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Gertel S, Rokach M, Polachek A, Levartovsky D, Broyde A, Furer V, Dovrat TO, Wollman J, Pel S, Neufeld Y, Elkayam O. Ex vivo cell-based assay for assessment of response to TNF inhibitors in patients with rheumatic diseases. Rheumatology (Oxford) 2025; 64:2233-2241. [PMID: 38796682 DOI: 10.1093/rheumatology/keae309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 05/08/2024] [Accepted: 05/15/2024] [Indexed: 05/28/2024] Open
Abstract
OBJECTIVE There are five TNF inhibitors (TNFis), whose structure and signalling differ. An individual patient with a rheumatic disease may respond to one TNFi but not to another. In addition, 30-40% of patients with rheumatic diseases may respond inadequately to TNFis. The downstream signalling of the various TNFis may determine their clinical efficacy. Several reports have shown that the different TNFis exhibited differential effects on Th17 cells. We analysed the effects of the various TNFis on IL-17A expression in peripheral blood mononuclear cells (PBMCs) of patients with rheumatic diseases, in order to evaluate the possibility of predicting responses in an ex vivo setting. METHODS PBMCs were co-cultured with the various TNFis or medium (control), and IL-17A mRNA levels were analysed by quantitative PCR. IL-17A expression levels in response to four TNFis (not including certolizumab pegol) were compared with that of the control. The IL-17A expression level as determined by the assay was correlated with the clinical response. The assay sensitivity and specificity for distinguishing responders from non-responders was calculated by receiver-operating characteristic (ROC) analysis. RESULTS The results of the assay for a retrospective cohort of patients with rheumatic diseases (n = 82) correlated with their therapeutic responses to the various TNFis with 89.5% accuracy. Our results indicated that the assay predicted the responses of a prospective cohort (n = 54) to specific TNFis with 79% accuracy. CONCLUSION This functional assay could assist in predicting the odds for response to TNFi therapy, indicating whether a given patient is likely to respond to a specific TNFi.
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Affiliation(s)
- Smadar Gertel
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - May Rokach
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ari Polachek
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - David Levartovsky
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Adi Broyde
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Victoria Furer
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tali Ofir Dovrat
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Jonathan Wollman
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Sara Pel
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yoram Neufeld
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ori Elkayam
- Department of Rheumatology, Tel Aviv Sourasky Medical Center, Affiliated with the Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Schnell A, Aicher C, Schnegelsberg PA, Schwarz B, Schmidt H, Allabauer I, Rueckel A, Regensburger AP, Woelfle J, Hoerning A. Exhausted Lag-3+ CD4+ T cells are increased in pediatric Inflammatory Bowel Disease. Clin Exp Immunol 2025; 219:uxae066. [PMID: 39044534 PMCID: PMC11771200 DOI: 10.1093/cei/uxae066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 06/17/2024] [Accepted: 07/22/2024] [Indexed: 07/25/2024] Open
Abstract
T cells are one of the main drivers of inflammatory bowel diseases (IBD). Infliximab (IFX) is used in the treatment of IBD as an anti-inflammatory drug to induce remission by neutralizing TNFα. We determined the individual chemokine/homing receptor and cytokine profile in pediatric IBD patients before and during IFX therapy to identify predictive biomarkers for therapy success. Peripheral blood CD4+ cells from pediatric patients with IBD were immunomagnetically isolated and either directly analyzed by FACS for cell distribution and chemokine/homing receptor expression or evaluated for cytokine production after in-vitro-stimulation. Twenty-one responders (RS) and 21 non-responders (NRS) were recruited. Before IFX therapy, flow cytometry revealed decreased percentages of naïve conventional T cells in pediatric IBD patients. The proportions of CD62-L+ T cells were decreased in both CD and UC therapy responders. The cytokine profile of T cells was highly altered in IBD patients compared to healthy controls (HC). During IFX therapy, the frequencies of conventional memory and regulatory memory T cells expanded in both cohorts. IFX response was marked by a decrease of α4β7+ and IFNγ+ memory T cells in both CD and UC. In contrast, frequencies of Lag-3+ T cells proved to be significantly increased in NRS. These observations were irrespective of the underlying disease. T cells of pediatric IBD patients display an activated and rather Th1/Th17-shifted phenotype. The increased expression of the checkpoint molecule Lag-3 on T cells of NRS resembles a more exhausted phenotype than in RS and HC which appeared to be a relevant predictive marker for therapy failure.
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Affiliation(s)
- Alexander Schnell
- Pediatric Gastroenterology, Hepatology and Endoscopy, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-UniversityErlangen-Nuremberg, Erlangen, Bavaria, Germany
| | - Carmen Aicher
- Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-UniversityErlangen-Nuremberg, Erlangen, Bavaria, Germany
| | - Philipp A Schnegelsberg
- Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-UniversityErlangen-Nuremberg, Erlangen, Bavaria, Germany
| | - Benedikt Schwarz
- Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-UniversityErlangen-Nuremberg, Erlangen, Bavaria, Germany
| | - Hannah Schmidt
- Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-UniversityErlangen-Nuremberg, Erlangen, Bavaria, Germany
| | - Ida Allabauer
- Pediatric Gastroenterology, Hepatology and Endoscopy, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-UniversityErlangen-Nuremberg, Erlangen, Bavaria, Germany
| | - Aline Rueckel
- Pediatric Gastroenterology, Hepatology and Endoscopy, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-UniversityErlangen-Nuremberg, Erlangen, Bavaria, Germany
| | - Adrian P Regensburger
- Pediatric Gastroenterology, Hepatology and Endoscopy, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-UniversityErlangen-Nuremberg, Erlangen, Bavaria, Germany
| | - Joachim Woelfle
- Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-UniversityErlangen-Nuremberg, Erlangen, Bavaria, Germany
| | - André Hoerning
- Pediatric Gastroenterology, Hepatology and Endoscopy, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, Friedrich-Alexander-UniversityErlangen-Nuremberg, Erlangen, Bavaria, Germany
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Pu D, Wang P, Wang X, Tian Y, Gong H, Ma X, Li M, Zhang D. Focusing on non-responders to infliximab with ulcerative colitis, what can we do first and next? Int Immunopharmacol 2024; 141:112943. [PMID: 39191122 DOI: 10.1016/j.intimp.2024.112943] [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: 05/20/2024] [Revised: 07/31/2024] [Accepted: 08/12/2024] [Indexed: 08/29/2024]
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic immune-mediated inflammation of the colorectum, for which infliximab (IFX) is currently the mainstay of treatment. However, one-third of patients with UC still fail to benefit from the IFX therapy, and early exposure to IFX impairs the efficacy of other subsequent biologics. Therefore, personalized therapeutic system is urgently needed to assist in clinical decision-making and precision treatment. METHODS Four microarray datasets of colonic biopsies from UC patients treated with IFX were obtained from the GEO database to form the Training Cohort and Validation Cohort. Differentially expressed genes (DEGs) in Training Cohort were identified and enriched for GO, KEGG and immune cell infiltration analysis. A prediction model for IFX efficacy was developed based on the LASSO and Logistic regression. The predictive accuracy of the model was verified by the Validation Cohort, and the model-genes/proteins were validated by immunohistochemistry. Gene-drug, gene-ncRNA interaction analysis were performed to identify drugs or non-coding RNAs (ncRNAs) that potentially interacted with the model-genes. Homology Modeling and Molecular Docking were conducted to filter the optimal candidate as the subsequent adjuvant or alternative for IFX in predicted non-responders. At last, the down-regulation of the key model-gene/protein CYP24A1 by the drug candidate Deferasirox was verified by Western Blot and qRT-PCR Assay based on cellular experiments. RESULTS A total of 113 DEGs were identified in the Training Cohort, mainly enriched in inflammatory cell chemotaxis, migration, and response to molecules derived from intestinal microbiota. Activated pro-inflammatory innate immune cells, including neutrophils, M1 macrophages, activated dendritic cells and mast cells, were significantly enriched in colons of non-responders. The prediction model based on three model-genes (IFI44L, CYP24A1, and RGS1) exhibited strong predictive efficacy, with AUC values of 0.901 and 0.80 in the Training and Validation Cohorts, respectively. Higher expression of the three model-genes/proteins in colons of non-responders to IFX was confirmed by clinical colonic mucosal biopsies. 4 Drugs (Calcitriol, Lunacalcipol, Deferasirox, Telaprevir), 15 miRNAs and 66 corresponding lnRNAs interacting with model-genes were identified. The protein 3D structure of the key model-gene/protein (human-derived CYP24A1) was developed. Through the Molecular Docking and cellular experimental validation, Deferasirox, which significantly down-regulated both the RNA and protein expression of CYP24A1, was identified as the optimal adjuvant or alternative for IFX in predicted non-responders with UC. CONCLUSION This study developed a novel prediction model for pre-assessing the efficacy of IFX in patients with UC, as the first step towards personalized therapy. Meanwhile, drugs and non-coding RNAs were provided as potential candidates to develop the next-step precise treatment for the predicted non-responders. In particular, Defeasirox appears to hold promise as an adjuvant or alternative to IFX for the optimization of UC therapy.
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Affiliation(s)
- Dan Pu
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China
| | - Pengfei Wang
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China
| | - Xiang Wang
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China
| | - Yonggang Tian
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China
| | - Hang Gong
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China
| | - Xueni Ma
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China
| | - Muyang Li
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China
| | - Dekui Zhang
- Department of Gastroenterology, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China; Key Laboratory of Digestive Diseases, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou City, Gansu Province, China.
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Yasmeen F, Pirzada RH, Ahmad B, Choi B, Choi S. Understanding Autoimmunity: Mechanisms, Predisposing Factors, and Cytokine Therapies. Int J Mol Sci 2024; 25:7666. [PMID: 39062908 PMCID: PMC11277571 DOI: 10.3390/ijms25147666] [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: 06/27/2024] [Revised: 07/05/2024] [Accepted: 07/06/2024] [Indexed: 07/28/2024] Open
Abstract
Autoimmunity refers to an organism's immune response against its own healthy cells, tissues, or components, potentially leading to irreversible damage to vital organs. Central and peripheral tolerance mechanisms play crucial roles in preventing autoimmunity by eliminating self-reactive T and B cells. The disruption of immunological tolerance, characterized by the failure of these mechanisms, results in the aberrant activation of autoreactive lymphocytes that target self-tissues, culminating in the pathogenesis of autoimmune disorders. Genetic predispositions, environmental exposures, and immunoregulatory disturbances synergistically contribute to the susceptibility and initiation of autoimmune pathologies. Within the realm of immune therapies for autoimmune diseases, cytokine therapies have emerged as a specialized strategy, targeting cytokine-mediated regulatory pathways to rectify immunological imbalances. Proinflammatory cytokines are key players in inducing and propagating autoimmune inflammation, highlighting the potential of cytokine therapies in managing autoimmune conditions. This review discusses the etiology of autoimmune diseases, current therapeutic approaches, and prospects for future drug design.
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Affiliation(s)
- Farzana Yasmeen
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; (F.Y.); (B.C.)
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, Republic of Korea
| | - Rameez Hassan Pirzada
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; (F.Y.); (B.C.)
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, Republic of Korea
| | - Bilal Ahmad
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, Republic of Korea
| | - Bogeum Choi
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; (F.Y.); (B.C.)
| | - Sangdun Choi
- Department of Molecular Science and Technology, Ajou University, Suwon 16499, Republic of Korea; (F.Y.); (B.C.)
- S&K Therapeutics, Ajou University Campus Plaza 418, Worldcup-ro 199, Yeongtong-gu, Suwon 16502, Republic of Korea
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Lu J, Lu Y. Paradoxical psoriasis: The flip side of idiopathic psoriasis or an autocephalous reversible drug reaction? J Transl Autoimmun 2023; 7:100211. [PMID: 37731549 PMCID: PMC10507642 DOI: 10.1016/j.jtauto.2023.100211] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/21/2023] [Accepted: 09/05/2023] [Indexed: 09/22/2023] Open
Abstract
Psoriasis is a common, chronic skin disease that results mainly from the complex interplay between T cells, dendritic cells, and inflammatory cytokines including TNF-α, IL-17, IL-12, and IL-23. Successful therapy with anti-cytokine antibodies has proved the importance of these key cytokines, especially TNF-α. During the anti-TNF-α treatment of classical idiopathic psoriasis, a small portion of patients develop new psoriasiform lesions. This contradictory phenomenon was named paradoxical psoriasis which resembles idiopathic psoriasis clinically but presents overlapped histological patterns and distinct immunological processes. In this review, we discuss the differences between idiopathic psoriasis and paradoxical psoriasis with an emphasis on their innate immunity, as it is predominant in paradoxical psoriasis which exhibits type I IFN-mediated immunity without the activation of autoreactive T cells and memory T cells. We also put up an instructive algorithm for the management of paradoxical psoriasis. The decision on drug discontinuation or switching of biologics should be made based on the condition of underlying diseases and the severity of lesions.
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Affiliation(s)
- Jiawei Lu
- Department of Dermatology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, PR China
| | - Yan Lu
- Department of Dermatology, The First Affiliated Hospital, Nanjing Medical University, Nanjing, PR China
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Vale N, Pereira M, Mendes RA. Systemic Inflammatory Disorders, Immunosuppressive Treatment and Increase Risk of Head and Neck Cancers-A Narrative Review of Potential Physiopathological and Biological Mechanisms. Cells 2023; 12:2192. [PMID: 37681925 PMCID: PMC10487135 DOI: 10.3390/cells12172192] [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: 07/22/2023] [Revised: 08/28/2023] [Accepted: 08/30/2023] [Indexed: 09/09/2023] Open
Abstract
Head and neck cancers (HNCs) are known to present multiple factors likely to influence their development. This review aims to provide a comprehensive overview of the current scientific literature on the interplay between systemic inflammatory disorders, immunosuppressive treatments and their synergistic effect on HNC risk. Both cell-mediated and humoral-mediated systemic inflammatory disorders involve dysregulated immune responses and chronic inflammation and these inflammatory conditions have been associated with an increased risk of HNC development, primarily in the head and neck region. Likewise, the interaction between systemic inflammatory disorders and immunosuppressive treatments appears to amplify the risk of HNC development, as chronic inflammation fosters a tumor-promoting microenvironment, while immunosuppressive therapies further compromise immune surveillance and anti-tumor immune responses. Understanding the molecular and cellular mechanisms underlying this interaction is crucial for developing targeted prevention strategies and therapeutic interventions. Additionally, the emerging field of immunotherapy provides potential avenues for managing HNCs associated with systemic inflammatory disorders, but further research is needed to determine its efficacy and safety in this specific context. Future studies are warranted to elucidate the underlying mechanisms and optimize preventive strategies and therapeutic interventions.
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Affiliation(s)
- Nuno Vale
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
| | - Mariana Pereira
- OncoPharma Research Group, Center for Health Technology and Services Research (CINTESIS), Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal;
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Rui Amaral Mendes
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Department of Community Medicine, Information and Health Decision Sciences (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
- Department of Oral and Maxillofacial Medicine and Diagnostic Sciences, Case Western Reserve University, 10900 Euclid Ave, Cleveland, OH 44106-7401, USA
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Jhun J, Moon J, Kwon JY, Cho KH, Lee SY, Na HS, Cho ML, Min JK. Small heterodimer partner interacting leucine zipper protein (SMILE) ameliorates autoimmune arthritis via AMPK signaling pathway and the regulation of B cell activation. Cell Commun Signal 2023; 21:98. [PMID: 37143079 PMCID: PMC10161652 DOI: 10.1186/s12964-023-01054-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Accepted: 01/16/2023] [Indexed: 05/06/2023] Open
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease that causes joint swelling and inflammation and can involve the entire body. RA is characterized by the increase of pro-inflammatory cytokines such as interleukin (IL) and tumor necrosis factor, and the over-activation of T lymphocytes and B lymphocytes, which may lead to severe chronic inflammation of joints. However, despite numerous studies the pathogenesis and treatment of RA remain unresolved. This study investigated the use of small heterodimer partner-interacting leucine zipper protein (SMILE) overexpression to treat a mouse model of RA. SMILE is an insulin-inducible corepressor through adenosine monophosphate-activated kinase (AMPK) signaling pathway. The injection of a SMILE overexpression vector to mice with collagen induced-arthritis resulted in a milder clinical pathology and a reduced incidence of arthritis, less joint tissue damage, and lower levels of Th17 cells and plasma B cells in the spleen. Immunohistochemistry of the joint tissue showed that SMILE decreased B-cell activating factor (BAFF) receptor (BAFF-R), mTOR, and STAT3 expression but increased AMPK expression. In SMILE-overexpressing transgenic mice with collagen antibody-induced arthritis (CAIA), a decrease in the arthritis score and reductions in tissue damage, the number of B cells, and antibody production were observed. The treatment of immune cells in vitro with curcumin, a known SMILE-inducing agent, led to decreases in plasma B cells, germinal center B cells, IL-17-producing B cells, and BAFF-R-positive B cells. Taken together, our findings demonstrate the therapeutic potential of SMILE in RA, based on its inhibition of B cell activation mediated by the AMPK/mTOR and STAT3 signaling pathway and BAFF-R expression. Video abstract.
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Affiliation(s)
- JooYeon Jhun
- Rheumatism Research Center, College of Medicine, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, 06591, Korea
- Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, 222, Banpo-Daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Jeonghyeon Moon
- Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, 06511, CT, USA
| | - Ji Ye Kwon
- Rheumatism Research Center, College of Medicine, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, 06591, Korea
| | - Keun-Hyung Cho
- Rheumatism Research Center, College of Medicine, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, 06591, Korea
- Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, 222, Banpo-Daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Seang Yoon Lee
- Rheumatism Research Center, College of Medicine, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, 06591, Korea
- Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, 222, Banpo-Daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Hyun Sik Na
- Rheumatism Research Center, College of Medicine, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, 06591, Korea
- Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea
- Department of Biomedicine and Health Sciences, College of Medicine, The Catholic University of Korea, 222, Banpo-Daero, Seocho-gu, Seoul, 06591, Republic of Korea
| | - Mi-La Cho
- Rheumatism Research Center, College of Medicine, Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, 06591, Korea.
- Lab of Translational ImmunoMedicine, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Korea.
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.
| | - Jun-Ki Min
- Department of Internal Medicine, The Clinical Medicine Research Institute of Bucheon St. Mary's Hospital, Bucheon-si, South Korea.
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De Stefano L, Pallavicini FB, Mauric E, Piccin V, Vismara EM, Montecucco C, Bugatti S. Tumor necrosis factor-α inhibitor-related immune disorders. Autoimmun Rev 2023; 22:103332. [PMID: 37062440 DOI: 10.1016/j.autrev.2023.103332] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 04/13/2023] [Indexed: 04/18/2023]
Abstract
Biotechnological monoclonal antibodies and receptor antagonists capable of targeting specific inflammatory actors, such as cytokines, cytokines receptors, co-stimulatory molecules or leukocyte populations, have emerged as an alternative to conventional therapies for treating systemic inflammatory diseases with immune pathogenesis. However, there is no doubt that, with a frequency that is not exceptionally high but also not negligible, immunotherapies can favour the development of systemic and organ-specific immune-mediated disorders. It has become increasingly evident that interference with a specific immune pathway may favour the activation of opposing compensatory signalling, which may exacerbate underlying subclinical disorders or cause immune-mediated diseases completely different from the underlying disease. The 'compensatory immunological switch' has emerged primarily in patients treated with tumor necrosis factor (TNF) -α inhibitors, the first biological drugs approved for treating systemic inflammatory diseases with immune pathogenesis. In this Review, we describe the clinical features and predisposing factors of the main TNF-α inhibitor-related immune disorders, organising them into subclinical serological autoimmunity, autoimmune disorders other than those for which TNF-α inhibitors are indicated, and paradoxical reactions. We also discuss the underlying pathogenetic mechanisms and precautions for use in the therapeutic management of these patients. Better understanding of the complex phenomenon of the 'compensatory immunological switch', which TNF-α inhibitors and other biological drugs might trigger, can help not only appropriately managing immune-mediated disorders, but also better interpreting the heterogeneity of the pathogenetic mechanisms underlying certain chronic inflammatory conditions that, although different from each other, are arbitrarily placed in the context of overly generic nosological entities.
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Affiliation(s)
- Ludovico De Stefano
- Department of Internal Medicine and Therapeutics, Università di Pavia, Italy; Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.
| | | | - Eleonora Mauric
- Department of Internal Medicine and Therapeutics, Università di Pavia, Italy; Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Veronica Piccin
- Department of Internal Medicine and Therapeutics, Università di Pavia, Italy; Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Enrico Maria Vismara
- Department of Internal Medicine and Therapeutics, Università di Pavia, Italy; Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Carlomaurizio Montecucco
- Department of Internal Medicine and Therapeutics, Università di Pavia, Italy; Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Serena Bugatti
- Department of Internal Medicine and Therapeutics, Università di Pavia, Italy; Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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Wang J, Conlon D, Rivellese F, Nerviani A, Lewis MJ, Housley W, Levesque MC, Cao X, Cuff C, Long A, Pitzalis C, Ruzek MC. Synovial Inflammatory Pathways Characterize Anti-TNF-Responsive Rheumatoid Arthritis Patients. Arthritis Rheumatol 2022; 74:1916-1927. [PMID: 35854416 DOI: 10.1002/art.42295] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 05/16/2022] [Accepted: 06/30/2022] [Indexed: 11/06/2022]
Abstract
OBJECTIVE This study was undertaken to understand the mechanistic basis of response to anti-tumor necrosis factor (anti-TNF) therapies and to determine whether transcriptomic changes in the synovium are reflected in peripheral protein markers. METHODS Synovial tissue from 46 rheumatoid arthritis (RA) patients was profiled with RNA sequencing before and 12 weeks after treatment with anti-TNF therapies. Pathway and gene signature analyses were performed on RNA expression profiles of synovial biopsies to identify mechanisms that could discriminate among patients with a good response, a moderate response, or no response, according to the American College of Rheumatology (ACR)/EULAR response criteria. Serum proteins encoded by synovial genes that were differentially expressed between ACR/EULAR response groups were measured in the same patients. RESULTS Gene signatures predicted which patients would have good responses, and pathway analysis identified elevated immune pathways, including chemokine signaling, Th1/Th2 cell differentiation, and Toll-like receptor signaling, uniquely in good responders. These inflammatory pathways were correspondingly down-modulated by anti-TNF therapy only in good responders. Based on cell signature analysis, lymphocyte, myeloid, and fibroblast cell populations were elevated in good responders relative to nonresponders, consistent with the increased inflammatory pathways. Cell signatures that decreased following anti-TNF treatment were predominately associated with lymphocytes, and fewer were associated with myeloid and fibroblast populations. Following anti-TNF treatment, and only in good responders, several peripheral inflammatory proteins decreased in a manner that was consistent with corresponding synovial gene changes. CONCLUSION Collectively, these data suggest that RA patients with robust responses to anti-TNF therapies are characterized at baseline by immune pathway activation, which decreases following anti-TNF treatment. Understanding mechanisms that define patient responsiveness to anti-TNF treatment may assist in development of predictive markers of patient response and earlier treatment options.
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Affiliation(s)
- Jing Wang
- Immunology Systems Computational Biology, Genomic Research Center, AbbVie, Cambridge, Massachusetts
| | - Donna Conlon
- Immunology Discovery, AbbVie Research Center, Worcester, Massachusetts
| | - Felice Rivellese
- Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Alessandra Nerviani
- Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Myles J Lewis
- Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - William Housley
- Immunology Discovery, AbbVie Research Center, Worcester, Massachusetts
| | - Marc C Levesque
- Immunology Discovery, Cambridge Research Center, Cambridge, Massachusetts
| | - Xiaohong Cao
- Immunology Systems Computational Biology, Genomic Research Center, AbbVie, Cambridge, Massachusetts
| | - Carolyn Cuff
- Immunology Discovery, AbbVie Research Center, Worcester, Massachusetts
| | - Andrew Long
- Immunology Discovery, AbbVie Research Center, Worcester, Massachusetts
| | - Costantino Pitzalis
- Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute and Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Melanie C Ruzek
- Immunology Discovery, AbbVie Research Center, Worcester, Massachusetts
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10
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Roodenrijs NMT, Welsing PMJ, van Roon J, Schoneveld JLM, van der Goes MC, Nagy G, Townsend MJ, van Laar JM. Mechanisms underlying DMARD inefficacy in difficult-to-treat rheumatoid arthritis: a narrative review with systematic literature search. Rheumatology (Oxford) 2022; 61:3552-3566. [PMID: 35238332 PMCID: PMC9434144 DOI: 10.1093/rheumatology/keac114] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/07/2022] [Accepted: 02/14/2022] [Indexed: 12/03/2022] Open
Abstract
Management of RA patients has significantly improved over the past decades. However, a substantial proportion of patients is difficult-to-treat (D2T), remaining symptomatic after failing biological and/or targeted synthetic DMARDs. Multiple factors can contribute to D2T RA, including treatment non-adherence, comorbidities and co-existing mimicking diseases (e.g. fibromyalgia). Additionally, currently available biological and/or targeted synthetic DMARDs may be truly ineffective ('true' refractory RA) and/or lead to unacceptable side effects. In this narrative review based on a systematic literature search, an overview of underlying (immune) mechanisms is presented. Potential scenarios are discussed including the influence of different levels of gene expression and clinical characteristics. Although the exact underlying mechanisms remain largely unknown, the heterogeneity between individual patients supports the assumption that D2T RA is a syndrome involving different pathogenic mechanisms.
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Affiliation(s)
- Nadia M T Roodenrijs
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht
| | - Paco M J Welsing
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht
| | - Joël van Roon
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht
| | | | - Marlies C van der Goes
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht
- Department of Rheumatology, Meander Medical Center, Amersfoort, The Netherlands
| | - György Nagy
- Department of Rheumatology & Clinical Immunology
- Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary
| | - Michael J Townsend
- Biomarker Discovery OMNI, Genentech Research & Early Development, South San Francisco, CA, USA
| | - Jacob M van Laar
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht
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11
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Gene Ontology Analysis Highlights Biological Processes Influencing Non-Response to Anti-TNF Therapy in Rheumatoid Arthritis. Biomedicines 2022; 10:biomedicines10081808. [PMID: 36009355 PMCID: PMC9404936 DOI: 10.3390/biomedicines10081808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 07/22/2022] [Accepted: 07/26/2022] [Indexed: 11/20/2022] Open
Abstract
Anti-TNF therapy has significantly improved disease control in rheumatoid arthritis, but a fraction of rheumatoid arthritis patients do not respond to anti-TNF therapy or lose response over time. Moreover, the mechanisms underlying non-response to anti-TNF therapy remain largely unknown. To date, many single biomarkers of response to anti-TNF therapy have been published but they have not yet been analyzed as a system of interacting nodes. The aim of our study is to systematically elucidate the biological processes underlying non-response to anti-TNF therapy in rheumatoid arthritis using the gene ontologies of previously published predictive biomarkers. Gene networks were constructed based on published biomarkers and then enriched gene ontology terms were elucidated in subgroups using gene ontology software tools. Our results highlight the novel role of proteasome-mediated protein catabolic processes (p = 2.91 × 10−15) and plasma lipoproteins (p = 4.55 × 10−11) in anti-TNF therapy response. The results of our gene ontology analysis help elucidate the biological processes underlying non-response to anti-TNF therapy in rheumatoid arthritis and encourage further study of the highlighted processes.
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12
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Pharmacogenomics of Anti-TNF Treatment Response Marks a New Era of Tailored Rheumatoid Arthritis Therapy. Int J Mol Sci 2022; 23:ijms23042366. [PMID: 35216481 PMCID: PMC8879844 DOI: 10.3390/ijms23042366] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 02/19/2022] [Accepted: 02/19/2022] [Indexed: 12/12/2022] Open
Abstract
Rheumatoid arthritis (RA) is the most commonly occurring chronic inflammatory arthritis, the exact mechanism of which is not fully understood. Tumor Necrosis Factor (TNF)-targeting drugs has been shown to exert high effectiveness for RA, which indicates the key importance of this cytokine in this disease. Nevertheless, the response to TNF inhibitors varies, and approximately one third of RA patients are non-responders, which is explained by the influence of genetic factors. Knowledge in the field of pharmacogenomics of anti-TNF drugs is growing, but has not been applied in the clinical practice so far. Different genome-wide association studies identified a few single nucleotide polymorphisms associated with anti-TNF treatment response, which largely map genes involved in T cell function. Studies of the gene expression profile of RA patients have also indicated specific gene signatures that may be useful to develop novel prognostic tools. In this article, we discuss the significance of TNF in RA and present the current knowledge in pharmacogenomics related to anti-TNF treatment response.
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13
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Jung SM, Kim WU. Targeted Immunotherapy for Autoimmune Disease. Immune Netw 2022; 22:e9. [PMID: 35291650 PMCID: PMC8901705 DOI: 10.4110/in.2022.22.e9] [Citation(s) in RCA: 83] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/09/2022] [Accepted: 02/10/2022] [Indexed: 12/04/2022] Open
Abstract
In the past few decades, biological drugs and small molecule inhibitors targeting inflammatory cytokines, immune cells, and intracellular kinases have become the standard-of-care to treat autoimmune diseases. Inhibition of TNF, IL-6, IL-17, and IL-23 has revolutionized the treatment of autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis. B cell depletion therapy using anti-CD20 mAbs has shown promising results in patients with neuroinflammatory diseases, and inhibition of B cell survival factors is approved for treatment of systemic lupus erythematosus. Targeting co-stimulatory molecules expressed on Ag-presenting cells and T cells is also expected to have therapeutic potential in autoimmune diseases by modulating T cell function. Recently, small molecule kinase inhibitors targeting the JAK family, which is responsible for signal transduction from multiple receptors, have garnered great interest in the field of autoimmune and hematologic diseases. However, there are still unmet medical needs in terms of therapeutic efficacy and safety profiles. Emerging therapies aim to induce immune tolerance without compromising immune function, using advanced molecular engineering techniques.
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Affiliation(s)
- Seung Min Jung
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
| | - Wan-Uk Kim
- Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea
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14
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Insights into the biology and therapeutic implications of TNF and regulatory T cells. Nat Rev Rheumatol 2021; 17:487-504. [PMID: 34226727 DOI: 10.1038/s41584-021-00639-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2021] [Indexed: 02/06/2023]
Abstract
Treatments that block tumour necrosis factor (TNF) have major beneficial effects in several autoimmune and rheumatic diseases, including rheumatoid arthritis. However, some patients do not respond to TNF inhibitor treatment and rare occurrences of paradoxical disease exacerbation have been reported. These limitations on the clinical efficacy of TNF inhibitors can be explained by the differences between TNF receptor 1 (TNFR1) and TNFR2 signalling and by the diverse effects of TNF on multiple immune cells, including FOXP3+ regulatory T cells. This basic knowledge sheds light on the consequences of TNF inhibitor therapies on regulatory T cells in treated patients and on the limitations of such treatment in the control of diseases with an autoimmune component. Accordingly, the next generation of drugs targeting TNF is likely to be based on agents that selectively block the binding of TNF to TNFR1 and on TNFR2 agonists. These approaches could improve the treatment of rheumatic diseases in the future.
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15
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TLR expression profiles are a function of disease status in rheumatoid arthritis and experimental arthritis. J Autoimmun 2021; 118:102597. [PMID: 33493980 DOI: 10.1016/j.jaut.2021.102597] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/21/2020] [Accepted: 01/07/2021] [Indexed: 11/23/2022]
Abstract
The role of the innate immune system has been established in the initiation and perpetuation of inflammatory disease, but less attention has been paid to its role in the resolution of inflammation and return to homeostasis. Toll-like receptor (TLR) expression profiles were analysed in tissues with differing disease status in rheumatoid arthritis (RA), ankylosing spondylitis (AS), and in experimental arthritis. TLR gene expression was measured in whole blood and monocytes, before and after TNF blockade. In RA and osteoarthritis synovia, the expression of TLRs was quantified by standard curve qPCR. In addition, four distinct stages of disease were defined and validated in collagen-induced arthritis (CIA), the gold standard animal model for RA - pre-onset, early disease, late disease and immunised mice that were resistant to the development of disease. TLR expression was measured in spleens, lymph nodes, blood cells, liver and the paws (inflamed and unaffected). In RA whole blood, the expression of TLR1, 4 and 6 was significantly reduced by TNF blockade but the differences in TLR expression profiles between responders and non-responders were less pronounced than the differences between RA and AS patients. In RA non-responders, monocytes had greater TLR2 expression prior to therapy compared to responders. The expression of TLR1, 2, 4 and 8 was higher in RA synovium compared to control OA synovium. Circulating cytokine levels in CIA resistant mice were similar to naïve mice, but anti-collagen antibodies were similar to arthritic mice. Distinct profiles of inflammatory gene expression were mapped in paws and organs with differing disease status. TLR expression in arthritic paws tended to be similar in early and late disease, with TLR1 and 2 moderately higher in late disease. TLR expression in unaffected paws varied according to gene and disease status but was generally lower in resistant paws. Disease status-specific profiles of TLR expression were observed in spleens, lymph nodes, blood cells and the liver. Notably, TLR2 expression rose then fell in the transition from naïve to pre-onset to early arthritis. TLR gene expression profiles are strongly associated with disease status. In particular, increased expression in the blood precedes clinical manifestation.
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16
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Montfort A, Filleron T, Virazels M, Dufau C, Milhès J, Pagès C, Olivier P, Ayyoub M, Mounier M, Lusque A, Brayer S, Delord JP, Andrieu-Abadie N, Levade T, Colacios C, Ségui B, Meyer N. Combining Nivolumab and Ipilimumab with Infliximab or Certolizumab in Patients with Advanced Melanoma: First Results of a Phase Ib Clinical Trial. Clin Cancer Res 2020; 27:1037-1047. [PMID: 33272982 DOI: 10.1158/1078-0432.ccr-20-3449] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 10/27/2020] [Accepted: 11/30/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE TNF blockers can be used to manage gastrointestinal inflammatory side effects following nivolumab and/or ipilimumab treatment in patients with advanced melanoma. Our preclinical data showed that anti-TNF could promote the efficacy of immune checkpoint inhibitors. PATIENTS AND METHODS TICIMEL (NTC03293784) is an open-label, two-arm phase Ib clinical trial. Fourteen patients with advanced and/or metastatic melanoma (stage IIIc/IV) were enrolled. Patients were treated with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) combined to infliximab (5 mg/kg, N = 6) or certolizumab (400/200 mg, N = 8). The primary endpoint was safety and the secondary endpoint was antitumor activity. Adverse events (AEs) were graded according to the NCI Common Terminology Criteria for Adverse Events and response was assessed following RECIST 1.1. RESULTS Only one dose-limiting toxicity was observed in the infliximab cohort. The two different combinations were found to be safe. We observed lower treatment-related AEs with infliximab as compared with certolizumab. In the certolizumab cohort, one patient was not evaluable for response. In this cohort, four of eight patients exhibited hepatobiliary disorders and seven of seven evaluable patients achieved objective response including four complete responses (CRs) and three partial responses (PRs). In the infliximab cohort, we observed one CR, two PRs, and three progressive diseases. Signs of activation and maturation of systemic T-cell responses were seen in patients from both cohorts. CONCLUSIONS Our results show that both combinations are safe in human and provide clinical and biological activities. The high response rate in the certolizumab-treated patient cohort deserves further investigations.
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Affiliation(s)
- Anne Montfort
- INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France
- Equipe Labellisée Fondation ARC pour la recherche sur le cancer, Toulouse, France
| | - Thomas Filleron
- Methodology, biostatistics and clinical operations, Institut Claudius Regaud, IUCT-O, Toulouse, France
- Institut Universitaire du Cancer (IUCT-O), Toulouse, France
| | - Mathieu Virazels
- INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France
- Equipe Labellisée Fondation ARC pour la recherche sur le cancer, Toulouse, France
| | - Carine Dufau
- INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France
- Equipe Labellisée Fondation ARC pour la recherche sur le cancer, Toulouse, France
- Université Toulouse III - Paul Sabatier, Toulouse, France
| | - Jean Milhès
- INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France
- Equipe Labellisée Fondation ARC pour la recherche sur le cancer, Toulouse, France
| | - Cécile Pagès
- Institut Universitaire du Cancer (IUCT-O), Toulouse, France
- Service d'Oncodermatologie, IUCT-O, CHU de Toulouse, Toulouse, France
| | - Pascale Olivier
- Service de Pharmacologie médicale et clinique, Centre Régional de Pharmacovigilance, de Pharmacoépidémiologie et d'information sur le médicament du CHU de Toulouse, Toulouse, France
| | - Maha Ayyoub
- INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France
- Institut Universitaire du Cancer (IUCT-O), Toulouse, France
- Université Toulouse III - Paul Sabatier, Toulouse, France
| | - Muriel Mounier
- Methodology, biostatistics and clinical operations, Institut Claudius Regaud, IUCT-O, Toulouse, France
- Institut Universitaire du Cancer (IUCT-O), Toulouse, France
| | - Amélie Lusque
- Methodology, biostatistics and clinical operations, Institut Claudius Regaud, IUCT-O, Toulouse, France
- Institut Universitaire du Cancer (IUCT-O), Toulouse, France
| | - Stéphanie Brayer
- INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France
- Equipe Labellisée Fondation ARC pour la recherche sur le cancer, Toulouse, France
- Service d'Oncodermatologie, IUCT-O, CHU de Toulouse, Toulouse, France
| | - Jean-Pierre Delord
- INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France
- Institut Universitaire du Cancer (IUCT-O), Toulouse, France
- Université Toulouse III - Paul Sabatier, Toulouse, France
| | - Nathalie Andrieu-Abadie
- INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France
- Equipe Labellisée Fondation ARC pour la recherche sur le cancer, Toulouse, France
| | - Thierry Levade
- INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France
- Equipe Labellisée Fondation ARC pour la recherche sur le cancer, Toulouse, France
- Université Toulouse III - Paul Sabatier, Toulouse, France
- Laboratoire de Biochimie, Institut Fédératif de Biologie, CHU Purpan, Toulouse, France
| | - Céline Colacios
- INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France
- Equipe Labellisée Fondation ARC pour la recherche sur le cancer, Toulouse, France
- Université Toulouse III - Paul Sabatier, Toulouse, France
| | - Bruno Ségui
- INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France.
- Equipe Labellisée Fondation ARC pour la recherche sur le cancer, Toulouse, France
- Université Toulouse III - Paul Sabatier, Toulouse, France
| | - Nicolas Meyer
- INSERM UMR 1037, Cancer Research Center of Toulouse (CRCT), Toulouse, France.
- Equipe Labellisée Fondation ARC pour la recherche sur le cancer, Toulouse, France
- Institut Universitaire du Cancer (IUCT-O), Toulouse, France
- Université Toulouse III - Paul Sabatier, Toulouse, France
- Service d'Oncodermatologie, IUCT-O, CHU de Toulouse, Toulouse, France
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Drug-resistance in rheumatoid arthritis: the role of p53 gene mutations, ABC family transporters and personal factors. Curr Opin Pharmacol 2020; 54:59-71. [PMID: 32942096 DOI: 10.1016/j.coph.2020.08.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 12/15/2022]
Abstract
Rheumatoid arthritis (RA) is an autoimmune disease that is associated with chronic inflammation in joints, which contribute to synovial membrane hyperplasia and cartilage damage. Conventional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX) and leflunomide (LEF), are the common RA therapy to reduce inflammation and disease progression. Recently, drug-resistance in RA with conventional treatment has become an issue. Mutations in p53 tumor suppressor gene and overexpression of ABCB1/MDR-1/P-gp transporters may contribute to antirheumatic drug-resistance in RA. Biologic DMARDs (bDMARDs) are often prescribed, when conventional DMARDs fail to treat RA, by targeting proinflammatory mediators such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6. The efficacy of bDMARDs is affected by personal factors, for example, age, smoking, body mass index (BMI), immunogenicity, and genetic polymorphisms. This review highlights the role of p53 gene mutations, ABC family transporters and personal factors in antirheumatic drug-resistance, which may lead to new personalized therapies against RA with an increased drug-sensitivity.
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Talotta R, Atzeni F, Laska MJ. Therapeutic peptides for the treatment of systemic lupus erythematosus: a place in therapy. Expert Opin Investig Drugs 2020; 29:845-867. [PMID: 32500750 DOI: 10.1080/13543784.2020.1777983] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Studies in vitro and in vivo have identified several peptides that are potentially useful in treating systemic lupus erythematosus (SLE). The rationale for their use lies in the cost-effective production, high potency, target selectivity, low toxicity, and a peculiar mechanism of action that is mainly based on the induction of immune tolerance. Three therapeutic peptides have entered clinical development, but they have yielded disappointing results. However, some subsets of patients, such as those with the positivity of anti-dsDNA antibodies, appear more likely to respond to these medications. AREAS COVERED This review evaluates the potential use of therapeutic peptides for SLE and gives an opinion on how they may offer advantages for SLE treatment. EXPERT OPINION Given their acceptable safety profile, therapeutic peptides could be added to agents traditionally used to treat SLE and this may offer a synergistic and drug-sparing effect, especially in selected patient populations. Moreover, they could temporarily be utilized to manage SLE flares, or be administered as a vaccine in subjects at risk. Efforts to ameliorate bioavailability, increase the half-life and prevent immunogenicity are ongoing. The formulation of hybrid compounds, like peptibodies or peptidomimetic small molecules, is expected to yield renewed treatments with a better pharmacologic profile and increased efficacy.
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Affiliation(s)
- Rossella Talotta
- Department of Clinical and Experimental Medicine, Rheumatology Unit, Azienda Ospedaliera "Gaetano Martino", University of Messina , Messina, Italy
| | - Fabiola Atzeni
- Department of Clinical and Experimental Medicine, Rheumatology Unit, Azienda Ospedaliera "Gaetano Martino", University of Messina , Messina, Italy
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de Wolf ACMT, Herberts CA, Hoefnagel MHN. Dawn of Monitoring Regulatory T Cells in (Pre-)clinical Studies: Their Relevance Is Slowly Recognised. Front Med (Lausanne) 2020; 7:91. [PMID: 32300597 PMCID: PMC7142310 DOI: 10.3389/fmed.2020.00091] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 03/03/2020] [Indexed: 12/14/2022] Open
Abstract
Regulatory T cells (Tregs) have a prominent role in the control of immune homeostasis. Pharmacological impact on their activity or balance with effector T cells could contribute to (impaired) clinical responses or adverse events. Monitoring treatment-related effects on T cell subsets may therefore be part of (pre-)clinical studies for medicinal products. However, the extent of immune monitoring performed in studies for marketing authorisation and the degree of correspondence with data available in the public domain is not known. We evaluated the presence of T cell immunomonitoring in 46 registration dossiers of monoclonal antibodies indicated for immune-related disorders and published scientific papers. We found that the depth of Treg analysis in registration dossiers was rather small. Nevertheless, data on treatment-related Treg effects are available in public academia-driven studies (post-registration) and suggest that Tregs may act as a biomarker for clinical responses. However, public data are fragmented and obtained with heterogeneity of experimental approaches from a diversity of species and tissues. To reveal the potential added value of T cell (and particular Treg) evaluation in (pre-)clinical studies, more cell-specific data should be acquired, at least for medicinal products with an immunomodulatory mechanism. Therefore, extensive analysis of T cell subset contribution to clinical responses and the relevance of treatment-induced changes in their levels is needed. Preferably, industry and academia should work together to obtain these data in a standardised manner and to enrich our knowledge about T cell activity in disease pathogenesis and therapies. This will ultimately elucidate the necessity of T cell subset monitoring in the therapeutic benefit-risk assessment.
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Altered expression of microRNAs may predict therapeutic response in rheumatoid arthritis patients. Int Immunopharmacol 2020; 83:106404. [PMID: 32197230 DOI: 10.1016/j.intimp.2020.106404] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/10/2020] [Accepted: 03/11/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND Epigenetic alternations of microRNAs (miRNAs) can contribute to the pathogenesis and progression of rheumatoid arthritis (RA). This study aimed to measure the expression level of peripheral blood miRNAs, as well as their target mRNAs, in RA patients and healthy controls (HCs), and to evaluate the potential of miRNAs as promising non-invasive biomarkers of treatment response. METHODS The peripheral expression of miRNAs, including miR-146a, miR-146b, miR-150, miR-155, miR-125a-5p, miR-223, miR-26a, and miR-21, as well as their target mRNAs, was analyzed in 90 RA patients and 30 HCs via quantitative real-time polymerase chain reaction (RT-PCR) assay. We compared differences between the patients in terms of good response (GR; n = 55) and poor response (PR; n = 35) to the conventional therapeutic approach. RESULTS All miRNAs were significantly overexpressed in RA patients. The expression of miR-155, miR-150, miR-146a, miR-146b, miR-125a-5p, and miR-223 increased in both groups of RA patients, compared to HCs, and miR-26a and miR-21 were the only upregulated miRNAs in the GR group versus HCs. Among the upregulated miRNAs, miR-125a-5p expression significantly changed in GR and PR patients (P = 0.047). The ROC curve analysis indicated the potential involvement of miR-125a-5p in the pathogenesis of RA. We also observed the downregulated expression of GATA3, RORC, FOXP3, TBX21, STAT1, and TRAF6 in RA patients versus HCs. CONCLUSION Our findings indicated that different expression levels of miR-125a-5p in the GR and PR groups of patients may serve as a therapeutic response biomarker, which can be also used as a target for therapeutic interventions.
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Xu XL, Lu KJ, Yao XQ, Ying XY, Du YZ. Stimuli-responsive Drug Delivery Systems as an Emerging Platform for Treatment of Rheumatoid Arthritis. Curr Pharm Des 2020; 25:155-165. [PMID: 30907308 DOI: 10.2174/1381612825666190321104424] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 03/16/2019] [Indexed: 12/21/2022]
Abstract
Rheumatoid Arthritis (RA) is a systemic autoimmune disease accompanied by chronic inflammation. Due to the long-term infiltration in inflammatory sites, joints get steadily deteriorated, eventually resulting in functional incapacitation and disability. Despite the considerable effect, RA sufferers treated with current drug therapeutic efficacy are exposed to severe side effects. Application of Drug Delivery Systems (DDS) has improved these situations while the problem of limited drug exposure remains untackled. Stimuli-responsive DDS that are responsive to a variety of endogenous and exogenous stimuli, such as pH, redox status, and temperature, have emerged as a promising therapeutic strategy to optimize the drug release. Herein, we discussed the therapeutic regimes and serious side effects of current RA therapy, as well as focused on some of the potential stimuliresponsive DDS utilized in RA therapy. Besides, the prospective room in designing DDS for RA treatment has also been discussed.
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Affiliation(s)
- Xiao-Ling Xu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Kong-Jun Lu
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Xiao-Qin Yao
- School of Medicine, Zhejiang University City College, Hangzhou 310058, China
| | - Xiao-Ying Ying
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Yong-Zhong Du
- Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
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22
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Takeuchi Y, Hirota K, Sakaguchi S. Impaired T cell receptor signaling and development of T cell-mediated autoimmune arthritis. Immunol Rev 2020; 294:164-176. [PMID: 31944330 DOI: 10.1111/imr.12841] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 12/31/2019] [Indexed: 12/22/2022]
Abstract
Mutations of the genes encoding T-cell receptor (TCR)-proximal signaling molecules, such as ZAP-70, can be causative of immunological diseases ranging from T-cell immunodeficiency to T-cell-mediated autoimmune disease. For example, SKG mice, which carry a hypomorphic point mutation of the Zap-70 gene, spontaneously develop T-cell-mediated autoimmune arthritis immunopathologically similar to human rheumatoid arthritis (RA). The Zap-70 mutation alters the sensitivity of developing T cells to thymic positive/negative selection by self-peptides/MHC complexes, shifting self-reactive TCR repertoire to include a dominant arthritogenic specificity and also affecting thymic development and function of autoimmune suppressive regulatory T (Treg) cells. Polyclonal self-reactive T cells, including potentially arthritogenic T cells, thus produced by the thymus recognize self-peptide/MHC complexes on antigen-presenting cells (APCs) in the periphery and stimulate them to produce cytokines including IL-6 to drive the arthritogenic T cells to differentiate into arthritogenic T-helper 17 (Th17) cells. Insufficient Treg suppression or activation of APCs via microbial and other environmental stimuli evokes arthritis by activating granulocyte-macrophage colony-stimulating factor-secreting effector Th17 cells, mediating chronic bone-destructive joint inflammation by activating myeloid cells, innate lymphoid cells, and synoviocytes in the joint. These findings obtained from the study of SKG mouse arthritis are instrumental in understanding how arthritogenic T cells are produced, become activated, and differentiate into effector T cells mediating arthritis, and may help devising therapeutic measures targeting autoimmune pathogenic Th17 cells or autoimmune-suppressing Treg cells to treat and prevent RA.
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Affiliation(s)
- Yusuke Takeuchi
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keiji Hirota
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan.,Laboratory of Experimental Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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23
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Khoury T, Ilan Y. Introducing Patterns of Variability for Overcoming Compensatory Adaptation of the Immune System to Immunomodulatory Agents: A Novel Method for Improving Clinical Response to Anti-TNF Therapies. Front Immunol 2019; 10:2726. [PMID: 31824506 PMCID: PMC6879658 DOI: 10.3389/fimmu.2019.02726] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 11/06/2019] [Indexed: 12/18/2022] Open
Abstract
Primary lack of response and secondary loss of response (LOR) are major obstacles to the use of anti-tumor necrosis factor (TNF)-based therapies in patients with rheumatoid arthritis or inflammatory bowel disease. Here, we review the mechanisms and methods for predicting LOR and the currently used methods for overcoming the ineffectiveness of anti-TNFs. The complex functions of TNF and anti-TNF antibodies, which can promote both pro- or anti-inflammatory actions, and the factors that affect the induction of immune tolerance to their effects are presented. The lack of rules and the continuous dynamics of the immune processes partly underlie the unpredictability of the response to anti-TNFs. Variability is inherent to biological systems, including immune processes, and intra/inter-patient variability has been described in the response to drugs. This variability is viewed as a compensatory adaptation mechanism of the immune system in response to drugs and may contribute to treatment LOR. Dose reductions and drug holidays have been tested in patients treated with anti-TNFs. Regular dose-based regimens may be incompatible with physiological variability, further contributing to treatment inefficacy. We present the concept of overcoming immune system adaptation to anti-TNFs by introducing patient-tailored patterns of variability to treatment regimens.
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Affiliation(s)
- Tawfik Khoury
- Department of Gastroenterology, Galilee Medical Center, Nahariya, Israel
- Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel
| | - Yaron Ilan
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
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24
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Takeuchi Y, Hirota K, Sakaguchi S. Synovial Tissue Inflammation Mediated by Autoimmune T Cells. Front Immunol 2019; 10:1989. [PMID: 31497022 PMCID: PMC6712680 DOI: 10.3389/fimmu.2019.01989] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 08/06/2019] [Indexed: 01/08/2023] Open
Abstract
In rheumatoid arthritis (RA), various hematopoietic and non-hematopoietic cells present in the synovial tissue secrete numerous inflammatory mediators including pro-inflammatory cytokines critical for the induction of chronic joint inflammation and bone destruction. Fibroblast-like synoviocytes (FLSs) in the non-hematopoietic cell compartment are key inflammatory cells activated in inflamed joints and driving the disease; yet how synovial tissue inflammation is modulated by autoimmune T cells is not fully understood. In this review, mainly based on recent findings with a mouse model of spontaneous autoimmune arthritis, we discuss the mechanism of Th17-mediated synovial tissue inflammation; that is, what environmental stimuli and arthritogenic self-antigens trigger arthritis, how arthritogenic T cells initiate joint inflammation by stimulating FLSs, and how the cellular sources of GM-CSF from lymphoid and tissue stromal cells in the synovium contribute to the development of arthritis. We also highlight possible plasticity of Th17 cells toward pathogenic GM-CSF producers, and the functional instability of regulatory T cells under inflammatory conditions in RA joints.
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Affiliation(s)
- Yusuke Takeuchi
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Keiji Hirota
- Laboratory of Integrative Biological Science, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.,Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan.,Laboratory of Experimental Immunology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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25
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Iwahashi C, Ono H, Haruta M, Minami T, Mashimo H, Shimojo H, Ohguro N. New onset or exacerbation of uveitis with infliximab: paradoxical effects? BMJ Open Ophthalmol 2019; 4:e000250. [PMID: 31355342 PMCID: PMC6615868 DOI: 10.1136/bmjophth-2018-000250] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Revised: 06/17/2019] [Accepted: 06/18/2019] [Indexed: 12/13/2022] Open
Abstract
Objective To report four cases of new onset or exacerbation of uveitis following administration of infliximab. Methods This retrospective observational case series includes four patients who developed new onset or exacerbation of uveitis paradoxically during infliximab treatment. Results Four patients were assessed, including three women, with a mean age of 33 (14–84) years. Infliximab was introduced for the treatment of scleritis associated with rheumatoid arthritis (two cases), chronic anterior uveitis associated with juvenile idiopathic arthritis (JIA) (one case) and Crohn’s disease (one case). Anterior scleritis associated with rheumatoid arthritis successfully improved following infliximab administration; however, macular oedema or dense vitritis paradoxically developed in two cases. In one case, infliximab was switched to tocilizumab. In another case, infliximab was discontinued, and additional corticosteroids and immunosuppressive medications were added. In one patient with JIA, new-onset macular oedema and exacerbation of anterior uveitis were observed during infliximab treatment, so the patient was switched to adalimumab. In the patient with Crohn’s disease treated with infliximab, severe vasculitis and macular oedema occurred, requiring intravitreal triamcinolone injection. The patient was switched to adalimumab. Given that these reactions were paradoxical effects of infliximab, infliximab treatment was discontinued in all cases, and additional corticosteroids or immunosuppressive medications were added. All cases remained free of ocular inflammation at the last visit. Conclusion Uveitis rarely occurs de novo or is exacerbated during infliximab treatment. Cessation of infliximab led to resolution of this paradoxical adverse effect.
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Affiliation(s)
- Chiharu Iwahashi
- Ophthalmology, Sumitomo Hospital, Osaka, Japan.,Ophthalmology, Kindai University Faculty of Medicine Hospital, Osakasayama, Japan
| | - Hikari Ono
- Ophthalmology, Japan Community Health Care Organization Hospital, Osaka, Japan
| | - Mami Haruta
- Ophthalmology, Japan Community Health Care Organization Hospital, Osaka, Japan
| | - Takamasa Minami
- Ophthalmology, Japan Community Health Care Organization Hospital, Osaka, Japan
| | - Hisashi Mashimo
- Ophthalmology, Japan Community Health Care Organization Hospital, Osaka, Japan
| | - Hiroshi Shimojo
- Ophthalmology, Japan Community Health Care Organization Hospital, Osaka, Japan
| | - Nobuyuki Ohguro
- Ophthalmology, Japan Community Health Care Organization Hospital, Osaka, Japan
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26
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Kawalkowska JZ, Ogbechi J, Venables PJ, Williams RO. cIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing T regs. SCIENCE ADVANCES 2019; 5:eaaw5422. [PMID: 31049403 PMCID: PMC6494502 DOI: 10.1126/sciadv.aaw5422] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 03/19/2019] [Indexed: 06/09/2023]
Abstract
IL-17 and TNF-α are major effector cytokines in chronic inflammation. TNF-α inhibitors have revolutionized the treatment of rheumatoid arthritis (RA), although not all patients respond, and most relapse after treatment withdrawal. This may be due to a paradoxical exacerbation of TH17 responses by TNF-α inhibition. We examined the therapeutic potential of targeting cellular inhibitors of apoptosis 1 and 2 (cIAP1/2) in inflammation by its influence on human TH subsets and mice with collagen-induced arthritis. Inhibition of cIAP1/2 abrogated CD4+ IL-17A differentiation and IL-17 production. This was a direct effect on T cells, mediated by reducing NFATc1 expression. In mice, cIAP1/2 inhibition, when combined with etanercept, abrogated disease activity, which was associated with an increase in Tregs and was sustained after therapy retraction. We reveal an unexpected role for cIAP1/2 in regulating the balance between TH17 and Tregs and suggest that combined therapeutic inhibition could induce long-term remission in inflammatory diseases.
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27
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Menegatti S, Bianchi E, Rogge L. Anti-TNF Therapy in Spondyloarthritis and Related Diseases, Impact on the Immune System and Prediction of Treatment Responses. Front Immunol 2019; 10:382. [PMID: 30941119 PMCID: PMC6434926 DOI: 10.3389/fimmu.2019.00382] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 02/14/2019] [Indexed: 12/14/2022] Open
Abstract
Immune-mediated inflammatory diseases (IMIDs), such as spondyloarthritis (SpA), psoriasis, Crohn's disease (CD), and rheumatoid arthritis (RA) remain challenging illnesses. They often strike at a young age and cause lifelong morbidity, representing a considerable burden for the affected individuals and society. Pioneering studies have revealed the presence of a TNF-dependent proinflammatory cytokine cascade in several IMIDs, and the introduction of anti-TNF therapy 20 years ago has proven effective to reduce inflammation and clinical symptoms in RA, SpA, and other IMID, providing unprecedented clinical benefits and a valid alternative in case of failure or intolerable adverse effects of conventional disease-modifying antirheumatic drugs (DMARDs, for RA) or non-steroidal anti-inflammatory drugs (NSAIDs, for SpA). However, our understanding of how TNF inhibitors (TNFi) affect the immune system in patients is limited. This question is relevant because anti-TNF therapy has been associated with infectious complications. Furthermore, clinical efficacy of TNFi is limited by a high rate of non-responsiveness (30–40%) in RA, SpA, and other IMID, exposing a substantial fraction of patients to side-effects without clinical benefit. Despite the extensive use of TNFi, it is still not possible to determine which patients will respond to TNFi before treatment initiation. The recent introduction of antibodies blocking IL-17 has expanded the therapeutic options for SpA, as well as psoriasis and psoriatic arthritis. It is therefore essential to develop tools to guide treatment decisions for patients affected by SpA and other IMID, both to optimize clinical care and contain health care costs. After a brief overview of the biology of TNF, its receptors and currently used TNFi in the clinics, we summarize the progress that has been made to increase our understanding of the action of TNFi on the immune system in patients. We then summarize efforts dedicated to identify biomarkers that can predict treatment responses to TNFi and we conclude with a section dedicated to the recently introduced inhibitors of IL-17A and IL-23 in SpA and related diseases. The focus of this review is on SpA, however, we also refer to RA on topics for which only limited information is available on SpA in the literature.
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Affiliation(s)
- Silvia Menegatti
- Immunoregulation Unit, Department of Immunology, Institut Pasteur, Paris, France.,Unité Mixte de Recherche, Institut Pasteur/AP-HP Hôpital Cochin, Paris, France.,Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | - Elisabetta Bianchi
- Immunoregulation Unit, Department of Immunology, Institut Pasteur, Paris, France.,Unité Mixte de Recherche, Institut Pasteur/AP-HP Hôpital Cochin, Paris, France
| | - Lars Rogge
- Immunoregulation Unit, Department of Immunology, Institut Pasteur, Paris, France.,Unité Mixte de Recherche, Institut Pasteur/AP-HP Hôpital Cochin, Paris, France
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28
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Talotta R, Rucci F, Canti G, Scaglione F. Pros and cons of the immunogenicity of monoclonal antibodies in cancer treatment: a lesson from autoimmune diseases. Immunotherapy 2019; 11:241-254. [DOI: 10.2217/imt-2018-0081] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The aim of this review is to report the current evidence on immunogenicity of monoclonal antibodies (moAbs) used in cancer compared with autoimmune diseases, focusing on local microenvironment. English abstracts were identified in Medline and www.clinicaltrials.gov . A total of 82 papers were selected. The percentage of immunogenicity of moAbs used for cancer therapy, evaluated as the serum concentration of antidrug antibodies, is significantly lower than that of moAbs used for the treatment of autoimmune diseases. This condition may rely on a different immunologic background characterized by a hyperactivation of immune cells in autoimmune diseases. The formation of complexes between antidrug antibodies and non-neutralizing moAbs bound to neoplastic antigens may allow more efficient elimination of cancer cells, but additional studies are needed.
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Affiliation(s)
- Rossella Talotta
- Postgraduate School of Clinical Pharmacology & Toxicology, University of Milan, 20162, Milan, Italy
- Laboratory of Genetics, ASST ‘Grande Ospedale Metropolitano Niguarda’, 20162, Milan, Italy
| | - Francesco Rucci
- Postgraduate School of Clinical Pharmacology & Toxicology, University of Milan, 20162, Milan, Italy
- Laboratory of Genetics, ASST ‘Grande Ospedale Metropolitano Niguarda’, 20162, Milan, Italy
| | - Gianfranco Canti
- Department of Medical Biotechnology & Traslational Medicine, University of Milan, 20129, Milan, Italy
| | - Francesco Scaglione
- Department of Oncology & Onco-Hematology, University of Milan, 20162, Milan, Italy
- Clinical Pharmacology Unit, ASST ‘Grande Ospedale Metropolitano Niguarda’, 20162, Milan, Italy
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29
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Dostert C, Grusdat M, Letellier E, Brenner D. The TNF Family of Ligands and Receptors: Communication Modules in the Immune System and Beyond. Physiol Rev 2019; 99:115-160. [DOI: 10.1152/physrev.00045.2017] [Citation(s) in RCA: 175] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies (TNFSF/TNFRSF) include 19 ligands and 29 receptors that play important roles in the modulation of cellular functions. The communication pathways mediated by TNFSF/TNFRSF are essential for numerous developmental, homeostatic, and stimulus-responsive processes in vivo. TNFSF/TNFRSF members regulate cellular differentiation, survival, and programmed death, but their most critical functions pertain to the immune system. Both innate and adaptive immune cells are controlled by TNFSF/TNFRSF members in a manner that is crucial for the coordination of various mechanisms driving either co-stimulation or co-inhibition of the immune response. Dysregulation of these same signaling pathways has been implicated in inflammatory and autoimmune diseases, highlighting the importance of their tight regulation. Investigation of the control of TNFSF/TNFRSF activities has led to the development of therapeutics with the potential to reduce chronic inflammation or promote anti-tumor immunity. The study of TNFSF/TNFRSF proteins has exploded over the last 30 yr, but there remains a need to better understand the fundamental mechanisms underlying the molecular pathways they mediate to design more effective anti-inflammatory and anti-cancer therapies.
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Affiliation(s)
- Catherine Dostert
- Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark; and Life Sciences Research Unit, Molecular Disease Mechanisms Group, University of Luxembourg, Belvaux, Luxembourg
| | - Melanie Grusdat
- Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark; and Life Sciences Research Unit, Molecular Disease Mechanisms Group, University of Luxembourg, Belvaux, Luxembourg
| | - Elisabeth Letellier
- Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark; and Life Sciences Research Unit, Molecular Disease Mechanisms Group, University of Luxembourg, Belvaux, Luxembourg
| | - Dirk Brenner
- Department of Infection and Immunity, Experimental and Molecular Immunology, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg; Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark; and Life Sciences Research Unit, Molecular Disease Mechanisms Group, University of Luxembourg, Belvaux, Luxembourg
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30
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Davignon JL, Rauwel B, Degboé Y, Constantin A, Boyer JF, Kruglov A, Cantagrel A. Modulation of T-cell responses by anti-tumor necrosis factor treatments in rheumatoid arthritis: a review. Arthritis Res Ther 2018; 20:229. [PMID: 30314507 PMCID: PMC6235207 DOI: 10.1186/s13075-018-1725-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Tumor necrosis factor (TNF) is a pleiotropic cytokine involved in many aspects of immune regulation. Anti-TNF biological therapy has been considered a breakthrough in the treatment of chronic autoimmune diseases, such as rheumatoid arthritis (RA). In this review, because of the major involvement of T cells in RA pathogenesis, we discuss the effects of anti-TNF biotherapy on T-cell responses in RA patients. We also outline the potential fields for future research in the area of anti-TNF therapy in RA.This could be useful to better understand the therapeutic efficiency and the side effects that are encountered in RA patients. Better targeting of T cells in RA could help set more specific anti-TNF strategies and develop prediction tools for response.
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Affiliation(s)
- Jean-Luc Davignon
- Centre de Physiopathologie Toulouse Purpan, INSERM-CNRS-UPS, UMR 1043, CHU Purpan, 1 Place Baylac, 31024, Toulouse Cedex, France. .,Centre de Rhumatologie, CHU de Toulouse, 31059, Toulouse, France.
| | - Benjamin Rauwel
- Centre de Physiopathologie Toulouse Purpan, INSERM-CNRS-UPS, UMR 1043, CHU Purpan, 1 Place Baylac, 31024, Toulouse Cedex, France
| | - Yannick Degboé
- Centre de Physiopathologie Toulouse Purpan, INSERM-CNRS-UPS, UMR 1043, CHU Purpan, 1 Place Baylac, 31024, Toulouse Cedex, France.,Centre de Rhumatologie, CHU de Toulouse, 31059, Toulouse, France.,Faculté de Médecine, Université Paul Sabatier Toulouse III, 31062, Toulouse, France
| | - Arnaud Constantin
- Centre de Physiopathologie Toulouse Purpan, INSERM-CNRS-UPS, UMR 1043, CHU Purpan, 1 Place Baylac, 31024, Toulouse Cedex, France.,Centre de Rhumatologie, CHU de Toulouse, 31059, Toulouse, France.,Faculté de Médecine, Université Paul Sabatier Toulouse III, 31062, Toulouse, France
| | - Jean-Fredéric Boyer
- Centre de Physiopathologie Toulouse Purpan, INSERM-CNRS-UPS, UMR 1043, CHU Purpan, 1 Place Baylac, 31024, Toulouse Cedex, France.,Centre de Rhumatologie, CHU de Toulouse, 31059, Toulouse, France
| | - Andrey Kruglov
- Lomonosov Moscow State University, 119991, Moscow, Russia.,German Rheumatism Research Center (DRFZ), 10117, Berlin, Germany
| | - Alain Cantagrel
- Centre de Physiopathologie Toulouse Purpan, INSERM-CNRS-UPS, UMR 1043, CHU Purpan, 1 Place Baylac, 31024, Toulouse Cedex, France.,Centre de Rhumatologie, CHU de Toulouse, 31059, Toulouse, France.,Faculté de Médecine, Université Paul Sabatier Toulouse III, 31062, Toulouse, France
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31
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Defendenti C, Atzeni F, Malandrin S, Ardizzone S, Almasio PL, Saibeni S, Bezzio C, Bollani S, Salerno R, Declich P, Sarno Z, Bruno S, Talotta R, Sarzi-Puttini P. Anti-tumour necrosis factor-α antibodies and B cell homeostasis in human inflammatory bowel diseases. Int Immunopharmacol 2018; 54:329-335. [PMID: 29197269 DOI: 10.1016/j.intimp.2017.11.016] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 11/05/2017] [Accepted: 11/12/2017] [Indexed: 02/05/2023]
Abstract
BACKGROUND The expression of CD70 on T cells is greatly enhanced by antigen-presenting cell (APC)-associated signals, such as tumour necrosis factor(TNF)-α, which is constitutionally high in patients with inflammatory bowel disease (IBD). Experimentally, the chronic activation of CD27 as a result of the constitutive expression of CD70 leads to the demise of B cells in bone marrow (BM) and the secondary lymphoid organs. The aim of this study was to assess the number and phenotype of circulating B cell in untreated IBD patients and their counterparts treated with biological anti-TNF drugs. METHODS The study involved 13 untreated IBD patients, 36 IBD patients treated with biological drugs, and 10 healthy controls. The B cell phenotypes were assessed by means of flow cytometry using monoclonal antibodies specific for CD20, CD19, CD3, CD27 and CD43. In order to evaluate B cell development in bone marrow and peripheral B cell activation, we identified four B cell subsets: hematogones (HBs: CD20+19+3-27-43+), memory B cells (MBs: CD20+19+3-27+43-), pre-plasmablasts (PPBs: CD20+19+3-27+43+), and plasmablasts (PBs: CD20-19+3-27+43+). RESULTS The total number of B cells in the untreated patients was three times lower than that in the patients treated with biological drug (p<0.001), and half that in the healthy controls (p=0.03). The between-group differences (including the healthy donors) were statistically significant in the case of HBs and MBs, but not in the case of PPBs and PBs. Only one treated patient showed a transiently large increase in PPBs. There were statistically significant differences in all of the parameters between the untreated patients and those receiving biological therapy, and in some cases between the untreated patients and healthy controls, but never between the controls and the treated patients. Four non-responders to anti-TNF therapy had a smaller number of total circulating B cells than the untreated patients. CONCLUSIONS Anti-TNF drugs disinhibit B cell production in IBD patients, but maintain the constant homeostasis of circulating B cells. The presence of individual variations may allow the activity of anti-TNF drugs to be monitored by studying B cell subgroups.
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Affiliation(s)
| | | | - Sergio Malandrin
- Microbiology and Virology Unit, ASST Ospedale San Gerardo, Monza, Italy
| | - Sandro Ardizzone
- Division of Gastroenterology, ASST Fatebenefratelli Sacco Buzzi, Milan, Italy
| | - Piero Luigi Almasio
- Biomedical Department of Internal and Specialized Medicine (DI.BI.M.I.S.), University of Palermo, Palermo, Italy
| | - Simone Saibeni
- Division of Gastroenterology, Guido Salvini Hospital, Rho, Italy
| | - Cristina Bezzio
- Division of Gastroenterology, Guido Salvini Hospital, Rho, Italy
| | - Simona Bollani
- Division of Gastroenterology, ASST Fatebenefratelli Sacco Buzzi, Milan, Italy
| | - Raffaele Salerno
- Division of Gastroenterology, ASST Fatebenefratelli Sacco Buzzi, Milan, Italy
| | - Paolo Declich
- Division of Pathology, ASST della Valtellina e dell'Alto Lario, Sondrio, Italy
| | - Zoe Sarno
- Laboratory, ASST Fatebenefratelli Sacco Buzzi, Milan, Italy
| | | | - Rossella Talotta
- Rheumatology Unit, ASST Fatebenefratelli Sacco Buzzi, Milan, Italy
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32
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Dulic S, Vasarhelyi Z, Bajnok A, Szalay B, Toldi G, Kovacs L, Balog A. The Impact of Anti-TNF Therapy on CD4+ and CD8+ Cell Subsets in Ankylosing Spondylitis. Pathobiology 2017; 85:201-210. [PMID: 29212085 DOI: 10.1159/000484250] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 10/16/2017] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Ankylosing spondylitis (AS) is a chronic, progressive immune-mediated inflammatory disease, driven primarily by Th1 and Th17 cells. Anti-TNF therapies are successfully used in AS to achieve and maintain remission. However, their influence on the composition of T-cell subsets is not clear. We aimed to characterize the changes in the T-cell repertoire after a long-term anti-TNF treatment in AS patients. METHODS Twenty-two AS patients under long-term anti-TNF therapy were evaluated (15 anti-TNF responders and 7 nonresponders). A wide range of cell subtypes was analyzed with flow cytometry and compared with therapy-naïve and short-term data too. RESULTS Key findings include decreased proportions of naïve CD4 and CD8 cells, increased frequencies of Th1 and Th17 cells and higher Th1/Th2 ratios in the long-term anti-TNF-treated patients (responders, nonresponders and total), which was found to be significant not only when compared with healthy controls, but also with therapy-naïve and short-term anti-TNF-treated AS patients. We noted several alterations within the various activated T-cell subsets - increase in CD4HLADR cells in responders, in CD8HLADR cells in the whole AS group and in responders, and in CD4CD25 cells in responders, and decrease in CD4CD69 cell percentages in long-term treated patients - becoming evident only after long-term anti-TNF therapy. CONCLUSIONS This study provides a comprehensive assessment of the impact of anti-TNF therapy on the T-cell repertoire in AS. Changes in T-cell phenotype seem to develop progressively during therapy, even in inactive disease, and reflect an ongoing effector T-cell differentiation and activation, along with the parallel compensatory increase in regulatory T cells.
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Affiliation(s)
- Sonja Dulic
- Department of Rheumatology and Immunology, Faculty of Medicine, Albert Szent-Gyorgyi Health Centre, University of Szeged, Szeged, Hungary
| | - Zsofia Vasarhelyi
- First Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary
| | - Anna Bajnok
- First Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Balazs Szalay
- Department of Laboratory Medicine, Semmelweis University, Budapest, Hungary
| | - Gergely Toldi
- First Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary
| | - Laszlo Kovacs
- Department of Rheumatology and Immunology, Faculty of Medicine, Albert Szent-Gyorgyi Health Centre, University of Szeged, Szeged, Hungary
| | - Attila Balog
- Department of Rheumatology and Immunology, Faculty of Medicine, Albert Szent-Gyorgyi Health Centre, University of Szeged, Szeged, Hungary
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Kalden JR, Schulze-Koops H. Immunogenicity and loss of response to TNF inhibitors: implications for rheumatoid arthritis treatment. Nat Rev Rheumatol 2017; 13:707-718. [PMID: 29158574 DOI: 10.1038/nrrheum.2017.187] [Citation(s) in RCA: 124] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The availability of monoclonal antibodies has revolutionized the treatment of an increasingly broad spectrum of diseases. Inflammatory diseases are among those most widely treated with protein-based therapeutics, termed biologics. Following the first large-scale clinical trials with monoclonal antibodies performed in the 1990s by rheumatologists and clinical immunologists, the approval of these agents for use in daily clinical practice led to substantial progress in the treatment of rheumatic diseases. Despite this progress, however, only a proportion of patients achieve a long-term clinical response. Data on the use of agents blocking TNF, which were among the first biologics introduced into clinical practice, provide ample evidence of primary and secondary treatment inefficacy in patients with rheumatoid arthritis (RA). Important issues relevant to primary and secondary failure of these agents in RA include immunogenicity, methodological problems for the detection of antidrug antibodies and trough drug levels, and the implications for treatment strategies. Although there is no strong evidence to support the routine estimation of antidrug antibodies or serum trough levels during anti-TNF therapy, these assessments might be helpful in a few clinical situations; in particular, they might guide decisions on switching the therapeutic biologic in certain instances of secondary clinical failure.
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Affiliation(s)
- Joachim R Kalden
- Friedrich-Alexander University Erlangen-Nürnberg, Division of Molecular Immunology, Nikolaus-Fiebiger Center, Glückstraße 6, D-91054 Erlangen, Germany
| | - Hendrik Schulze-Koops
- Ludwig-Maximilians-University, Division of Rheumatology and Clinical Immunology, Department of Internal Medicine IV, Pettenkoferstraße 8a, D-80336 Munich, Germany
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The Immunogenicity of Branded and Biosimilar Infliximab in Rheumatoid Arthritis According to Th9-Related Responses. Int J Mol Sci 2017; 18:ijms18102127. [PMID: 29023386 PMCID: PMC5666809 DOI: 10.3390/ijms18102127] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 10/04/2017] [Accepted: 10/04/2017] [Indexed: 12/23/2022] Open
Abstract
Our objective was to evaluate the immunogenicity of branded and biosimilar infliximab by detecting changes in T-helper-9 (Th9) percentages induced by an in vitro stimulation test. METHODS Peripheral blood mononuclear cells collected from 55 consecutive rheumatoid arthritis (RA) outpatients (15 drug free, 20 successfully treated with branded infliximab, 20 branded infliximab inadequate responders) and 10 healthy controls were cultured, with or without 50 μg/mL of infliximab originator (Remicade®) or 50 μg/mL of infliximab biosimilar (Remsima®) for 18 h. Th9 lymphocytes were identified by means of flow cytometry as PU.1 and IRF4-expressing, IL-9-secreting CD4⁺ T cells. Furthermore, the markers CCR7 and CD45RA were used to distinguish naïve from memory IL-9 producer cells. RESULTS Under unstimulated conditions, the drug-free RA patients had the highest percentages of Th9 lymphocytes. Following stimulation with branded infliximab, the percentages of PU.1 and IRF4-expressing Th9 cells, CCR7⁺, CD45RA- (central memory) and CCR7-, CD45RA- (effector memory) cells significantly increased in the group of inadequate responders, but no significant variation was observed after exposure to the biosimilar of infliximab. CONCLUSIONS Th9 cells seem to be involved in the immune response to the epitopes of branded, but not biosimilar, infliximab, and this may depend on the recall and stimulation of both central and effector memory cells.
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Kim EY, Moudgil KD. Immunomodulation of autoimmune arthritis by pro-inflammatory cytokines. Cytokine 2017; 98:87-96. [PMID: 28438552 PMCID: PMC5581685 DOI: 10.1016/j.cyto.2017.04.012] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 04/09/2017] [Accepted: 04/10/2017] [Indexed: 12/18/2022]
Abstract
Pro-inflammatory cytokines promote autoimmune inflammation and tissue damage, while anti-inflammatory cytokines help resolve inflammation and facilitate tissue repair. Over the past few decades, this general feature of cytokine-mediated events has offered a broad framework to comprehend the pathogenesis of autoimmune and other immune-mediated diseases, and to successfully develop therapeutic approaches for diseases such as rheumatoid arthritis (RA). Anti-tumor necrosis factor-α (TNF-α) therapy is a testimony in support of this endeavor. However, many patients with RA fail to respond to this or other biologics, and some patients may suffer unexpected aggravation of arthritic inflammation or other autoimmune effects. These observations combined with rapid advancements in immunology in regard to newer cytokines and T cell subsets have enforced a re-evaluation of the perceived pathogenic attribute of the pro-inflammatory cytokines. Studies conducted by others and us in experimental models of arthritis involving direct administration of IFN-γ or TNF-α; in vivo neutralization of the cytokine; the use of animals deficient in the cytokine or its receptor; and the impact of the cytokine or anti-cytokine therapy on defined T cell subsets have revealed paradoxical anti-inflammatory and immunoregulatory attributes of these two cytokines. Similar studies in other models of autoimmunity as well as limited studies in arthritis patients have also unveiled the disease-protective effects of these pro-inflammatory cytokines. A major mechanism in this regard is the altered balance between the pathogenic T helper 17 (Th17) and protective T regulatory (Treg) cells in favor of the latter. However, it is essential to consider that this aspect of the pro-inflammatory cytokines is context-dependent such that the dose and timing of intervention, the experimental model of the disease under study, and the differences in individual responsiveness can influence the final outcomes. Nevertheless, the realization that pro-inflammatory cytokines can also be immunoregulatory offers a new perspective in fully understanding the pathogenesis of autoimmune diseases and in designing better therapies for controlling them.
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Affiliation(s)
- Eugene Y Kim
- Department of Pharmaceutical Sciences, School of Pharmacy, Washington State University, Spokane, WA, USA
| | - Kamal D Moudgil
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Division of Rheumatology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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Meley D, Héraud A, Gouilleux-Gruart V, Ivanes F, Velge-Roussel F. Tocilizumab Contributes to the Inflammatory Status of Mature Dendritic Cells through Interleukin-6 Receptor Subunits Modulation. Front Immunol 2017; 8:926. [PMID: 28861079 PMCID: PMC5561017 DOI: 10.3389/fimmu.2017.00926] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Accepted: 07/20/2017] [Indexed: 12/28/2022] Open
Abstract
Tocilizumab, a humanized anti-IL-6 receptor α (IL-6Rα) is widely used in the treatment of a panel of pathologies such as adult and juvenile rheumatoid arthritis (RA) and the systemic form of juvenile idiopathic arthritis in children. Its indications are expected to be largely extended to other inflammatory diseases in close future. Dendritic cells (DCs) appear to be deeply involved in the immunopathology of these diseases, yet the effects of tocilizumab on these cells were poorly studied. In this study, we explored the effect of tocilizumab on the regulation of IL-6R subunits [gp130, soluble form of IL-6Rα (sIL-6Rα), and mIL-6Rα] in human monocyte-derived DCs. Human DCs were derived from CD14+ monocytes purified with beads with IL-4 and granulocyte macrophage colony-stimulating factor. Ex vivo cultures of DCs were performed in the presence of tocilizumab. Using lipopolysaccharide (LPS) maturation of DCs, we demonstrated that tocilizumab did not inhibit IL-6 secretion, enhanced mIL-6Rα expression, and largely increased sIL-6Rα secretion. MAPK modulated STAT3 phosphorylation and surface expression of IL-6Rα in LPS-DCs. Tocilizumab had no impact on STAT3 phosphorylation in LPS-DCs while both LPS and IL-6 increased its activation. Tocilizumab modulated the regulation of IL-6R subunits leading to an inflammatory status of DCs and a massive secretion of IL-6Rα. Our results demonstrate that DCs acquire a pro-inflammatory profile following tocilizumab treatment, becoming a major source of IL-6 trans-signaling activation that might explain the poor clinical benefit in some RA patients.
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Affiliation(s)
- Daniel Meley
- EA 4245 Cellules Dendritiques, Immuno-modulation et Greffes, Université François-Rabelais de Tours, UFR de Médecine, Tours, France
| | - Audrey Héraud
- EA 4245 Cellules Dendritiques, Immuno-modulation et Greffes, Université François-Rabelais de Tours, UFR de Médecine, Tours, France
| | - Valerie Gouilleux-Gruart
- CNRS UMR 7292; Université François-Rabelais de Tours, UFR de Médecine, Tours, France.,Department of Immunology, CHRU de Tours, Tours, France
| | - Fabrice Ivanes
- EA 4245 Cellules Dendritiques, Immuno-modulation et Greffes, Université François-Rabelais de Tours, UFR de Médecine, Tours, France.,Service de Cardiologie, CHRU de Tours, Tours, France
| | - Florence Velge-Roussel
- EA 4245 Cellules Dendritiques, Immuno-modulation et Greffes, Université François-Rabelais de Tours, UFR de Médecine, Tours, France.,UFR des Sciences Pharmaceutiques, Tours, France
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Wu R, Long L, Chen Q, Wu X, Zhu J, Zhou B, Cheng J. Effects of Tim-3 silencing on the viability of fibroblast-like synoviocytes and lipopolysaccharide-induced inflammatory reactions. Exp Ther Med 2017; 14:2721-2727. [PMID: 28962218 DOI: 10.3892/etm.2017.4819] [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: 08/16/2016] [Accepted: 05/16/2017] [Indexed: 12/19/2022] Open
Abstract
The objective of the present study was to investigate the effects of Tim-3 silencing on cell viability and lipopolysaccharide (LPS)-induced inflammatory reactions in fibroblast-like synoviocytes (FLS). T-cell immunoglobulin mucin domain molecule (Tim)-3 expression in FLS obtained from patients with rheumatoid arthritis (RA) and normal controls were detected by western blot analysis and reverse transcription-polymerase chain reaction (RT-PCR). Small interfering (si)RNA was transfected using Lipofectamine® 2000 to decrease Tim-3 expression. Following transfection, FLS were stimulated by LPS. An MTT assay, RT-PCR and western blot analysis were performed to measure cell viability, Toll-like receptor 4 (TLR4) signaling pathway-related protein expression and inflammatory cytokine release, respectively. The results of the present study indicated that Tim-3 expression was increased in FLS from patients with RA compared with FLS from healthy controls. Transfection of Tim-3 siRNA significantly decreased Tim-3 expression in FLS from patients with RA. Notably, Tim-3 silencing decreased FLS cell viability. Following stimulation with LPS, cell viability and the expression of TLR4, myeloid differentiation protein gene 88 (MyD88) and nuclear factor-κB (NF-κB) p65 were enhanced in FLS. By contrast, Tim-3 silencing attenuated LPS-induced cell proliferation and the expression of TLR4, MyD88 and NF-κB p65. In addition, LPS significantly increased levels of cytokines in the supernatant, including tumor necrosis factor-α, interferon-γ and interleukin-6 (P<0.01). By contrast, Tim-3 silencing significantly decreased LPS-induced cytokine release (P<0.01). However, Tim-3 silencing did not affect TLR4, MyD88 and NF-κB p65 expression and the release of cytokines in cells that did not undergo treatment with LPS. Therefore, the results of the present study indicate that Tim-3 silencing decreases the viability of FLS in RA and attenuates the LPS-induced inflammatory reaction.
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Affiliation(s)
- Rui Wu
- Department of Rheumatology and Immunology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Li Long
- Department of Rheumatology and Immunology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Qiqi Chen
- Department of Rheumatology and Immunology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Xiaodan Wu
- Department of Rheumatology and Immunology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Jing Zhu
- Department of Rheumatology and Immunology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Bin Zhou
- Department of Rheumatology and Immunology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
| | - Jia Cheng
- Department of Rheumatology and Immunology, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, P.R. China
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Zorzopulos J, Opal SM, Hernando-Insúa A, Rodriguez JM, Elías F, Fló J, López RA, Chasseing NA, Lux-Lantos VA, Coronel MF, Franco R, Montaner AD, Horn DL. Immunomodulatory oligonucleotide IMT504: Effects on mesenchymal stem cells as a first-in-class immunoprotective/immunoregenerative therapy. World J Stem Cells 2017; 9:45-67. [PMID: 28396715 PMCID: PMC5368622 DOI: 10.4252/wjsc.v9.i3.45] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/12/2016] [Accepted: 12/19/2016] [Indexed: 02/06/2023] Open
Abstract
The immune responses of humans and animals to insults (i.e., infections, traumas, tumoral transformation and radiation) are based on an intricate network of cells and chemical messengers. Abnormally high inflammation immediately after insult or abnormally prolonged pro-inflammatory stimuli bringing about chronic inflammation can lead to life-threatening or severely debilitating diseases. Mesenchymal stem cell (MSC) transplant has proved to be an effective therapy in preclinical studies which evaluated a vast diversity of inflammatory conditions. MSCs lead to resolution of inflammation, preparation for regeneration and actual regeneration, and then ultimate return to normal baseline or homeostasis. However, in clinical trials of transplanted MSCs, the expectations of great medical benefit have not yet been fulfilled. As a practical alternative to MSC transplant, a synthetic drug with the capacity to boost endogenous MSC expansion and/or activation may also be effective. Regarding this, IMT504, the prototype of a major class of immunomodulatory oligonucleotides, induces in vivo expansion of MSCs, resulting in a marked improvement in preclinical models of neuropathic pain, osteoporosis, diabetes and sepsis. IMT504 is easily manufactured and has an excellent preclinical safety record. In the small number of patients studied thus far, IMT504 has been well-tolerated, even at very high dosage. Further clinical investigation is necessary to demonstrate the utility of IMT504 for resolution of inflammation and regeneration in a broad array of human diseases that would likely benefit from an immunoprotective/immunoregenerative therapy.
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Salomon S, Guignant C, Morel P, Flahaut G, Brault C, Gourguechon C, Fardellone P, Marolleau JP, Gubler B, Goëb V. Th17 and CD24 hiCD27 + regulatory B lymphocytes are biomarkers of response to biologics in rheumatoid arthritis. Arthritis Res Ther 2017; 19:33. [PMID: 28183330 PMCID: PMC5301325 DOI: 10.1186/s13075-017-1244-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Accepted: 01/24/2017] [Indexed: 12/29/2022] Open
Abstract
Background The aim was to describe the regulatory B and T cells (Breg and Treg) and T helper 17 (Th17) lymphocytes before and under treatment with biologic drugs, and to assess their potential predictive value as biomarkers of response in rheumatoid arthritis (RA). Methods This was a non-randomised, single-centre, prospective study. Patients with active RA (American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010) who required the initiation or switch to any biologic drug except rituximab were included. The main judgement criterion was the frequency and absolute number of CD24hiCD27+ Breg and CD24hiCD38hi T2/Breg cells, CD25hiCD127low Treg and CD45RA−CD161+CCR6+ Th17 cells measured at inclusion in both patients and controls, and after 1, 3 and 6 months of treatment (M1, M3 and M6) in patients with RA, and compared with the M6 response to treatment (EULAR response and Disease Activity Score in 28 joints (DAS28) remission). Results Thirty-one patients with RA and 17 controls were included. There was a reduction in T2/Breg frequency at M0 in patients (p < 0.001) and absolute numbers (p = 0.014) and in immunopositive vs. immunonegative RA (p = 0.016). DAS28 remission at M6 was associated with increased frequency of Treg (p = 0.01). A higher level of CD24hiCD27+ Breg at baseline was associated with DAS28 remission at M6 (p = 0.04) and a good EULAR response at M6 for abatacept-treated patients (p = 0.01). A lower M0 level of Th17 was associated with a good EULAR response at M6 (p = 0.007), notably under anti-cytokine drugs (p = 0.048). Conclusions Altogether, these data, although preliminary, suggest that phenotyping of T and B cells has potential value for the stratification of biologic drugs, notably with respect to choosing between abatacept and anti-cytokine blockade.
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Affiliation(s)
- Sarah Salomon
- Rheumatology Department & EA 4666, Amiens University Hospital, University of Picardie-Jules Verne, Amiens, France
| | - Caroline Guignant
- Immunology laboratory & EA 4666, Amiens University Hospital, University of Picardie-Jules Verne, Amiens, France
| | - Pierre Morel
- Hematology laboratory & EA 4666, Amiens University Hospital, University of Picardie-Jules Verne, Amiens, France
| | - Gauthier Flahaut
- Immunology laboratory & EA 4666, Amiens University Hospital, University of Picardie-Jules Verne, Amiens, France
| | - Clément Brault
- Immunology laboratory & EA 4666, Amiens University Hospital, University of Picardie-Jules Verne, Amiens, France
| | - Clément Gourguechon
- Immunology laboratory & EA 4666, Amiens University Hospital, University of Picardie-Jules Verne, Amiens, France
| | - Patrice Fardellone
- Rheumatology Department & EA 4666, Amiens University Hospital, University of Picardie-Jules Verne, Amiens, France
| | - Jean-Pierre Marolleau
- Hematology laboratory & EA 4666, Amiens University Hospital, University of Picardie-Jules Verne, Amiens, France
| | - Brigitte Gubler
- Immunology laboratory & EA 4666, Amiens University Hospital, University of Picardie-Jules Verne, Amiens, France
| | - Vincent Goëb
- Rheumatology Department & EA 4666, Amiens University Hospital, University of Picardie-Jules Verne, Amiens, France.
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Shiri-Shahsavar MR, Mirshafiee A, Parastouei K, Ebrahimi-Kalan A, Yekaninejad S, Soleymani F, Chahardoli R, Mazaheri Nezhad Fard R, Saboor-Yaraghi AA. A Novel Combination of Docosahexaenoic Acid, All-Trans Retinoic Acid, and 1, 25-Dihydroxyvitamin D 3 Reduces T-Bet Gene Expression, Serum Interferon Gamma, and Clinical Scores but Promotes PPARγ Gene Expression in Experimental Autoimmune Encephalomyelitis. J Mol Neurosci 2016; 60:498-508. [PMID: 27647308 DOI: 10.1007/s12031-016-0834-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 08/30/2016] [Indexed: 12/19/2022]
Abstract
Vitamins are immunologically interesting due to their significant immunomodulatory activities. Experimental autoimmune encephalomyelitis (EAE) is one of the most commonly used experimental models for studying autoimmune disorder in multiple sclerosis (MS). The aim of this study was to evaluate the protective and ameliorative effects of novel combination of all-trans retinoic acid (ATRA), 1,25-dihydroxyvitamin D3 (D3), and docosahexaenoic acid (DHA) on EAE-specific determinants and target gene expressions. Mice were randomly categorized into three groups before EAE induction [non-treated EAE (Group E), treated EAE (Group T), and healthy mice (Group H)]. Encephalomyelitis was induced in female C57BL/6 mice by subcutaneous immunization using commercial kits. Preceding day of EAE induction, combination of ATRA, D3, and DHA was administered with a single IP injection every 48 h and continued until day 26. Findings of present study showed that administration of vitamins A, D, and DHA significantly decreased average clinical scores, cumulative EAE score, and EAE incidence in Group T, compared to Group E (p values <0.001). Interferon γ secretion in serum and T-bet mRNA expression in splenocytes were significantly reduced (p = 0.004, p = 0.029, respectively) while PPARγ mRNA expression was significantly increased in Group T compared to Group E (p = 0.021). These findings highlighted that ATRA, D3, and DHA combination modulated PPARγ and T-bet gene expression and resulted in decrease in Th1 response and lymphocyte invasion into the central nervous system (CNS) and resultant inflammation. In conclusion, the results of this study suggested the potential use of this intervention in treatment and/or prevention of EAE/MS and probably other Th1 cell-mediated autoimmune diseases.
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Affiliation(s)
- Mohammad Reza Shiri-Shahsavar
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, International Campus, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Mirshafiee
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Karim Parastouei
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Ebrahimi-Kalan
- Neuroscience Department, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Yekaninejad
- Department of Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Farid Soleymani
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Chahardoli
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Mazaheri Nezhad Fard
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Saboor-Yaraghi
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, International Campus, Tehran University of Medical Sciences, Tehran, Iran.
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.
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Bystrom J, Clanchy FI, Taher TE, Mangat P, Jawad AS, Williams RO, Mageed RA. TNFα in the regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmune inflammatory diseases. Cytokine 2016; 101:4-13. [PMID: 27639923 DOI: 10.1016/j.cyto.2016.09.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 08/31/2016] [Accepted: 09/02/2016] [Indexed: 01/08/2023]
Abstract
TNFα is a principal pro-inflammatory cytokine vital for immunity to infections. However, its excessive production is involved in chronic inflammation and disease pathology in autoimmune diseases. Evidence for its pathogenic role is validated by the fact that its neutralisation by therapeutic agents in vivo is beneficial in ameliorating disease and controlling symptoms. Paradoxically, however, treatment with TNFα inhibitors can either have no clinical effects, or even exacerbate disease in some patients. The explanation for such contradictory outcomes may lay in how and which downstream signalling pathways are activated and drive disease. TNFα causes its effects by binding to either or both of two membrane-bound receptors, TNFR1 and TNFR2. Engagement of the receptors can induce cell death or cell proliferation. T cells both produce and respond to TNFα and depending on whether the cytokine is membrane-bound or soluble and the level of expression of its two receptors, the biological outcome can be distinct. In addition, polymorphisms in genes encoding TNFα and T cell signalling proteins can significantly impact the outcome of TNFα receptor engagement. Early studies revealed that effector T cells in patients with rheumatoid arthritis (RA) are hyporesponsive due to chronic exposure to TNFα. However, recent evidence indicates that the relationship between TNFα and T cell responses is complex and, at times, can be paradoxical. In addition, there is controversy as to the specific effects of TNFα on different T cell subsets. This review will summarise knowledge on how TNFα modulates T cell responses and the effect of engaging either of its two receptors. Furthermore, we discuss how such interactions can dictate the outcome of treatment with TNFα inhibitors.
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Affiliation(s)
- Jonas Bystrom
- Experimental Medicine and Rheumtology, William Harvey Research Institute, Queen Mary University of London, London, UK.
| | - F I Clanchy
- Kennedy Institute of Rheumatology, Oxford University, Oxford, UK
| | - Taher E Taher
- Experimental Medicine and Rheumtology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Pam Mangat
- Department of Rheumatology, Royal Free Hospital, NHS Foundation Trust, London, UK
| | - Ali S Jawad
- Experimental Medicine and Rheumtology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | | | - Rizgar A Mageed
- Experimental Medicine and Rheumtology, William Harvey Research Institute, Queen Mary University of London, London, UK
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Sapir-Koren R, Livshits G. Rheumatoid arthritis onset in postmenopausal women: Does the ACPA seropositive subset result from genetic effects, estrogen deficiency, skewed profile of CD4(+) T-cells, and their interactions? Mol Cell Endocrinol 2016; 431:145-63. [PMID: 27178986 DOI: 10.1016/j.mce.2016.05.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 05/04/2016] [Accepted: 05/09/2016] [Indexed: 12/28/2022]
Abstract
Rheumatoid arthritis (RA) incidence displays a differentiated age-dependent female-to-male ratio in which women outnumber men. Evidence that the peak incidence of RA in women coincides with menopause age, suggests a potential estrogenic role to disease etiology. Estrogens exert physiologically both stimulatory and inhibitory effects on the immune system. Epidemiologic and animal model studies with estrogen deprivation or supplementation suggested estrogens as to play, mainly, a protective role in RA immunopathology. In this review, we propose that some yet unidentified disturbances associated with estrogen circulating levels, differentiated by the menopausal status, play a major role in women's RA susceptibility. We focus on the interaction between estrogen deprivation and genetic risk alleles for anti-citrullinated protein antibodies (ACPA) seropositive RA, as a major driving force for increased immune reactivity and RA susceptibility, in postmenopausal women. This opens up new fields for research concerning the association among different irregular estrogenic conditions, the cytokine milieu, and age/menopausal status bias in RA.
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Affiliation(s)
- Rony Sapir-Koren
- Human Population Biology Research Group, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Gregory Livshits
- Human Population Biology Research Group, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Lilian and Marcel Pollak Chair of Biological Anthropology, Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
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Luan L, Han S, Wang H, Liu X. Down-regulation of the Th1, Th17, and Th22 pathways due to anti-TNF-α treatment in psoriasis. Int Immunopharmacol 2015; 29:278-284. [PMID: 26585971 DOI: 10.1016/j.intimp.2015.11.005] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2015] [Revised: 11/03/2015] [Accepted: 11/04/2015] [Indexed: 12/27/2022]
Abstract
BACKGROUND Psoriasis is a T-cell-mediated chronic inflammatory dermatosis. Th1, Th17 and Th22 cells are suggested to contribute to the pathogenesis of psoriasis. OBJECTIVE To determine whether treatment with the anti-tumor-necrosis-factor antagonist, adalimumab, induces significant modulation of the Th1, Th17 and Th22 pathways, and correlates cellular activity with clinical response. METHODS This study included 21 patients with moderate-to-severe psoriasis who were treated with adalimumab, and 10 healthy control subjects. Blood samples were collected at baseline and at week 12. Flow cytometry was used to analyze the frequency of circulating Th1, Th17 and Th22 cells. Real-time polymerase chain reaction was used to analyze the expression of T-bet (Th1-related), retinoid-acid receptor-related orphan receptor gamma t (RORγt, Th17-related) and aryl hydrocarbon receptor (AHR, Th22-related). An enzyme-linked immunosorbent assay was used to analyze the serum levels of IFN-γ, IL-17, IL-22, IL-6 and tumor necrosis factor-α (TNF-α). RESULTS At baseline, the frequencies of Th1, Th17 and Th22 cells were higher in psoriasis patients compared to the healthy controls. The expression of transcription factors T-bet, RORγt and AHR, and the serum levels of IFN-γ, IL-17, IL-22, IL-6 and TNF-α were higher in psoriasis patients compared to the healthy controls. After adalimumab therapy, there was a significant decline in the frequencies of Th1, Th17 and Th22 cells, and a concomitant decrease in the levels of their associated transcription factors and cytokines. CONCLUSION The results suggest that the anti-tumor-necrosis-factor antagonist, adalimumab, disrupts the Th1, Th17 and Th22 pathways, resulting in clinical improvement of psoriasis.
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Affiliation(s)
- Li Luan
- Department of Dermatology and Venereology, The Affiliated Zhongshan Hospital of DaLian University, 116001, China
| | - Shixin Han
- Department of Dermatology and Venereology, 1st Affiliated Hospital of DaLian Medical University, 116011, China
| | - Hua Wang
- Department of Dermatology and Venereology, 1st Affiliated Hospital of DaLian Medical University, 116011, China
| | - Xiaoming Liu
- Department of Dermatology and Venereology, 1st Affiliated Hospital of DaLian Medical University, 116011, China; Department of Dermatology and Venereology, Shenzhen Hospital of Hong Kong University, 518053, China.
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