to recognize a vast array of antigens enables them to destroy tumor cells while inflicting minimal collateral damage. Nevertheless, tumor antigens often are a form of self-antigen, and thus tumor immunity can be dampened by tolerance mechanisms that evolved to prevent autoimmunity. Since tolerance can be induced by steady-state antigen-presenting cells that provide insufficient co-stimulation, the exogenous administration of co-stimulatory agonists can favor the expansion and tumoricidal functions of tumor-specific T cells. Agonists of the co-stimulatory tumor necrosis factor receptor (TNFR) family members CD134 and CD137 exert antitumor activity in mice, and as monotherapies have exhibited encouraging results in clinical trials. This review focuses on how the dual administration of CD134 and CD137 agonists synergistically boosts T-cell priming and elaborates a multi-pronged antitumor immune response, as well as how such dual co-stimulation might be translated into effective anticancer therapies.
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Affiliation(s)
- Adam J Adler
- Department of Immunology; University of Connecticut Health Center; Farmington, CT USA
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Signaling by Fyn-ADAP via the Carma1-Bcl-10-MAP3K7 signalosome exclusively regulates inflammatory cytokine production in NK cells. Nat Immunol 2013; 14:1127-36. [PMID: 24036998 PMCID: PMC3855032 DOI: 10.1038/ni.2708] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 08/09/2013] [Indexed: 11/29/2022]
Abstract
Inflammation is a critical component of the immune response. However, acute or chronic inflammation can be highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma, and multiple autoimmune disorders. Here, we identify a signaling pathway that is exclusively responsible for inflammatory cytokine production but not for cytotoxicity. Recognition of H60+ or CD137L+ tumor cells by murine NK cells led to efficient cytotoxicity and inflammatory cytokine production. Both of these effector functions required Lck, Fyn, PI(3)K-p85α, PI(3)K-p110δ, and PLC-γ2. However, the complex of Fyn and the adapter ADAP exclusively regulated inflammatory cytokine production but not cytotoxicity in NK cells. This unique function of ADAP required a Carma1-Bcl10-MAP3K7 signaling axis. Our results identify molecules that can be targeted to regulate inflammation without compromising NK cell cytotoxicity.
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Schoenbrunn A, Frentsch M, Kohler S, Keye J, Dooms H, Moewes B, Dong J, Loddenkemper C, Sieper J, Wu P, Romagnani C, Matzmohr N, Thiel A. A Converse 4-1BB and CD40 Ligand Expression Pattern Delineates Activated Regulatory T Cells (Treg) and Conventional T Cells Enabling Direct Isolation of Alloantigen-Reactive Natural Foxp3+ Treg. THE JOURNAL OF IMMUNOLOGY 2012; 189:5985-94. [DOI: 10.4049/jimmunol.1201090] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Immunological mechanisms of epidermal damage in toxic epidermal necrolysis. Curr Opin Allergy Clin Immunol 2012; 12:376-82. [PMID: 22688730 DOI: 10.1097/aci.0b013e328355b865] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
PURPOSE OF REVIEW The purpose of the present review is to introduce recent findings on the pathomechanisms of toxic epidermal necrolysis (TEN), which is characterized by widespread epidermal detachment due to keratinocyte apoptosis. RECENT FINDINGS In the mechanism of epidermal damage, the roles of drug metabolites, cytotoxic lymphocytes, and apoptosis-inducing factors have been noted. In addition, recent studies have focused on monocytes/macrophages, which may participate in epidermal damage through the production of apoptosis-inducing factors and the expression of costimulatory factors with the ability to activate CD8 T cells. SUMMARY Epidermal keratinocyte death is a hallmark of TEN. In a very high proportion of cases, drugs are responsible for TEN. It has been suggested that toxic drug metabolites produced by keratinocytes act like electrophilic agents to induce apoptosis and inflammation. Next, cytotoxic lymphocytes and monocytes function in the development of widespread epidermal damage through direct or indirect cytotoxic pathways. In addition, T-cell activation may be strengthened by the impairment of regulatory T-cell function and activated monocytes. The development of epidermal damage in TEN may require the coordinated action of these factors.
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Tohyama M, Watanabe H, Murakami S, Shirakata Y, Sayama K, Iijima M, Hashimoto K. Possible involvement of CD14+ CD16+ monocyte lineage cells in the epidermal damage of Stevens-Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol 2011; 166:322-30. [PMID: 21936856 DOI: 10.1111/j.1365-2133.2011.10649.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are characterized by keratinocyte apoptosis and necrosis, resulting in epidermal detachment. Although monocytes abundantly infiltrate the epidermis in SJS/TEN skin lesions, the properties and functions of these cells have not been fully examined. OBJECTIVES To determine the properties of monocytes infiltrating into the epidermis in SJS/TEN. METHODS Immunostaining of skin sections was performed to examine the membrane markers of monocytes infiltrating into skin lesions. RESULTS Immunostaining of cryosections from 11 SJS/TEN skin lesions revealed numerous CD14+ monocytes located along the dermoepidermal junction and throughout the epidermis. The cells coexpressed CD16, CD11c and HLA-DR. CD14+ CD16+ cells were identified in very early lesions without epidermal damage, suggesting that their infiltration is a cause, rather than a result, of epidermal damage. Moreover, these cells expressed CD80, CD86 and CD137 ligand, indicative of their ability to facilitate the proliferation and cytotoxicity of CD8+ T cells. CD16+ cells infiltrating the epidermis and detected at the dermoepidermal junction were immunostained and counted in paraffin-embedded skin sections obtained from 47 patients with drug rash manifested as TEN, SJS, maculopapular-type rash or erythema multiform-type rash. The number of CD16+ monocytes infiltrating the epidermis increased significantly, depending on the grade of epidermal damage. CONCLUSIONS These findings suggest that the appearance of CD14+ CD16+ cells of monocyte lineage plays an important role in the epidermal damage associated with SJS/TEN, most probably by enhancing the cytotoxicity of CD8+ T cells.
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Affiliation(s)
- M Tohyama
- Department of Dermatology, Ehime University Graduate School of Medicine, Shitsukawa, Toon-city, Ehime 791-0295, Japan.
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Kim YH, Choi BK, Shin SM, Kim CH, Oh HS, Park SH, Lee DG, Lee MJ, Kim KH, Vinay DS, Kwon BS. 4-1BB triggering ameliorates experimental autoimmune encephalomyelitis by modulating the balance between Th17 and regulatory T cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2011; 187:1120-8. [PMID: 21715692 DOI: 10.4049/jimmunol.1002681] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Agonistic anti-4-1BB Ab is known to ameliorate experimental autoimmune encephalomyelitis. 4-1BB triggering typically leads to the expansion of CD8(+) T cells, which produce abundant IFN-γ, and this in turn results in IDO-dependent suppression of autoimmune responses. However, because neutralization of IFN-γ or depletion of CD8(+) T cell only partially abrogates the effect of 4-1BB triggering, we sought to identify an additional mechanism of 4-1BB-triggered suppression of autoimmune responses using IFN-γ- or IFN-γR-deficient mice. 4-1BB triggering inhibited the generation of Th17 cells that is responsible for experimental autoimmune encephalomyelitis induction and progression, and increased Foxp3(+)CD4(+) regulatory T (Treg) cells, particularly among CD4(+) T cells. This was not due to a direct effect of 4-1BB signaling on CD4(+) T cell differentiation: 4-1BB signaling not only reduced Th17 cells and increased Treg cells in wild-type mice, which could be due to IFN-γ production by the CD8(+) T cells, but also did so in IFN-γ-deficient mice, in that case by downregulating IL-6 production. These results show that although secondary suppressive mechanisms evoked by 4-1BB triggering are usually masked by the strong effects of IFN-γ, 4-1BB signaling seems to modulate autoimmune responses by a number of mechanisms, and modulation of the Th17 versus Treg cell balance is one of those mechanisms.
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MESH Headings
- Amino Acid Sequence
- Animals
- CD4 Lymphocyte Count
- Cell Differentiation/genetics
- Cell Differentiation/immunology
- Cells, Cultured
- Disease Progression
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Encephalomyelitis, Autoimmune, Experimental/therapy
- Interferon-gamma/deficiency
- Interferon-gamma/metabolism
- Interferon-gamma/physiology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Molecular Sequence Data
- Receptors, Interferon/deficiency
- Receptors, Interferon/genetics
- Receptors, Interferon/physiology
- Signal Transduction/genetics
- Signal Transduction/immunology
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/metabolism
- T-Lymphocytes, Regulatory/pathology
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Th17 Cells/pathology
- Tumor Necrosis Factor Receptor Superfamily, Member 9/antagonists & inhibitors
- Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology
- Tumor Necrosis Factor Receptor Superfamily, Member 9/physiology
- Interferon gamma Receptor
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Affiliation(s)
- Young H Kim
- Immune and Cell Therapy Branch, Division of Cancer Biology, National Cancer Center, Goyang-si, Gyeongi-do 410-769, Korea
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Eckstrum K, Bany BM. Tumor necrosis factor receptor subfamily 9 (Tnfrsf9) gene is expressed in distinct cell populations in mouse uterus and conceptus during implantation period of pregnancy. Cell Tissue Res 2011; 344:567-76. [PMID: 21560035 PMCID: PMC3104000 DOI: 10.1007/s00441-011-1171-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2011] [Accepted: 04/12/2011] [Indexed: 12/22/2022]
Abstract
Tumor necrosis factor receptor subfamily 9 (TNFRSF9) plays a potentially important general role in immune function. Tnfrsf9 gene expression has previously been characterized in late pregnant mouse uterus and placenta. However, little is known about its expression in the uterus during the implantation phase of early pregnancy. We have assessed the levels and localization of Tnfrsf9 expression in the mouse uterus and conceptus during implantation. Relative Tnfrsf9 mRNA levels were significantly higher in implantation than in non-implantation site tissue on days 6.5-8.5 of pregnancy. This increase did not depend on the presence of the conceptus, as mRNA levels were not significantly different between pregnant implantation sites and artificially induced deciduomas. Localization by in situ hybridization revealed a subpopulation of endothelial and uterine natural killer cells expressing Tnfrsf9 in the endometrium during implantation. In the developing conceptus, primary trophoblast giant and ectoplacental cells expressed Tnfrsf9 on days 6.5-8.5, followed by expression in the trophoblast giant cell layers surrounding the conceptus on day 9.5 of pregnancy. Two main splice forms of Tnfrsf9 mRNA exist and encode proteins with distinct biological functions; both mRNA splice forms were present in uterine and conceptus tissues as determined by reverse transcription with the polymerase chain reaction. Thus, both membrane and soluble forms of Tnfrsf9 are expressed in specific cell types of the uterus and conceptus during the progression of implantation in mice and possibly have an important function in this process.
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Affiliation(s)
- Kirsten Eckstrum
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois, USA, 62901
| | - Brent M. Bany
- Department of Physiology, Southern Illinois University School of Medicine, Carbondale, Illinois, USA, 62901
- Department of Obstetrics & Gynecology, Southern Illinois University School of Medicine, Carbondale, Illinois, USA, 62901
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Lee H, Park HJ, Sohn HJ, Kim JM, Kim SJ. Combinatorial therapy for liver metastatic colon cancer: dendritic cell vaccine and low-dose agonistic anti-4-1BB antibody co-stimulatory signal. J Surg Res 2011; 169:e43-50. [PMID: 21571303 DOI: 10.1016/j.jss.2011.03.067] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2011] [Revised: 03/23/2011] [Accepted: 03/25/2011] [Indexed: 01/08/2023]
Abstract
BACKGROUND The combination of dendritic cell (DC) vaccine and 4-1BB ligation may be a suitable choice of immunotherapy for incurable cancer. However, at anti-tumor effector doses over 100 μg, 4-1BB Ab ligation is toxic to CD4(+) T cells, thus limiting its therapeutic use. MATERIALS AND METHODS A liver metastatic colon cancer model was established by hepatic injection of CT26 cells into Balb/c mice. Intraperitoneal administration of 1 × 10(6)/200 μL/mouse therapeutic-DCs (tumor lysate pulsed-DCs, P-DCs) began on d 7 after tumor cell inoculation. A P-DC injection was performed twice within a 1-wk interval. Agonistic anti 4-1BB Ab was intraperitoneally injected on d 7, 9, and 11 after tumor cell inoculation. Animals were sacrificed on d 21, and tumor growth was determined by weighing the liver with the tumor. RESULTS In the 20 μg 4-1BB ligation group, significant induction of CD3(+)CD8(+) T cells was observed without toxicity to CD3(+)CD4(+) T cells. DC vaccine treatment induced tumor antigen-specific Th1 cytokine (IL-2 and IFN-γ) secretion from the splenic lymphocytes. Ligation of 4-1BB reduced the DC vaccine-related IL-10 secretion and regulatory T cell population. Compared with anti-tumor effect of DC vaccine or 20 μg 4-1BB Ab alone, the combination therapy significantly increased the tumor rejection power to the level observed with higher doses of 4-1BB Ab alone. The combination therapy did not induce high-dose 4-1BB-related toxicity with CD4(+) T cell reduction, but did significantly induce tumor antigen-specific IFN-γ secreting effector CD8(+) cytotoxic T cells. CONCLUSIONS The data from our study reveal the value of using a DC vaccine combined with as little as 20 μg 4-1BB Ab as an improved immunotherapeutic for cancer.
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Affiliation(s)
- Hyunah Lee
- Office of Biomedical Sciences, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong, Gangnam-gu, Seoul, Korea
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27
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Cheng L, Wang J, Li X, Xing Q, Du P, Su L, Wang S. Interleukin-6 induces Gr-1+CD11b+ myeloid cells to suppress CD8+ T cell-mediated liver injury in mice. PLoS One 2011; 6:e17631. [PMID: 21394214 PMCID: PMC3048877 DOI: 10.1371/journal.pone.0017631] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2010] [Accepted: 02/04/2011] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Agonist antibodies against CD137 (4-1BB) on T lymphocytes are used to increase host anti-tumor immunity, but often leading to severe liver injury in treated mice or in patients during clinical trials. Interleukin-6 (IL-6) has been reported to protect hepatocyte death, but the role of IL-6 in protecting chronic T cell-induced liver diseases is not clearly defined due to lack of relevant animal models. We aimed to define the role of IL-6 in CD8+ T cell-mediated liver injury induced by a CD137 agonistic mAb (clone 2A) in mice. METHODS/PRINCIPAL FINDINGS We expressed IL-6 in the liver by hydrodynamic gene delivery in mice treated with 2A or control mAb and studied how IL-6 treatment affected host immunity and T cell-mediated liver injury. We found that ectopic IL-6 expression in the liver elevated intrahepatic leukocyte infiltration but prevented CD8+ T cell-mediated liver injury. In IL-6 treated mice, CD8+ T cells proliferation and IFN-γ expression were inhibited in the liver. We discovered that IL-6 increased accumulation of Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) in the liver and spleen. These MDSCs had the ability to inhibit T cells proliferation and activation. Finally, we showed that the MDSCs were sufficient and essential for IL-6-mediated protection of anti-CD137 mAb-induced liver injury. CONCLUSIONS/SIGNIFICANCE We concluded that IL-6 induced Gr-1+CD11b+ MDSCs in the liver to inhibit T cell-mediated liver injury. The findings have defined a novel mechanism of IL-6 in protecting liver from CD8+ T cell-mediated injury.
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Affiliation(s)
- Liang Cheng
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- Graduate University, Chinese Academy of Sciences, Beijing, China
| | - Jun Wang
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- Graduate University, Chinese Academy of Sciences, Beijing, China
| | - Xiaozhu Li
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Qiao Xing
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Peishuang Du
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Lishan Su
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- Department of Microbiology and Immunology, School of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- * E-mail: (LS); (SW)
| | - Shengdian Wang
- Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
- * E-mail: (LS); (SW)
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28
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Palazón A, Teijeira A, Martínez-Forero I, Hervás-Stubbs S, Roncal C, Peñuelas I, Dubrot J, Morales-Kastresana A, Pérez-Gracia JL, Ochoa MC, Ochoa-Callejero L, Martínez A, Luque A, Dinchuk J, Rouzaut A, Jure-Kunkel M, Melero I. Agonist anti-CD137 mAb act on tumor endothelial cells to enhance recruitment of activated T lymphocytes. Cancer Res 2011; 71:801-11. [PMID: 21266358 DOI: 10.1158/0008-5472.can-10-1733] [Citation(s) in RCA: 108] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Agonist monoclonal antibodies (mAb) to the immune costimulatory molecule CD137, also known as 4-1BB, are presently in clinical trials for cancer treatment on the basis of their costimulatory effects on primed T cells and perhaps other cells of the immune system. Here we provide evidence that CD137 is selectively expressed on the surface of tumor endothelial cells. Hypoxia upregulated CD137 on murine endothelial cells. Treatment of tumor-bearing immunocompromised Rag(-/-) mice with agonist CD137 mAb did not elicit any measurable antiangiogenic effects. In contrast, agonist mAb stimulated tumor endothelial cells, increasing cell surface expression of the adhesion molecules intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin. When adoptively transferred into mice, activated T lymphocytes derived from CD137-deficient animals entered more avidly into tumor tissue after treatment with agonist mAb. This effect could be neutralized with anti-ICAM-1 and anti-VCAM-1 blocking antibodies. Thus, stimulation of CD137 not only enhanced T-cell activation but also augmented their trafficking into malignant tissue, through direct actions on the blood vessels that irrigate the tumor. Our findings identify an additional mechanism of action that can explain the immunotherapeutic effects of agonist CD137 antibodies.
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Affiliation(s)
- Asís Palazón
- CIMA and CUN University of Navarra, Pamplona, Spain
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29
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Wang J, Zhao W, Cheng L, Guo M, Li D, Li X, Tan Y, Ma S, Li S, Yang Y, Chen L, Wang S. CD137-mediated pathogenesis from chronic hepatitis to hepatocellular carcinoma in hepatitis B virus-transgenic mice. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2010; 185:7654-62. [PMID: 21059892 PMCID: PMC3601909 DOI: 10.4049/jimmunol.1000927] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is characterized by sustained liver inflammation with an influx of lymphocytes, which contributes to the development of cirrhosis and hepatocellular carcinoma. The mechanisms underlying this immune-mediated hepatic pathogenesis remain ill defined. We report in this article that repetitive infusion of anti-CD137 agonist mAb in HBV-transgenic mice closely mimics this process by sequentially inducing hepatitis, fibrosis, cirrhosis, and, ultimately, liver cancer. CD137 mAb initially triggers hepatic inflammatory infiltration due to activation of nonspecific CD8(+) T cells with memory phenotype. CD8(+) T cell-derived IFN-γ plays a central role in the progression of chronic liver diseases by actively recruiting hepatic macrophages to produce fibrosis-promoting cytokines and chemokines, including TNF-α, IL-6, and MCP-1. Importantly, the natural ligand of CD137 was upregulated significantly in circulating CD14(+) monocytes in patients with chronic hepatitis B infection and closely correlated with development of liver cirrhosis. Thus, sustained CD137 stimulation may be a contributing factor for liver immunopathology in chronic HBV infection. Our studies reveal a common molecular pathway that is used to defend against viral infection but also causes chronic hepatic diseases.
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MESH Headings
- Animals
- Antibodies, Monoclonal/immunology
- Antibodies, Monoclonal/pharmacology
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- CD8-Positive T-Lymphocytes/pathology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Cytokines/genetics
- Cytokines/immunology
- Cytokines/metabolism
- Hepatitis B virus/genetics
- Hepatitis B virus/immunology
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/metabolism
- Humans
- Immunologic Memory/drug effects
- Immunologic Memory/genetics
- Immunologic Memory/immunology
- Lipopolysaccharide Receptors/genetics
- Lipopolysaccharide Receptors/immunology
- Lipopolysaccharide Receptors/metabolism
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/immunology
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/pathology
- Liver Neoplasms, Experimental/virology
- Mice
- Mice, Transgenic
- Monocytes/immunology
- Monocytes/metabolism
- Monocytes/pathology
- Tumor Necrosis Factor Receptor Superfamily, Member 9/agonists
- Tumor Necrosis Factor Receptor Superfamily, Member 9/biosynthesis
- Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology
- Tumor Necrosis Factor Receptor Superfamily, Member 9/metabolism
- Up-Regulation/drug effects
- Up-Regulation/genetics
- Up-Regulation/immunology
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Affiliation(s)
- Jun Wang
- Key Laboratory of Infection and Immunity, Institute of Biophysics, 301 General Hospital, Beijing
- Graduate University, Chinese Academy of Sciences, 301 General Hospital, Beijing
| | - Wenxia Zhao
- Department of Medicine, The First Affiliated Hospital, Henan College of Traditional Medicine, Zhengzhou, China
| | - Liang Cheng
- Key Laboratory of Infection and Immunity, Institute of Biophysics, 301 General Hospital, Beijing
- Graduate University, Chinese Academy of Sciences, 301 General Hospital, Beijing
| | - Mingzhou Guo
- Department of Gastroenterology and Hepatology, 301 General Hospital, Beijing
| | - Dongling Li
- Key Laboratory of Infection and Immunity, Institute of Biophysics, 301 General Hospital, Beijing
| | - Xiaozhu Li
- Key Laboratory of Infection and Immunity, Institute of Biophysics, 301 General Hospital, Beijing
| | - Yi Tan
- Key Laboratory of Infection and Immunity, Institute of Biophysics, 301 General Hospital, Beijing
- Graduate University, Chinese Academy of Sciences, 301 General Hospital, Beijing
| | - Suping Ma
- Department of Medicine, The First Affiliated Hospital, Henan College of Traditional Medicine, Zhengzhou, China
| | - Suyun Li
- Department of Medicine, The First Affiliated Hospital, Henan College of Traditional Medicine, Zhengzhou, China
| | - Yunsheng Yang
- Department of Gastroenterology and Hepatology, 301 General Hospital, Beijing
| | - Lieping Chen
- Key Laboratory of Infection and Immunity, Institute of Biophysics, 301 General Hospital, Beijing
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231
| | - Shengdian Wang
- Key Laboratory of Infection and Immunity, Institute of Biophysics, 301 General Hospital, Beijing
- Graduate University, Chinese Academy of Sciences, 301 General Hospital, Beijing
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30
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Pardee AD, Wesa AK, Storkus WJ. Integrating costimulatory agonists to optimize immune-based cancer therapies. Immunotherapy 2010; 1:249-64. [PMID: 20046961 DOI: 10.2217/1750743x.1.2.249] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
While immunotherapy for cancer has become increasingly popular, clinical benefits for such approaches remain limited. This is likely due to tumor-associated immune suppression, particularly in the advanced-disease setting. Thus, a major goal of novel immunotherapeutic design has become the coordinate reversal of existing immune dysfunction and promotion of specific tumoricidal T-cell function. Costimulatory members of the TNF-receptor family are important regulators of T-cell-mediated immunity. Notably, agonist ligation of these receptors restores potent antitumor immunity in the tumor-bearing host. Current Phase I/II evaluation of TNF-receptor agonists as single-modality therapies will illuminate their safety, mechanism(s) of action, and best use in prospective combinational immunotherapy approaches capable of yielding superior benefits to cancer patients.
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Affiliation(s)
- Angela D Pardee
- University of Pittsburgh School of Medicine, PA, Pittsburgh, USA
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31
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Dubrot J, Milheiro F, Alfaro C, Palazón A, Martinez-Forero I, Perez-Gracia JL, Morales-Kastresana A, Romero-Trevejo JL, Ochoa MC, Hervás-Stubbs S, Prieto J, Jure-Kunkel M, Chen L, Melero I. Treatment with anti-CD137 mAbs causes intense accumulations of liver T cells without selective antitumor immunotherapeutic effects in this organ. Cancer Immunol Immunother 2010; 59:1223-33. [PMID: 20336294 PMCID: PMC11030554 DOI: 10.1007/s00262-010-0846-9] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2009] [Accepted: 03/04/2010] [Indexed: 11/26/2022]
Abstract
BACKGROUND/AIMS Cancer therapy with agonist anti-CD137 mAbs has been shown to induce immune-mediated tumor rejections in mice, and equivalent agents of this kind are currently being tested in cancer patients. Previous reports indicated that CD137 stimulation induced polyclonal infiltrates of T lymphocytes in the liver. This study characterizes the liver infiltrates and the target dependency of the phenomena and addresses the question of whether tumors nested in the liver are a more favorable target for CD137-based immunotherapy. METHODS Liver infiltrates were studied with conventional histology and multiple color flow cytometry of total liver leukocytes. CD137(-/-) mice, mice with a single rearrangement of the TCR (OT-1 mice) and Rag(-/-) mice were used to clarify molecular requirements. Mice implanted with MC38 colon carcinomas either subcutaneously or inside the liver were used for comparative studies under treatment with agonist anti-CD137 mAbs. RESULTS CD137 treatment caused mononuclear inflammation in the portal spaces of the liver, which gave rise to moderate increases in transaminases without signs of cholestasis. Marked increases in the numbers of CD8+ T cells were observed, including CD8+ T lymphocytes co-expressing CD11c. Infiltrates were absent in CD137(-/-) mice and mitigated in mice harboring a single transgenic TCR on their CD8 T cells. Despite the tumor-independent accumulation of T cells in the liver, immunotherapeutic effects were not more prominent against tumors located in this organ. CONCLUSIONS Target-dependent effects of CD137 stimulation lead to liver infiltration with T cells, but lymphocyte enrichment in this organ does not privilege this site for immunotherapeutic effects against transplanted tumors.
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MESH Headings
- Amidinotransferases/immunology
- Amidinotransferases/metabolism
- Animals
- Antibodies, Monoclonal/administration & dosage
- CD8-Positive T-Lymphocytes/drug effects
- CD8-Positive T-Lymphocytes/immunology
- CD8-Positive T-Lymphocytes/metabolism
- CD8-Positive T-Lymphocytes/pathology
- Cell Count
- Cell Line, Tumor
- Cell Movement/drug effects
- Colonic Neoplasms/immunology
- Colonic Neoplasms/pathology
- Colonic Neoplasms/therapy
- Immunotherapy
- Liver/drug effects
- Liver/immunology
- Liver/metabolism
- Liver/pathology
- Lymphocytes, Tumor-Infiltrating/immunology
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Neoplasm Transplantation
- Organ Specificity
- Receptors, Antigen, T-Cell, alpha-beta/genetics
- Receptors, Antigen, T-Cell, alpha-beta/metabolism
- Tumor Necrosis Factor Receptor Superfamily, Member 9/genetics
- Tumor Necrosis Factor Receptor Superfamily, Member 9/immunology
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Affiliation(s)
- Juan Dubrot
- Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Av. Pio XII, 55, 31008 Pamplona, Spain
| | - Francisca Milheiro
- Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Av. Pio XII, 55, 31008 Pamplona, Spain
| | - Carlos Alfaro
- Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Av. Pio XII, 55, 31008 Pamplona, Spain
| | - Asis Palazón
- Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Av. Pio XII, 55, 31008 Pamplona, Spain
| | - Ivan Martinez-Forero
- Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Av. Pio XII, 55, 31008 Pamplona, Spain
| | | | - Aizea Morales-Kastresana
- Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Av. Pio XII, 55, 31008 Pamplona, Spain
| | - José L. Romero-Trevejo
- Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Av. Pio XII, 55, 31008 Pamplona, Spain
| | - María C. Ochoa
- Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Av. Pio XII, 55, 31008 Pamplona, Spain
| | - Sandra Hervás-Stubbs
- Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Av. Pio XII, 55, 31008 Pamplona, Spain
| | - Jesús Prieto
- Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Av. Pio XII, 55, 31008 Pamplona, Spain
- Clínica Universitaria, Universidad de Navarra, Pamplona, Spain
| | - Maria Jure-Kunkel
- Bristol Myers-Squibb Pharmaceutical Research Institute, Princeton, NJ USA
| | - Lieping Chen
- Sidney Kimmel Cancer Center, Johns Hopkins Medical School, Baltimore, MD USA
| | - Ignacio Melero
- Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Av. Pio XII, 55, 31008 Pamplona, Spain
- Clínica Universitaria, Universidad de Navarra, Pamplona, Spain
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32
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Regulation in chronic obstructive pulmonary disease: the role of regulatory T-cells and Th17 cells. Clin Sci (Lond) 2010; 119:75-86. [PMID: 20402669 DOI: 10.1042/cs20100033] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
COPD (chronic obstructive pulmonary disease) is an inflammatory disorder of the airways, which is associated with irreversible airway obstruction. The pathological hallmarks of COPD are destruction of the lung parenchyma (pulmonary emphysema), inflammation of the central airways (chronic bronchitis) and inflammation of the peripheral airways (respiratory bronchiolitis). Tobacco smoking is established as the main aetiological factor for COPD. A maladaptive modulation of inflammatory responses to inhalation of noxious particles and gases is generally accepted as being a key central pathogenic process; however, the precise regulatory mechanisms of the disease are poorly understood. Two cell types are known to be important in immune regulation, namely regulatory T-cells and the newly identified Th17 (T-helper 17) cells. Both types of cells are subsets of CD4 T-lymphocytes and modulate the immune response through secretion of cytokines, for example IL (interleukin)-10 and IL-17 respectively. The present review will begin by describing the current understanding of inflammatory cell involvement in the disease process, and then focus on the possible role of subsets of regulatory and helper T-cells in COPD.
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33
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Newcomb EW, Lukyanov Y, Kawashima N, Alonso-Basanta M, Wang SC, Liu M, Jure-Kunkel M, Zagzag D, Demaria S, Formenti SC. Radiotherapy enhances antitumor effect of anti-CD137 therapy in a mouse Glioma model. Radiat Res 2010; 173:426-32. [PMID: 20334514 PMCID: PMC3721320 DOI: 10.1667/rr1904.1] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Previously, we reported that peripheral vaccination of mice with modified autologous tumor cells secreting granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with ionizing radiation to the whole brain cured 50% of mice using a syngeneic, intracranial model of murine high-grade glioma. Here, we tested the combination of radiotherapy (4 Gy x 2) with an immunotherapeutic approach using an anti-CD137 antibody directed to the co-stimulatory molecule CD137. The CD137 antibody has shown promise in generating effective antitumor responses in several animal models and has demonstrated a favorable toxicity profile in the clinic. The combination of radiation and anti-CD137 therapy resulted in complete tumor eradication and prolonged survival in six of nine (67%) mice with established brain tumors (P = 0.0009). Five of six (83%) long-term survivors in the combination group demonstrated antitumor immunity by rejecting challenge tumors. Antitumor immunity was associated with an increased number of tumor-infiltrating lymphocytes (TILs) in brain tumors and increased tumor-specific production of gammaIFN. In view of the finding that radiation enhanced the antitumor effect of anti-CD137 therapy, this approach should be studied further for clinical translation.
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Affiliation(s)
- Elizabeth W Newcomb
- Departments of Pathology, New York University School of Medicine and NYU Cancer Institute and Langone Medical Center, New York, New York 10016, USA.
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Ménoret A, McAleer JP, Ngoi SM, Ray S, Eddy NA, Fenteany G, Lee SJ, Rossi RJ, Mukherji B, Allen DL, Chakraborty NG, Vella AT. The oxazolidinone derivative locostatin induces cytokine appeasement. THE JOURNAL OF IMMUNOLOGY 2009; 183:7489-96. [PMID: 19917702 DOI: 10.4049/jimmunol.0901414] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Damaging inflammation arising from autoimmune pathology and septic responses results in severe cases of disease. In both instances, anti-inflammatory compounds are used to limit the excessive or deregulated cytokine responses. We used a model of robust T cell stimulation to identify new proteins involved in triggering a cytokine storm. A comparative proteomic mining approach revealed the differential mapping of Raf kinase inhibitory protein after T cell recall in vivo. Treatment with locostatin, an Raf kinase inhibitory protein inhibitor, induced T cell anergy by blocking cytokine production after Ag recall. This was associated with a reduction in Erk phosphorylation. Importantly, in vivo treatment with locostatin profoundly inhibited TNF-alpha production upon triggering the Ag-specific T cells. This effect was not limited to a murine model because locostatin efficiently inhibited cytokine secretion by human lymphocytes. Therefore, locostatin should be a useful therapeutic to control inflammation, sepsis, and autoimmune diseases.
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Affiliation(s)
- Antoine Ménoret
- Department of Immunology, University of Connecticut Health Center, Farmington, CT 06032, USA
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35
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Wang C, Lin GHY, McPherson AJ, Watts TH. Immune regulation by 4-1BB and 4-1BBL: complexities and challenges. Immunol Rev 2009; 229:192-215. [PMID: 19426223 DOI: 10.1111/j.1600-065x.2009.00765.x] [Citation(s) in RCA: 238] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
SUMMARY The tumor necrosis factor receptor family member 4-1BB plays a key role in the survival of activated and memory CD8(+) T cells. Depending on the disease model, 4-1BB can participate at different stages and influence different aspects of the immune response, likely due to the differential expression of receptor and ligand relative to other costimulatory molecules. Studies comparing mild versus severe influenza infection of mice suggest that the immune system uses inducible receptors such as 4-1BB to prolong the immune response when pathogens take longer to clear. The expression of 4-1BB on diverse cell types, evidence for bidirectional as well as receptor-independent signaling by 4-1BBL, the unexpected hyperproliferation of 4-1BB-deficient T cells, and complex effects of agonistic anti-4-1BB therapy have revealed additional roles for the 4-1BB/4-1BBL receptor/ligand pair in the immune system. In this review, we discuss these diverse roles of 4-1BB and its ligand in the immune response, exploring possible mechanisms for the observed complexities and implications for therapeutic applications of 4-1BB/4-1BBL.
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Affiliation(s)
- Chao Wang
- Department of Immunology, University of Toronto, Toronto, ON, Canada
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36
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Sharma RK, Elpek KG, Yolcu ES, Schabowsky RH, Zhao H, Bandura-Morgan L, Shirwan H. Costimulation as a platform for the development of vaccines: a peptide-based vaccine containing a novel form of 4-1BB ligand eradicates established tumors. Cancer Res 2009; 69:4319-26. [PMID: 19435920 PMCID: PMC2755220 DOI: 10.1158/0008-5472.can-08-3141] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Vaccines represent an attractive treatment modality for the management of cancer primarily because of their specificity and generation of immunologic memory important for controlling recurrences. However, the efficacy of therapeutic vaccines may require formulations that not only generate effective immune responses but also overcome immune evasion mechanisms employed by progressing tumor. Costimulatory molecules play critical roles in modulating innate, adaptive, and regulatory immunity and have potential to serve as effective immunomodulatory components of therapeutic vaccines. In this study, we tested the function of a novel soluble form of 4-1BB ligand (4-1BBL) costimulatory molecule in modulating innate, adaptive, and regulatory immunity and assessed its therapeutic efficacy in the HPV-16 E7-expressing TC-1 cervical cancer and survivin-expressing 3LL lung carcinoma mouse models. Vaccination with 4-1BBL activated dendritic cells and enhanced antigen uptake, generated CD8(+) T-cell effector/memory responses, and endowed T effector cells refractory to suppression by CD4(+)CD25(+)FoxP3(+) T regulatory cells. Immunization with 4-1BBL in combination with an E7 peptide or survivin protein resulted in eradication of TC-1 and 3LL tumors, respectively. 4-1BBL was more effective than TLR agonists LPS, MPL, and CpG and an agonistic 4-1BB antibody as a component of E7 peptide-based therapeutic vaccine for the generation of immune responses and eradication of TC-1 established tumors in the absence of detectable toxicity. Therapeutic efficacy was associated with reversal of tumor-mediated nonresponsiveness/anergy as well as establishment of long-term CD8(+) T-cell memory. Potent pleiotropic immunomodulatory activities combined with lack of toxicity highlight the potential of 4-1BBL molecule as an effective component of therapeutic cancer vaccines.
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Affiliation(s)
- Rajesh K Sharma
- Institute for Cellular Therapeutics, Department of Microbiology and Immunology, and James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
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Matar P, Alaniz L, Rozados V, Aquino JB, Malvicini M, Atorrasagasti C, Gidekel M, Silva M, Scharovsky OG, Mazzolini G. Immunotherapy for liver tumors: present status and future prospects. J Biomed Sci 2009; 16:30. [PMID: 19272130 PMCID: PMC2662798 DOI: 10.1186/1423-0127-16-30] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2008] [Accepted: 03/06/2009] [Indexed: 12/22/2022] Open
Abstract
Increasing evidence suggests that immune responses are involved in the control of cancer and that the immune system can be manipulated in different ways to recognize and attack tumors. Progress in immune-based strategies has opened new therapeutic avenues using a number of techniques destined to eliminate malignant cells. In the present review, we overview current knowledge on the importance, successes and difficulties of immunotherapy in liver tumors, including preclinical data available in animal models and information from clinical trials carried out during the lasts years. This review shows that new options for the treatment of advanced liver tumors are urgently needed and that there is a ground for future advances in the field.
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Affiliation(s)
- Pablo Matar
- Institute of Experimental Genetics, School of Medical Sciences, National University of Rosario, Santa Fe 3100, (2000) Rosario, Argentina.
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Autoimmune destruction of skin melanocytes by perilesional T cells from vitiligo patients. J Invest Dermatol 2009; 129:2220-32. [PMID: 19242513 DOI: 10.1038/jid.2009.32] [Citation(s) in RCA: 357] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
In vitiligo, cytotoxic T cells infiltrating the perilesional margin are suspected to be involved in the pathogenesis of the disease. However, it remains to be elucidated whether these T cells are a cause or a consequence of the depigmentation process. T cells we obtained from perilesional skin biopsies, were significantly enriched for melanocyte antigen recognition, compared with healthy skin-infiltrating T cells, and were reactive to melanocyte antigen-specific stimulation. Using a skin explant model, we were able to dissect the in situ activities of perilesional T cells in the effector phase of depigmentation. We show that these T cells could infiltrate autologous normally pigmented skin explants and efficiently kill melanocytes within this microenvironment. Interestingly, melanocyte apoptosis was accompanied by suprabasal keratinocyte apoptosis. Perilesional T cells did, however, not induce apoptosis in lesional skin, which is devoid of melanocytes, indicating the melanocyte-specific cytotoxic activity of these cells. Melanocyte killing correlated to local infiltration of perilesional T cells. Our data show that perilesional cytotoxic T cells eradicate pigment cells, the characteristic hallmark of vitiligo, thereby providing evidence of T cells being able to mediate targeted autoimmune tissue destruction.
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Kim YH, Choi BK, Kang WJ, Kim KH, Kang SW, Mellor AL, Munn DH, Kwon BS. IFN-gamma-indoleamine-2,3 dioxygenase acts as a major suppressive factor in 4-1BB-mediated immune suppression in vivo. J Leukoc Biol 2009; 85:817-25. [PMID: 19218483 DOI: 10.1189/jlb.0408246] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
It has been reported that 4-1BB triggering in vivo selectively suppressed the recall response of staphylococcal enterotoxin A (SEA)-specific CD4(+) T cells, in which CD8(+) T-derived TGF-beta was involved. Here, we have examined an alternative mechanism for the 4-1BB-mediated CD4(+) T suppression, as the neutralization of TGF-beta is only effective in rescuing the SEA-specific recall response at high cellular concentrations. We show that this selective suppression of CD4(+) T cells by 4-1BB triggering in vivo is mediated mainly by induction of indoleamine 2,3-dioxygenase (IDO) in an IFN-gamma-dependent manner. SEA-specific CD4(+) T responses were suppressed partly by TGF-beta-expressing CD8(+) T cells, particularly CD11c(+)CD8(+) T cells, but strongly inhibited by dendritic cells (DCs) expressing IDO. IFN-gamma that increased IDO in DCs was produced primarily from CD11c(+)CD8(+) T cells, which were expanded selectively by 4-1BB stimulation. CD4(+), CD8(+), and plasmacytoid DCs exerted a similar suppressive activity toward the SEA-specific CD4(+) T cells. Neutralization of IFN-gamma or IDO activity in vivo largely reversed the 4-1BB-mediated CD4(+) T suppression. Collectively, these data indicate that 4-1BB-dependent suppression of SEA-specific CD4(+) T responses was mediated mainly by IFN-gamma-dependent IDO induction and partially by TGF-beta.
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Affiliation(s)
- Young H Kim
- Division of Cell and Immunobiology and R&D Center for Cancer Therapeutics, National Cancer Center, Kyonggi-do, Korea
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Murillo O, Arina A, Hervas-Stubbs S, Gupta A, McCluskey B, Dubrot J, Palazón A, Azpilikueta A, Ochoa MC, Alfaro C, Solano S, Pérez-Gracia JL, Oyajobi BO, Melero I. Therapeutic antitumor efficacy of anti-CD137 agonistic monoclonal antibody in mouse models of myeloma. Clin Cancer Res 2008; 14:6895-906. [PMID: 18980984 PMCID: PMC2583963 DOI: 10.1158/1078-0432.ccr-08-0285] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Eradication of post-treatment residual myeloma cells is needed to prevent relapses, and immunostimulatory monoclonal antibodies (mAb) such as anti-CD137, CTLA-4, CD40, etc., which enhance the immune response against malignancies, represent a means of achieving this purpose. This study explores anti-CD137 mAbs for multiple myeloma treatment in preclinical models of the disease because they safely augment tumor immunity and are in clinical trials for other cancers. EXPERIMENTAL DESIGN The antitumor effect of anti-CD137 mAb on mouse plasmacytomas derived from HOPC and NS0 cell lines was studied and compared with that of anti-CTLA-4, anti-CD40, and anti-ICAM-2 mAbs. The antitumor effect of anti-CD137 mAb was also examined in a mouse syngeneic disseminated myeloma (5TGM1) model, which more closely resembles human multiple myeloma. Depletions of specific cell populations and gene-targeted mice were used to unravel the requirements for tumor rejection. RESULTS Agonistic mAb against CD137 and blocking anti-CTLA-4 mAb showed activity against i.p. HOPC tumors, resulting in extended survival of mice that also became immune to rechallenge. Anti-CD137 mAbs induced complete eradications of established s.c. NS0-derived tumors that were dependent on IFN-gamma, natural killer cells, and CD8(+) T lymphocytes. Natural killer cells accumulated in tumor draining lymph nodes and showed increased IFN-gamma production. Antitumor efficacy of anti-CD137 mAb was preserved in CD28-deficient mice despite the fact that CD28 signaling increases the expression of CD137 on CD8(+) T cells. Importantly, anti-CD137 mAb treatment significantly decreased systemic tumor burden in the disseminated 5TGM1 model. CONCLUSIONS The immune-mediated antitumor activity of anti-CD137 mAb in mouse models holds promise for myeloma treatment in humans.
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Affiliation(s)
- Oihana Murillo
- Gene Therapy Unit. Centro de Investigación Médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Ainhoa Arina
- Gene Therapy Unit. Centro de Investigación Médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Sandra Hervas-Stubbs
- Gene Therapy Unit. Centro de Investigación Médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Anjana Gupta
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Brandon McCluskey
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Juan Dubrot
- Gene Therapy Unit. Centro de Investigación Médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Asís Palazón
- Gene Therapy Unit. Centro de Investigación Médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Arantza Azpilikueta
- Gene Therapy Unit. Centro de Investigación Médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Maria C. Ochoa
- Gene Therapy Unit. Centro de Investigación Médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Carlos Alfaro
- Gene Therapy Unit. Centro de Investigación Médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Sarai Solano
- Gene Therapy Unit. Centro de Investigación Médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | | | - Babatunde O. Oyajobi
- Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX
| | - Ignacio Melero
- Gene Therapy Unit. Centro de Investigación Médica aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
- Clinica Universitaria, Universidad de Navarra, Pamplona, Spain
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Abstract
T-cell activation and differentiation depend on the signal strength received by the T-cell receptor and on signals provided by co-stimulatory molecules. The most prominent co-stimulatory molecule is CD28, which controls the activation of naïve and memory T cells by antigen presented on professional antigen-presenting cells. Blocking of the CD28-CD80/86 pathway has been an appealing strategy for inducing tolerance in autoimmune diseases where the disease-inducing autoantigens are not known. Although CD28 has maintained its unique position, the past decade has witnessed the recognition that a large number of regulatory molecules on T cells must be stimulated to generate a fully protective immune response. These regulatory receptors differ in their preferential expression on T-cell subsets, in the ligands that they recognize, and in the signaling pathways that they trigger. They have in common the fact that they provide information on the cellular environment in which the T-cell response occurs. By intercepting these signals, we may be able to influence disease-relevant T-cell responses in autoimmune diseases while potentially minimizing broad immunosuppression.
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Affiliation(s)
- Jörg J Goronzy
- Kathleen B and Mason I Lowance Center for Human Immunology and Rheumatology, Emory University, Woodruff Circle, Atlanta, Georgia 30322, USA.
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Jiang D, Chen Y, Schwarz H. CD137 Induces Proliferation of Murine Hematopoietic Progenitor Cells and Differentiation to Macrophages. THE JOURNAL OF IMMUNOLOGY 2008; 181:3923-32. [DOI: 10.4049/jimmunol.181.6.3923] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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Induction of Proliferation and Monocytic Differentiation of Human CD34+Cells by CD137 Ligand Signaling. Stem Cells 2008; 26:2372-81. [DOI: 10.1634/stemcells.2008-0158] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Liu GZ, Gomes AC, Fang LB, Gao XG, Hjelmstrom P. Decreased 4-1BB expression on CD4+CD25 high regulatory T cells in peripheral blood of patients with multiple sclerosis. Clin Exp Immunol 2008; 154:22-9. [PMID: 18727631 DOI: 10.1111/j.1365-2249.2008.03730.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
As a tumour necrosis factor receptor superfamily member, 4-1BB (CD137) is preferentially expressed in CD4+CD25+ regulatory T cells (Tregs) and has been suggested to play an important role in regulating the generation or function of Tregs. Recent studies of human Tregs have shown that blood CD4+CD25(high) T cells were much closer to Tregs in terms of their functionality. Furthermore, CD4+CD25(high) Tregs have been found to have a decreased effector function in patients with multiple sclerosis (MS). In this study, we examined the expression of 4-1BB and soluble 4-1BB (s4-1BB) protein levels in the peripheral blood of MS patients. Compared with healthy controls, MS patients had decreased 4-1BB expression in their CD4+C25(high) Tregs and increased plasma s4-1BB protein levels. Moreover, the plasma s4-1BB levels of MS patients were shown to be inversely correlated with the 4-1BB surface expression of CD4+CD25(high) Tregs. The down-regulated 4-1BB expression on CD4+CD25(high) Tregs of MS patients may be involved in the impaired immunoactivity of these Tregs. The elevated s4-1BB levels may, at least in part, function as a self-regulatory attempt to inhibit antigen-driven proliferation of Tregs or their immunosuppressive activity.
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Affiliation(s)
- G-Z Liu
- Department of Neurology, Peking University People's Hospital, Beijing, China.
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Multi-layered action mechanisms of CD137 (4-1BB)-targeted immunotherapies. Trends Pharmacol Sci 2008; 29:383-90. [DOI: 10.1016/j.tips.2008.05.005] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2008] [Revised: 05/15/2008] [Accepted: 05/22/2008] [Indexed: 01/03/2023]
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Shao Z, Sun F, Koh DR, Schwarz H. Characterisation of soluble murine CD137 and its association with systemic lupus. Mol Immunol 2008; 45:3990-9. [PMID: 18640726 DOI: 10.1016/j.molimm.2008.05.028] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2008] [Revised: 05/21/2008] [Accepted: 05/25/2008] [Indexed: 12/20/2022]
Abstract
CD137 is a member of the tumor necrosis factor receptor family, and is involved in the regulation of activation, proliferation, differentiation and apoptosis of T cells, B cells, monocytes, dendritic cells, natural killer cells and granulocytes. Here report that soluble forms of murine CD137 (sCD137) are generated by differential splicing and are released by activated T cells. Levels of sCD137 correlate with cell activation and the extent of cell death but not with cellular proliferation. While CD8+ T cells express significantly more cell surface CD137 than CD4+ T cells, both T cell subsets express similar levels of sCD137, resulting a twofold increased ratio of soluble to cell surface CD137 for CD4+ T cells. sCD137 exists as a trimer and a higher order multimer, can bind to CD137 ligand, and inhibits secretion of IL-10 and IL-12. sCD137 is present in sera of mice with autoimmune disease but is undetectable in sera of healthy mice.
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Affiliation(s)
- Zhe Shao
- Department of Physiology, and Immunology Programme, Yong Loo Lin School of Medicine, Centre for Life Sciences, National University of Singapore, Singapore 117456, Singapore
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Immunosuppression routed via the kynurenine pathway: a biochemical and pathophysiologic approach. Adv Clin Chem 2008; 45:155-97. [PMID: 18429497 DOI: 10.1016/s0065-2423(07)00007-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
In the past years, it has been shown that kynurenines pathway is a regulator of both the innate and the adaptive immune responses. Particularly, the initial enzyme of this pathway, indoleamine 2,3-dioxygenase (IDO), is implicated in maintaining tolerance during pregnancy, and also can be expressed in tumors to avoid the immune attack. In this chapter, we will describe how the kynurenine pathway affects the immune system with important implications both in physiology and in pathology. The incorrect activation or blockade suppressive properties of the kynurenine pathway are also implicated in a number of other diseases such as AIDS or autoimmune diseases.
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McNamara JO, Kolonias D, Pastor F, Mittler RS, Chen L, Giangrande PH, Sullenger B, Gilboa E. Multivalent 4-1BB binding aptamers costimulate CD8+ T cells and inhibit tumor growth in mice. J Clin Invest 2008; 118:376-86. [PMID: 18060045 DOI: 10.1172/jci33365] [Citation(s) in RCA: 250] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2007] [Accepted: 10/29/2007] [Indexed: 12/14/2022] Open
Abstract
4-1BB is a major costimulatory receptor that promotes the survival and expansion of activated T cells. Administration of agonistic anti-4-1BB Abs has been previously shown to enhance tumor immunity in mice. Abs are cell-based products posing significant cost, manufacturing, and regulatory challenges. Aptamers are oligonucleotide-based ligands that exhibit specificity and avidity comparable to, or exceeding, that of Abs. To date, various aptamers have been shown to inhibit the function of their cognate target. Here, we have described the development of an aptamer that binds 4-1BB expressed on the surface of activated mouse T cells and shown that multivalent configurations of the aptamer costimulated T cell activation in vitro and mediated tumor rejection in mice. Because aptamers can be chemically synthesized, manufacturing and the regulatory approval process should be substantially simpler and less costly than for Abs. Agonistic aptamers could therefore represent a superior alternative to Abs for the therapeutic manipulation of the immune system.
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Affiliation(s)
- James O McNamara
- Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA
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49
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Bahrun U, Kimoto M, Tsukamoto H, Tsuneyoshi N, Kohara J, Fukudome K. Preparation and characterization of agonistic monoclonal antibodies against Toll-like receptor 4-MD-2 complex. Hybridoma (Larchmt) 2008; 26:393-9. [PMID: 18158784 DOI: 10.1089/hyb.2007.0523] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Ligands for toll-like receptors (TLR) are known to induce a variety of immune responses. Selective induction of desirable responses would be important for the treatment of individual diseases with various pathogenesis. For this purpose, we established six MAbs against the TLR4/MD-2 complex (UT MAbs) from TLR4(-/-) mice or MD-2(-/-) mice. Three MAbs (UT12, 18, and 22) induced NF-kappaB activation and production of pro-inflammatory cytokines, but the other three (UT15, 41, and 49) did not induce such cell responses. Unlike lipopolysaccharide (LPS), agonistic UT MAbs did not require serum components for the functions. UT41 and UT49 recognized TLR4 in the absence of MD-2. On the other hand, the other four MAbs reacted to the TLR4/MD-2 complex, but not to solo TLR4. Agonistic UT MAbs shared the epitopes, but non-agonistic UT15 reacted to distinct epitope on the complex. UT MAbs appear to be useful analyzing the molecular mechanism of TLR signaling and will contribute to the development of novel immunotherapies.
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Affiliation(s)
- Uleng Bahrun
- Department of Immunology, Saga Medical School, Saga, Japan
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50
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Kim DH, Chang WS, Lee YS, Lee KA, Kim YK, Kwon BS, Kang CY. 4-1BB Engagement Costimulates NKT Cell Activation and Exacerbates NKT Cell Ligand-Induced Airway Hyperresponsiveness and Inflammation. THE JOURNAL OF IMMUNOLOGY 2008; 180:2062-8. [DOI: 10.4049/jimmunol.180.4.2062] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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