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Lin X, Li X, Zhai Z, Zhang M. JAK-STAT pathway, type I/II cytokines, and new potential therapeutic strategy for autoimmune bullous diseases: update on pemphigus vulgaris and bullous pemphigoid. Front Immunol 2025; 16:1563286. [PMID: 40264772 PMCID: PMC12011800 DOI: 10.3389/fimmu.2025.1563286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Accepted: 03/20/2025] [Indexed: 04/24/2025] Open
Abstract
Autoimmune Bullous Diseases (AIBDs), characterized by the formation of blisters due to autoantibodies targeting structural proteins, pose significant therapeutic challenges. Current treatments, often involving glucocorticoids or traditional immunosuppressants, are limited by their non-specificity and side effects. Cytokines play a pivotal role in AIBDs pathogenesis by driving inflammation and immune responses. The JAK-STAT pathway is central to the biological effects of various type I and II cytokines, making it an attractive therapeutic target. Preliminary reports suggest that JAK inhibitors may be a promising approach in PV and BP, but further clinical validation is required. In AIBDs, particularly bullous pemphigoid (BP) and pemphigus vulgaris (PV), JAK inhibitors have shown promise in modulating pathogenic cytokine signaling. However, the safety and selectivity of JAK inhibitors remain critical considerations, with the potential for adverse effects and the need for tailored treatment strategies. This review explores the role of cytokines and the JAK-STAT pathway in BP and PV, evaluating the therapeutic potential and challenges associated with JAK inhibitors in managing these complex disorders.
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Affiliation(s)
| | | | - Zhifang Zhai
- Department of Dermatology, The First Affiliated Hospital, Army Medical University, Chongqing, China
| | - Mingwang Zhang
- Department of Dermatology, The First Affiliated Hospital, Army Medical University, Chongqing, China
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Tchouto MN, Bucher CH, Mess AK, Haas S, Schmidt-Bleek K, Duda GN, Beule D, Milek M. Pronounced impairment of B cell differentiation during bone regeneration in adult immune experienced mice. Front Immunol 2025; 16:1511902. [PMID: 40098964 PMCID: PMC11911212 DOI: 10.3389/fimmu.2025.1511902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 02/13/2025] [Indexed: 03/19/2025] Open
Abstract
Introduction Alterations of the adaptive immune system have been shown to impact bone healing and may result in impaired healing in some patients. Apart from T cells, B cells are the key drivers of adaptive immunity. Therefore, their role in age-associated impairments of bone healing might be essential to understand delays during the healing process. B cells are essential for bone formation, and their dysfunction has been associated with aging or autoimmune diseases. But whether age-associated changes in B cell phenotypes are involved in bone regeneration is unknown. Methods Here, we aimed to characterize the role of immune aging in B cell phenotypes during the early inflammatory phase of bone healing. By comparing non-immune experienced with young and immune experienced mice we aimed to analyze the effect of gained immune experience on B cells. Our single cell proteo-genomics analysis quantified thousands of transcriptomes of cells that were isolated from post osteotomy hematoma and the proximal and distal bone marrow cavities, and enabled us to evaluate cell proportion, differential gene expression and cell trajectories. Results While the B cell proportion in young and non-immune experienced animals did not significantly change from 2 to 5 days post osteotomy in the hematoma, we found a significant decrease of the B cell proportion in the immune experienced mice, which was accompanied by the decreased expression of B cell specific genes, suggesting a specific response in immune experienced animals. Furthermore, we detected the most extensive B cell differentiation block in immune-experienced mice compared to non-immune experienced and young animals, predominantly in the transition from immature to mature B cells. Discussion Our results suggest that the pronounced impairment of B cell production found in immune experienced animals plays an important role in the initial phase leading to delayed bone healing. Therefore, novel therapeutic approaches may be able target the B cell differentiation defect to retain B cell functionality even in the immune experienced setting, which is prone to delayed healing.
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Affiliation(s)
- Mireille Ngokingha Tchouto
- Julius Wolff Institute of Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- Core Unit Bioinformatics, Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christian H. Bucher
- Julius Wolff Institute of Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Ann-Kathrin Mess
- Julius Wolff Institute of Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies, Charité – Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Simon Haas
- Systems Hematology, Stem Cells & Precision Medicine, Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Katharina Schmidt-Bleek
- Julius Wolff Institute of Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Georg N. Duda
- Julius Wolff Institute of Biomechanics and Musculoskeletal Regeneration, Berlin Institute of Health at Charité – Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) Center for Regenerative Therapies, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Dieter Beule
- Core Unit Bioinformatics, Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Miha Milek
- Core Unit Bioinformatics, Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
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Young DJ, Edwards AJ, Quiroz Caceda KG, Liberzon E, Barrientos J, Hong SG, Turner J, Choyke PL, Arlauckas S, Lazorchak AS, Morgan RA, Sato N, Dunbar CE. In vivo tracking of ex-vivo-generated 89Zr-oxine-labeled plasma cells by PET in a non-human primate model. Mol Ther 2025; 33:580-594. [PMID: 39741408 PMCID: PMC11852699 DOI: 10.1016/j.ymthe.2024.12.042] [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: 05/24/2024] [Revised: 11/12/2024] [Accepted: 12/27/2024] [Indexed: 01/03/2025] Open
Abstract
B cells are an attractive platform for engineering to produce protein-based biologics absent in genetic disorders, and potentially for the treatment of metabolic diseases and cancer. As part of pre-clinical development of B cell medicines, we demonstrate a method to collect, ex vivo expand, differentiate, radioactively label, and track adoptively transferred non-human primate (NHP) B cells. These cells underwent 10- to 15-fold expansion, initiated IgG class switching, and differentiated into antibody-secreting cells. Zirconium-89-oxine-labeled cells were infused into autologous donors without any preconditioning and tracked by PET/CT imaging. Within 24 h of infusion, 20% of the initial dose homed to the bone marrow and spleen and distributed stably and equally between the two. Interestingly, approximately half of the dose homed to the liver. Image analysis of the bone marrow demonstrated inhomogeneous distribution of the cells. The subjects experienced no clinically significant side effects or laboratory abnormalities. A second infusion of B cells into one of the subjects resulted in an almost identical distribution of cells, suggesting possibly a non-limiting engraftment niche and feasibility of repeated infusions. This work supports the NHP as a valuable model to assess the potential of B cell medicines as potential treatment for human diseases.
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Affiliation(s)
- David J Young
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
| | | | - Kevin G Quiroz Caceda
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | | | | | - So Gun Hong
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | | | - Peter L Choyke
- National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | | | | | | | - Noriko Sato
- National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Cynthia E Dunbar
- National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Scapin G, Cagdas E, Grav LM, Lewis NE, Goletz S, Hafkenscheid L. Implications of glycosylation for the development of selected cytokines and their derivatives for medical use. Biotechnol Adv 2024; 77:108467. [PMID: 39447666 DOI: 10.1016/j.biotechadv.2024.108467] [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: 03/06/2024] [Revised: 09/13/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024]
Abstract
Cytokines are important regulators of immune responses, making them attractive targets for autoimmune diseases and cancer therapeutics. Yet, the significance of cytokine glycosylation remains underestimated. Many cytokines carry N- and O-glycans and some even undergo C-mannosylation. Recombinant cytokines produced in heterologous host cells may lack glycans or exhibit a different glycosylation pattern such as varying levels of galactosylation, sialylation, fucosylation or xylose addition compared to their human counterparts, potentially impacting critical immune interactions. We focused on cytokines that are currently utilized or designed in advanced therapeutic formats, including immunocytokines, fusokines, engager cytokines, and genetically engineered 'supercytokines.' Despite the innovative designs of these cytokine derivatives, their glycosylation patterns have not been extensively studied. By examining the glycosylation of the human native cytokines, G-CSF and GM-CSF, interferons β and γ, TNF-α and interleukins-2, -3 -4, -6, -7, -9, -12, -13, -15, -17A, -21, and - 22, we aim to assess its potential impact on their therapeutic derivatives. Understanding the glycosylation of the native cytokines could provide critical insights into the safety, efficacy, and functionality of these next-generation cytokine therapies, affecting factors such as stability, bioactivity, antigenicity, and half-life. This knowledge can guide the choice of optimal expression hosts for production and advance the development of effective cytokine-based therapeutics and synthetic immunology drugs.
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Affiliation(s)
- Giulia Scapin
- Department of Biotechnology and Biomedicine, Mammalian Cell Line Engineering, Technical University of Denmark, Søltofts Plads, 2800 Kgs Lyngby, Denmark
| | - Ece Cagdas
- Department of Biotechnology and Biomedicine, Mammalian Cell Line Engineering, Technical University of Denmark, Søltofts Plads, 2800 Kgs Lyngby, Denmark
| | - Lise Marie Grav
- Department of Biotechnology and Biomedicine, Mammalian Cell Line Engineering, Technical University of Denmark, Søltofts Plads, 2800 Kgs Lyngby, Denmark; The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Søltofts Plads, 2800 Kgs Lyngby, Denmark
| | - Nathan E Lewis
- Department of Pediatrics, University of California, San Diego, La Jolla, CA, USA; Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA
| | - Steffen Goletz
- Department of Biotechnology and Biomedicine, Biotherapeutic Glycoengineering and Immunology, Technical University of Denmark, Søltofts Plads, 2800 Kgs Lyngby, Denmark.
| | - Lise Hafkenscheid
- Department of Biotechnology and Biomedicine, Biotherapeutic Glycoengineering and Immunology, Technical University of Denmark, Søltofts Plads, 2800 Kgs Lyngby, Denmark.
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Young DJ, Edwards AJ, Quiroz Caceda KG, Liberzon E, Barrientos J, Hong S, Turner J, Choyke PL, Arlauckas S, Lazorchak AS, Morgan RA, Sato N, Dunbar CE. In vivo tracking of ex vivo generated 89 Zr-oxine labeled plasma cells by PET in a non-human primate model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.24.595782. [PMID: 38903108 PMCID: PMC11188104 DOI: 10.1101/2024.05.24.595782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
B cells are an attractive platform for engineering to produce protein-based biologics absent in genetic disorders, and potentially for the treatment of metabolic diseases and cancer. As part of pre-clinical development of B cell medicines, we demonstrate a method to collect, ex vivo expand, differentiate, radioactively label, and track adoptively transferred non-human primate (NHP) B cells. These cells underwent 10- to 15-fold expansion, initiated IgG class switching, and differentiated into antibody secreting cells. Zirconium-89-oxine labeled cells were infused into autologous donors without any preconditioning and tracked by PET/CT imaging. Within 24 hours of infusion, 20% of the initial dose homed to the bone marrow and spleen and distributed stably and equally between the two. Interestingly, approximately half of the dose homed to the liver. Image analysis of the bone marrow demonstrated inhomogeneous distribution of the cells. The subjects experienced no clinically significant side effects or laboratory abnormalities. A second infusion of B cells into one of the subjects resulted in an almost identical distribution of cells, suggesting a non-limiting engraftment niche and feasibility of repeated infusions. This work supports the NHP as a valuable model to assess the potential of B cell medicines as potential treatment for human diseases.
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6
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Kim J, Choi H, Jeun SS, Ahn S. From lymphopenia to restoration: IL-7 immunotherapy for lymphocyte recovery in glioblastoma. Cancer Lett 2024; 588:216714. [PMID: 38369003 DOI: 10.1016/j.canlet.2024.216714] [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: 12/12/2023] [Revised: 01/30/2024] [Accepted: 02/03/2024] [Indexed: 02/20/2024]
Abstract
Glioblastoma, the most prevalent malignant primary brain tumor, presents substantial treatment challenges because of its inherent aggressiveness and limited therapeutic options. Lymphopenia, defined as reduced peripheral blood lymphocyte count, commonly occurs as a consequence of the disease and its treatment. Recent studies have associated lymphopenia with a poor prognosis. Factors that contribute to lymphopenia include radiotherapy, chemotherapy, and the tumor itself. Patients who are female, older, using dexamethasone, or receiving higher doses of radiation therapy are particularly vulnerable to this condition. Several preclinical studies have explored the use of interleukin-7, a crucial cytokine for lymphocyte homeostasis, to restore lymphocyte counts and potentially rebuild the immune system to combat glioblastoma cells. With the development of recombinant interleukin-7 for prolonged activity in the body, various clinical trials are underway to explore this treatment in patients with glioblastoma. Our study provides a comprehensive summary of the incidence of lymphopenia, its potential biological background, and the associated clinical risk factors. Furthermore, we reviewed several clinical trials using IL-7 cytokine therapy in glioblastoma patients. We propose IL-7 as a promising immunotherapeutic strategy for glioblastoma treatment. We are optimistic that our study will enhance understanding of the complex interplay between lymphopenia and glioblastoma and will pave the way for the development of more effective treatment modalities.
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Affiliation(s)
- Joonseok Kim
- College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Haeyoun Choi
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sin-Soo Jeun
- Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Stephen Ahn
- Department of Neurosurgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Luo M, Gong W, Zhang Y, Li H, Ma D, Wu K, Gao Q, Fang Y. New insights into the stemness of adoptively transferred T cells by γc family cytokines. Cell Commun Signal 2023; 21:347. [PMID: 38049832 PMCID: PMC10694921 DOI: 10.1186/s12964-023-01354-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 10/11/2023] [Indexed: 12/06/2023] Open
Abstract
T cell-based adoptive cell therapy (ACT) has exhibited excellent antitumoral efficacy exemplified by the clinical breakthrough of chimeric antigen receptor therapy (CAR-T) in hematologic malignancies. It relies on the pool of functional T cells to retain the developmental potential to serially kill targeted cells. However, failure in the continuous supply and persistence of functional T cells has been recognized as a critical barrier to sustainable responses. Conferring stemness on infused T cells, yielding stem cell-like memory T cells (TSCM) characterized by constant self-renewal and multilineage differentiation similar to pluripotent stem cells, is indeed necessary and promising for enhancing T cell function and sustaining antitumor immunity. Therefore, it is crucial to identify TSCM cell induction regulators and acquire more TSCM cells as resource cells during production and after infusion to improve antitumoral efficacy. Recently, four common cytokine receptor γ chain (γc) family cytokines, encompassing interleukin-2 (IL-2), IL-7, IL-15, and IL-21, have been widely used in the development of long-lived adoptively transferred TSCM in vitro. However, challenges, including their non-specific toxicities and off-target effects, have led to substantial efforts for the development of engineered versions to unleash their full potential in the induction and maintenance of T cell stemness in ACT. In this review, we summarize the roles of the four γc family cytokines in the orchestration of adoptively transferred T cell stemness, introduce their engineered versions that modulate TSCM cell formation and demonstrate the potential of their various combinations. Video Abstract.
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Affiliation(s)
- Mengshi Luo
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjian Gong
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yuewen Zhang
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huayi Li
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ding Ma
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qinglei Gao
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yong Fang
- Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Lionakis MS. Exploiting antifungal immunity in the clinical context. Semin Immunol 2023; 67:101752. [PMID: 37001464 PMCID: PMC10192293 DOI: 10.1016/j.smim.2023.101752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Indexed: 03/31/2023]
Abstract
The continuous expansion of immunocompromised patient populations at-risk for developing life-threatening opportunistic fungal infections in recent decades has helped develop a deeper understanding of antifungal host defenses, which has provided the foundation for eventually devising immune-based targeted interventions in the clinic. This review outlines how genetic variation in certain immune pathway-related genes may contribute to the observed clinical variability in the risk of acquisition and/or severity of fungal infections and how immunogenetic-based patient stratification may enable the eventual development of personalized strategies for antifungal prophylaxis and/or vaccination. Moreover, this review synthesizes the emerging cytokine-based, cell-based, and other immunotherapeutic strategies that have shown promise as adjunctive therapies for boosting or modulating tissue-specific antifungal immune responses in the context of opportunistic fungal infections.
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Affiliation(s)
- Michail S Lionakis
- From the Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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Hou W, Zhang L, Chen J, Gu Y, Lv X, Zhang X, Li J, Liu H, Gao R. Expression Improvement of Recombinant Plasmids of the Interleukin-7 Gene in Chitosan-Derived Nanoparticles and Their Elevation of Mice Immunity. BIOLOGY 2023; 12:biology12050667. [PMID: 37237481 DOI: 10.3390/biology12050667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/27/2023] [Accepted: 04/24/2023] [Indexed: 05/28/2023]
Abstract
To investigate a safe and effective approach for enhancing the in vivo expression of recombinant genes and improving the systemic immunity of animals against infectious diseases, we employed the interleukin-7 (IL-7) gene from Tibetan pigs to construct a recombinant eukaryotic plasmid (VRTPIL-7). We first examined VRTPIL-7's bioactivity on porcine lymphocytes in vitro and then encapsulated it with polyethylenimine (PEI), chitosan copolymer (CS), PEG-modified galactosylated chitosan (CS-PEG-GAL) and methoxy poly (ethylene glycol) (PEG) and PEI-modified CS (CS-PEG-PEI) nanoparticles using the ionotropic gelation technique. Next, we intramuscularly or intraperitoneally injected mice with various nanoparticles containing VRTPIL-7 to evaluate their immunoregulatory effects in vivo. We observed a significant increase in neutralizing antibodies and specific IgG levels in response to the rabies vaccine in the treated mice compared to the controls. Treated mice also exhibited increased leukocytes, CD8+ and CD4+ T lymphocytes, and elevated mRNA levels of toll-like receptors (TLR1/4/6/9), IL-1, IL-2, IL-4, IL-6, IL-7, IL-23, and transforming growth factor-beta (TGF-β). Notably, the recombinant IL-7 gene encapsulated in CS-PEG-PEI induced the highest levels of immunoglobulins, CD4+ and CD8+ T cells, TLRs, and cytokines in the mice's blood, suggesting that chitosan-PEG-PEI may be a promising carrier for in vivo IL-7 gene expression and enhanced innate and adaptive immunity for the prevention of animal diseases.
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Affiliation(s)
- Wenli Hou
- Key Laboratory for Bioresource and Eco-Environment of the Education Ministry, College of Life Sciences, Sichuan University, Chengdu 610064, China
| | - Linhan Zhang
- Key Laboratory for Bioresource and Eco-Environment of the Education Ministry, College of Life Sciences, Sichuan University, Chengdu 610064, China
| | - Jianlin Chen
- School of Laboratory Medicine, Chengdu Medical College, Chengdu 610500, China
| | - Yiren Gu
- Sichuan Academy of Animal Science, Chengdu 610066, China
| | - Xuebin Lv
- Sichuan Academy of Animal Science, Chengdu 610066, China
| | - Xiuyue Zhang
- Key Laboratory for Bioresource and Eco-Environment of the Education Ministry, College of Life Sciences, Sichuan University, Chengdu 610064, China
| | - Jiangling Li
- Sichuan Academy of Animal Science, Chengdu 610066, China
| | - Hui Liu
- R&D Center, Chengdu Kanghua Biological Products Co., Ltd., Chengdu 610100, China
| | - Rong Gao
- Key Laboratory for Bioresource and Eco-Environment of the Education Ministry, College of Life Sciences, Sichuan University, Chengdu 610064, China
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In Vitro Human Haematopoietic Stem Cell Expansion and Differentiation. Cells 2023; 12:cells12060896. [PMID: 36980237 PMCID: PMC10046976 DOI: 10.3390/cells12060896] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 03/08/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023] Open
Abstract
The haematopoietic system plays an essential role in our health and survival. It is comprised of a range of mature blood and immune cell types, including oxygen-carrying erythrocytes, platelet-producing megakaryocytes and infection-fighting myeloid and lymphoid cells. Self-renewing multipotent haematopoietic stem cells (HSCs) and a range of intermediate haematopoietic progenitor cell types differentiate into these mature cell types to continuously support haematopoietic system homeostasis throughout life. This process of haematopoiesis is tightly regulated in vivo and primarily takes place in the bone marrow. Over the years, a range of in vitro culture systems have been developed, either to expand haematopoietic stem and progenitor cells or to differentiate them into the various haematopoietic lineages, based on the use of recombinant cytokines, co-culture systems and/or small molecules. These approaches provide important tractable models to study human haematopoiesis in vitro. Additionally, haematopoietic cell culture systems are being developed and clinical tested as a source of cell products for transplantation and transfusion medicine. This review discusses the in vitro culture protocols for human HSC expansion and differentiation, and summarises the key factors involved in these biological processes.
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Grčević D, Sanjay A, Lorenzo J. Interactions of B-lymphocytes and bone cells in health and disease. Bone 2023; 168:116296. [PMID: 34942359 PMCID: PMC9936888 DOI: 10.1016/j.bone.2021.116296] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 12/01/2021] [Accepted: 12/08/2021] [Indexed: 02/09/2023]
Abstract
Bone remodeling occurs through the interactions of three major cell lineages, osteoblasts, which mediate bone formation, osteocytes, which derive from osteoblasts, sense mechanical force and direct bone turnover, and osteoclasts, which mediate bone resorption. However, multiple additional cell types within the bone marrow, including macrophages, T lymphocytes and B lymphocytes influence the process. The bone marrow microenvironment, which is supported, in part, by bone cells, forms a nurturing network for B lymphopoiesis. In turn, developing B lymphocytes influence bone cells. Bone health during homeostasis depends on the normal interactions of bone cells with other lineages in the bone marrow. In disease state these interactions become pathologic and can cause abnormal function of bone cells and inadequate repair of bone after a fracture. This review summarizes what is known about the development of B lymphocytes and the interactions of B lymphocytes with bone cells in both health and disease.
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Affiliation(s)
- Danka Grčević
- Department of Physiology and Immunology, Croatian Institute for Brain Research, School of Medicine University of Zagreb, Zagreb, Croatia.
| | - Archana Sanjay
- Department of Orthopaedics, UConn Health, Farmington, CT, USA.
| | - Joseph Lorenzo
- Departments of Medicine and Orthopaedics, UConn Health, Farmington, CT, USA.
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12
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IL-7: Comprehensive review. Cytokine 2022; 160:156049. [DOI: 10.1016/j.cyto.2022.156049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 09/08/2022] [Accepted: 09/16/2022] [Indexed: 01/08/2023]
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13
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Wang C, Kong L, Kim S, Lee S, Oh S, Jo S, Jang I, Kim TD. The Role of IL-7 and IL-7R in Cancer Pathophysiology and Immunotherapy. Int J Mol Sci 2022; 23:ijms231810412. [PMID: 36142322 PMCID: PMC9499417 DOI: 10.3390/ijms231810412] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/06/2022] [Accepted: 09/06/2022] [Indexed: 12/03/2022] Open
Abstract
Interleukin-7 (IL-7) is a multipotent cytokine that maintains the homeostasis of the immune system. IL-7 plays a vital role in T-cell development, proliferation, and differentiation, as well as in B cell maturation through the activation of the IL-7 receptor (IL-7R). IL-7 is closely associated with tumor development and has been used in cancer clinical research and therapy. In this review, we first summarize the roles of IL-7 and IL-7Rα and their downstream signaling pathways in immunity and cancer. Furthermore, we summarize and discuss the recent advances in the use of IL-7 and IL-7Rα as cancer immunotherapy tools and highlight their potential for therapeutic applications. This review will help in the development of cancer immunotherapy regimens based on IL-7 and IL-7Rα, and will also advance their exploitation as more effective and safe immunotherapy tools.
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Affiliation(s)
- Chunli Wang
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
| | - Lingzu Kong
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
- Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon 34134, Korea
| | - Seokmin Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea
| | - Sunyoung Lee
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
- Department of Life Sciences, Korea University, Seoul 02841, Korea
| | - Sechan Oh
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea
| | - Seona Jo
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea
| | - Inhwan Jang
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea
| | - Tae-Don Kim
- Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
- Department of Functional Genomics, KRIBB School of Bioscience, Korea University of Science and Technology, Daejeon 34113, Korea
- Correspondence:
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14
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The Pleiotropy of PAX5 Gene Products and Function. Int J Mol Sci 2022; 23:ijms231710095. [PMID: 36077495 PMCID: PMC9456430 DOI: 10.3390/ijms231710095] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 08/23/2022] [Accepted: 08/26/2022] [Indexed: 11/17/2022] Open
Abstract
PAX5, a member of the Paired Box (PAX) transcription factor family, is an essential factor for B-lineage identity during lymphoid differentiation. Mechanistically, PAX5 controls gene expression profiles, which are pivotal to cellular processes such as viability, proliferation, and differentiation. Given its crucial function in B-cell development, PAX5 aberrant expression also correlates with hallmark cancer processes leading to hematological and other types of cancer lesions. Despite the well-established association of PAX5 in the development, maintenance, and progression of cancer disease, the use of PAX5 as a cancer biomarker or therapeutic target has yet to be implemented. This may be partly due to the assortment of PAX5 expressed products, which layers the complexity of their function and role in various regulatory networks and biological processes. In this review, we provide an overview of the reported data describing PAX5 products, their regulation, and function in cellular processes, cellular biology, and neoplasm.
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15
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Muromoto R, Oritani K, Matsuda T. Current understanding of the role of tyrosine kinase 2 signaling in immune responses. World J Biol Chem 2022; 13:1-14. [PMID: 35126866 PMCID: PMC8790287 DOI: 10.4331/wjbc.v13.i1.1] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 08/06/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Immune system is a complex network that clears pathogens, toxic substrates, and cancer cells. Distinguishing self-antigens from non-self-antigens is critical for the immune cell-mediated response against foreign antigens. The innate immune system elicits an early-phase response to various stimuli, whereas the adaptive immune response is tailored to previously encountered antigens. During immune responses, B cells differentiate into antibody-secreting cells, while naïve T cells differentiate into functionally specific effector cells [T helper 1 (Th1), Th2, Th17, and regulatory T cells]. However, enhanced or prolonged immune responses can result in autoimmune disorders, which are characterized by lymphocyte-mediated immune responses against self-antigens. Signal transduction of cytokines, which regulate the inflammatory cascades, is dependent on the members of the Janus family of protein kinases. Tyrosine kinase 2 (Tyk2) is associated with receptor subunits of immune-related cytokines, such as type I interferon, interleukin (IL)-6, IL-10, IL-12, and IL-23. Clinical studies on the therapeutic effects and the underlying mechanisms of Tyk2 inhibitors in autoimmune or chronic inflammatory diseases are currently ongoing. This review summarizes the findings of studies examining the role of Tyk2 in immune and/or inflammatory responses using Tyk2-deficient cells and mice.
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Affiliation(s)
- Ryuta Muromoto
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
| | - Kenji Oritani
- Department of Hematology, International University of Health and Welfare, Narita 286-8686, Japan
| | - Tadashi Matsuda
- Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
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16
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Sheikh A, Jackson J, Shim HB, Yau C, Seo JH, Abraham N. Selective dependence on IL-7 for antigen-specific CD8 T cell responses during airway influenza infection. Sci Rep 2022; 12:135. [PMID: 34997007 PMCID: PMC8741933 DOI: 10.1038/s41598-021-03936-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 12/06/2021] [Indexed: 11/08/2022] Open
Abstract
Interleukin-7 (IL-7) is a cytokine known for its importance in T cell development and survival. How IL-7 shapes CD8 T cell responses during an acute viral infection is less understood. We had previously shown that IL-7 signaling deficient mice have reduced accumulation of influenza-specific CD8 T cells following influenza infection. We sought to determine whether IL-7 affects early CD8 T cell expansion in the mediastinal lymph node and effector function in the lungs. Using IL-7Rα signaling deficient mice, we show that IL-7 is required for a normal sized mediastinal lymph node and the early clonal expansion of influenza-specific CD8 T cells therein. We show that IL-7 plays a cell-intrinsic role in the accumulation of NP366-374 and PA224-233-specific CD8 T cells in the lymph node. We also found that IL-7 shapes terminal differentiation, degranulation and cytokine production to a greater extent in PA224-233-specific than NP366-374-specific CD8 T cells. We further demonstrate that IL-7 is induced in the lung tissue by viral infection and we characterize multiple cellular sources that contribute to IL-7 production. Our findings on IL-7 and its effects on lower respiratory diseases will be important for expanding the utility of therapeutics that are currently available.
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Affiliation(s)
- Abdalla Sheikh
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Jennie Jackson
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Hanjoo Brian Shim
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
- Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
| | - Clement Yau
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
- Duke-NUS Medical School, 8 College Road, Singapore, Singapore
| | - Jung Hee Seo
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
- Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Ninan Abraham
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada.
- Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.
- Department of Zoology, University of British Columbia, Vancouver, BC, Canada.
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17
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Huang J, Long Z, Jia R, Wang M, Zhu D, Liu M, Chen S, Zhao X, Yang Q, Wu Y, Zhang S, Tian B, Mao S, Ou X, Sun D, Gao Q, Cheng A. The Broad Immunomodulatory Effects of IL-7 and Its Application In Vaccines. Front Immunol 2021; 12:680442. [PMID: 34956167 PMCID: PMC8702497 DOI: 10.3389/fimmu.2021.680442] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 11/24/2021] [Indexed: 12/30/2022] Open
Abstract
Interleukin-7 (IL-7) is produced by stromal cells, keratinocytes, and epithelial cells in host tissues or tumors and exerts a wide range of immune effects mediated by the IL-7 receptor (IL-7R). IL-7 is primarily involved in regulating the development of B cells, T cells, natural killer cells, and dendritic cells via the JAK-STAT, PI3K-Akt, and MAPK pathways. This cytokine participates in the early generation of lymphocyte subsets and maintain the survival of all lymphocyte subsets; in particular, IL-7 is essential for orchestrating the rearrangement of immunoglobulin genes and T-cell receptor genes in precursor B and T cells, respectively. In addition, IL-7 can aid the activation of immune cells in anti-virus and anti-tumor immunity and plays important roles in the restoration of immune function. These biological functions of IL-7 make it an important molecular adjuvant to improve vaccine efficacy as it can promote and extend systemic immune responses against pathogens by prolonging lymphocyte survival, enhancing effector cell activity, and increasing antigen-specific memory cell production. This review focuses on the biological function and mechanism of IL-7 and summarizes its contribution towards improved vaccine efficacy. We hope to provide a thorough overview of this cytokine and provide strategies for the development of the future vaccines.
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Affiliation(s)
- Juan Huang
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Zhiyao Long
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China
| | - Renyong Jia
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Mingshu Wang
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Dekang Zhu
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Mafeng Liu
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Shun Chen
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Xinxin Zhao
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Qiao Yang
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Ying Wu
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Shaqiu Zhang
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Bin Tian
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Sai Mao
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Xumin Ou
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Di Sun
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Qun Gao
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
| | - Anchun Cheng
- Research Center of Avian Disease, College of Veterinary Medicine of Sichuan Agricultural University, Chengdu, China.,Institute of Preventive Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, Sichuan Agricultural University, Chengdu, China
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18
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Chen D, Tang TX, Deng H, Yang XP, Tang ZH. Interleukin-7 Biology and Its Effects on Immune Cells: Mediator of Generation, Differentiation, Survival, and Homeostasis. Front Immunol 2021; 12:747324. [PMID: 34925323 PMCID: PMC8674869 DOI: 10.3389/fimmu.2021.747324] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 11/15/2021] [Indexed: 11/13/2022] Open
Abstract
Interleukin-7 (IL-7), a molecule known for its growth-promoting effects on progenitors of B cells, remains one of the most extensively studied cytokines. It plays a vital role in health maintenance and disease prevention, and the congenital deficiency of IL-7 signaling leads to profound immunodeficiency. IL-7 contributes to host defense by regulating the development and homeostasis of immune cells, including T lymphocytes, B lymphocytes, and natural killer (NK) cells. Clinical trials of recombinant IL-7 have demonstrated safety and potent immune reconstitution effects. In this article, we discuss IL-7 and its functions in immune cell development, drawing on a substantial body of knowledge regarding the biology of IL-7. We aim to answer some remaining questions about IL-7, providing insights essential for designing new strategies of immune intervention.
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Affiliation(s)
- Deng Chen
- Division of Trauma and Surgical Critical Care, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting-Xuan Tang
- Class 1901, School of Medicine, Wuhan University of Science and Technology, Wuhan, China
| | - Hai Deng
- Division of Trauma and Surgical Critical Care, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xiang-Ping Yang
- Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhao-Hui Tang
- Division of Trauma and Surgical Critical Care, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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19
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Ikuta K, Hara T, Abe S, Asahi T, Takami D, Cui G. The Roles of IL-7 and IL-15 in Niches for Lymphocyte Progenitors and Immune Cells in Lymphoid Organs. Curr Top Microbiol Immunol 2021; 434:83-101. [PMID: 34850283 DOI: 10.1007/978-3-030-86016-5_4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Lymphoid organs consist of immune cells and stromal cells. The stromal cells produce various cytokines that support the development, maintenance, and response of the immune cells. IL-7 and IL-15 are the major cytokines produced by stromal cells and are essential for the development and maintenance of lymphocytes and innate lymphoid cells (ILCs). In addition, IL-7 is indispensable for the organogenesis of lymphoid organs. However, because the amount of these two cytokines is relatively low, it has been difficult to directly detect their expression. Recently, several groups succeeded in establishing IL-7 and IL-15 reporter mouse lines. As expected, IL-7 and IL-15 were detected in mesenchymal stromal cells in the bone marrow and lymph nodes and in epithelial cells in the thymus. Furthermore, IL-7 and IL-15 were differentially expressed in lymphatic endothelial cells and blood endothelial cells, respectively. In addition to their expression, many groups have analyzed the local functions of IL-7 and IL-15 by using cell-type-specific knockout mice. From these experiments, CXCL12-expressing mesenchymal stromal cells were identified as the major niche for early B cell precursors. Single-cell RNA sequencing (scRNA-seq) analysis has revealed different subpopulations of stromal cells in the lymphoid organs, including those that express both IL-7 and IL-15. Future research is still needed to elucidate which stromal cells serve as the niche for the early precursors of ILCs and NK cells in the bone marrow.
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Affiliation(s)
- Koichi Ikuta
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.
| | - Takahiro Hara
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan
| | - Shinya Abe
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan
| | - Takuma Asahi
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.,Graduate School of Medicine, Kyoto University, Kyoto, 606-8501, Japan
| | - Daichi Takami
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan.,Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan
| | - Guangwei Cui
- Laboratory of Immune Regulation, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, 606-8507, Japan
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20
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Muromoto R, Shimoda K, Oritani K, Matsuda T. Therapeutic Advantage of Tyk2 Inhibition for Treating Autoimmune and Chronic Inflammatory Diseases. Biol Pharm Bull 2021; 44:1585-1592. [PMID: 34719635 DOI: 10.1248/bpb.b21-00609] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Tyrosine kinase 2 (Tyk2) is a member of the Janus family of protein tyrosine kinases (Jaks). Tyk2 associates with interferon (IFN)-α, IFN-β, interleukin (IL)-6, IL-10, IL-12, and IL-23 receptors and mediates their downstream signaling pathways. Based on our data using Tyk2-deficient mice and cells, Tyk2 plays crucial roles in the differentiation, maintenance, and function of T helper 1 (Th1) and Th17 cells, and its dysregulation may promote autoimmune and/or inflammatory diseases. IFN-α-induced growth inhibition of B lymphocyte progenitors is dependent on Tyk2-mediated signals to regulate death-associated protein (Daxx) nuclear localization and Daxx-promyelocytic leukemia protein interactions. Tyk2-deficient mice show impaired constitutive production of type I IFNs by macrophages under steady-state conditions. When heat-killed Cutibacterium acnes is injected intraperitoneally, Tyk2-deficient mice show less granuloma formation through enhanced prostaglandin E2 and protein kinase A activities, leading to high IL-10 production by macrophages. Thus, Tyk2 is widely involved in the immune and inflammatory response at multiple events; therefore, Tyk2 is likely to be a suitable target for treating patients with autoimmune and/or chronic inflammatory diseases. Clinical trials of Tyk2 inhibitors have shown higher response rates and improved tolerability in the treatment of patients with psoriasis and inflammatory bowel diseases. Taken together, Tyk2 inhibition has great potential for clinical application in the management of a variety of diseases.
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Affiliation(s)
- Ryuta Muromoto
- Department of Immunology, Graduate School of Pharmaceutical Sciences Hokkaido University
| | - Kazuya Shimoda
- Department of Internal Medicine II, Faculty of Medicine, University of Miyazaki
| | - Kenji Oritani
- Department of Hematology, International University of Health and Welfare
| | - Tadashi Matsuda
- Department of Immunology, Graduate School of Pharmaceutical Sciences Hokkaido University
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21
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Clever D, Thompson D, Gosselin M, Brouillet K, Guilak F, Luhmann SJ. Pilot Study Analysis of Serum Cytokines to Differentiate Pediatric Septic Arthritis and Transient Synovitis. J Pediatr Orthop 2021; 41:610-616. [PMID: 34483309 DOI: 10.1097/bpo.0000000000001909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND In pediatric patients, the presentation of the nontraumatic acutely painful joint/limb poses a diagnostic dilemma due to the similarity of presentations of the most likely diagnoses [septic arthritis (SA), transient synovitis (TS), osteomyelitis]. Current tools employed to differentiate these diagnoses rely on nonspecific inflammatory markers, radiologic imaging, and arthrocentesis. Diagnostic algorithms utilizing these clinical, radiographic, and biochemical parameters have produced conflicting results. The purpose of this study was to identify a serum-based inflammatory signature which can differentiate SA from TS in pediatric patients. METHODS Serum samples were collected from 22 pediatric patients presenting with joint/extremity pain whose working diagnosis included SA or TS. Each sample was analyzed for serum abundance of 72 distinct biomarkers and cytokines using enzyme linked immunosorbent assay based arrays. Linear discriminant analysis was performed to identify a combinatorial biomarker panel to predict a diagnosis of SA or TS. Efficacy of the biomarker panel was compared with definitive diagnoses as based on laboratory tests, arthrocentesis results, and clinical scenario. RESULTS At the time of presentation: (1) mean erythrocyte sedimentation rate in the SA group was 56.6 mm/h and 12.4 mm/h in the TS group (P<0.001), (2) mean C-reactive protein was 55.9 mg/dL in the SA group and 13.7 mg/dL in the TS group (P=0.12), and (3) mean white blood cell was 10.9 k/mm3 in the SA group and 11.0 k/mm3 in the TS group (P=0.95). A combined panel of 72 biomarkers was examined using discriminant analysis to identify a limited set of predictors which could accurately predict whether a patient was diagnosed with SA or TS. A diagnostic algorithm consisting of transforming growth factor alpha, interleukin (IL)-7, IL-33, and IL-28A serum concentration correctly classified 20 of the 22 cases with a sensitivity and specificity of 90.9% (95% confidence interval: 73.9%-100.0%). CONCLUSION This study identifies a novel serum-based 4-cytokine panel that accurately differentiates SA from TS in pediatric patients with joint/limb pain. LEVEL OF EVIDENCE Level II-diagnostic study.
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Affiliation(s)
| | | | | | - Kirsten Brouillet
- Pediatric Orthopaedic Surgery, Washington University School of Medicine
| | - Farshid Guilak
- Departments of Orthopedic Surgery
- Shriners Hospitals for Children-St. Louis, St. Louis, MO
| | - Scott J Luhmann
- Departments of Orthopedic Surgery
- Pediatric Orthopaedic Surgery, Washington University School of Medicine
- Shriners Hospitals for Children-St. Louis, St. Louis, MO
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22
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Aloufi NA, Ali AK, Burke Schinkel SC, Molyer B, Barros PO, McBane JE, Lee SH, Angel JB. Soluble CD127 potentiates IL-7 activity in vivo in healthy mice. IMMUNITY INFLAMMATION AND DISEASE 2021; 9:1798-1808. [PMID: 34525268 PMCID: PMC8589376 DOI: 10.1002/iid3.530] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 08/18/2021] [Accepted: 09/01/2021] [Indexed: 11/06/2022]
Abstract
Introduction Soluble forms of cytokine receptors can be involved in the endogenous regulation of cytokine activity. Soluble interleukin 7 receptor α (sCD127) naturally binds IL‐7, therefore there is interest in its potential application as an immunotherapeutic agent to regulate IL‐7. With the hypothesis that sCD127 enhances IL‐7 activity, thus promoting T‐cell proliferation in vivo, we sought to assess the effect of sCD127, IL‐7 or IL‐7 + sCD127 treatment on CD4+ and CD8+ T‐cells in the blood and spleen of mice. Methods Peripheral blood mononuclear cells and splenocytes were prepared, and analyzed for T‐cell number, phenotype and proliferation (Ki67+) by flow cytometry. Results IL‐7 treatment induced T‐cell proliferation, increased T‐cell number, and triggered T‐cell differentiation each of which was enhanced with the addition of sCD127. IL‐7 + sCD127 treatment significantly increased spleen weight over that seen with IL‐7 treatment alone. More pronounced proliferation and a greater increase in cell number was observed in CD8+ T‐cells relative to the effect on CD4+ T‐cells. Conclusions These findings suggest that the addition of sCD127 enhances IL‐7‐mediated T‐cell proliferation and suggests a potential therapeutic use for sCD127.
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Affiliation(s)
- Nawaf A Aloufi
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.,King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Chronic Diseases Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Alaa K Ali
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada
| | | | - Bengisu Molyer
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.,Chronic Diseases Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Priscila O Barros
- Chronic Diseases Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Joanne E McBane
- Chronic Diseases Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Canadian Institutes of Health Research (CIHR), Canadian HIV Trials Network (CTN), Vancouver, British Columbia, Canada
| | - Seung-Hwan Lee
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.,Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Ontario, Canada
| | - Jonathan B Angel
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.,Chronic Diseases Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, Ontario, Canada.,Department of Medicine, Division of Infectious Diseases, The Ottawa Hospital, University of Ottawa, Ottawa, Ontario, Canada
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23
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Clark IA. Background to new treatments for COVID-19, including its chronicity, through altering elements of the cytokine storm. Rev Med Virol 2021; 31:1-13. [PMID: 33580566 PMCID: PMC7883210 DOI: 10.1002/rmv.2210] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 12/08/2020] [Accepted: 12/09/2020] [Indexed: 12/11/2022]
Abstract
Anti-tumour necrosis factor (TNF) biologicals, Dexamethasone and rIL-7 are of considerable interest in treating COVID-19 patients who are in danger of, or have become, seriously ill. Yet reducing sepsis mortality by lowering circulating levels of TNF lost favour when positive endpoints in earlier simplistic models could not be reproduced in well-conducted human trials. Newer information with anti-TNF biologicals has encouraged reintroducing this concept for treating COVID-19. Viral models have had encouraging outcomes, as have the effects of anti-TNF biologicals on community-acquired COVID-19 during their long-term use to treat chronic inflammatory states. The positive outcome of a large scale trial of dexamethasone, and its higher potency late in the disease, harmonises well with its capacity to enhance levels of IL-7Rα, the receptor for IL-7, a cytokine that enhances lymphocyte development and is increased during the cytokine storm. Lymphoid germinal centres required for antibody-based immunity can be harmed by TNF, and restored by reducing TNF. Thus the IL-7- enhancing activity of dexamethasone may explain its higher potency when lymphocytes are depleted later in the infection, while employing anti-TNF, for several reasons, is much more logical earlier in the infection. This implies dexamethasone could prove to be synergistic with rIL-7, currently being trialed as a COVID-19 therapeutic. The principles behind these COVID-19 therapies are consistent with the observed chronic hypoxia through reduced mitochondrial function, and also the increased severity of this disease in ApoE4-positive individuals. Many of the debilitating persistent aspects of this disease are predictably susceptible to treatment with perispinal etanercept, since they have cerebral origins.
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Affiliation(s)
- Ian A. Clark
- Research School of BiologyAustralian National UniversityCanberraAustralia
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24
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Abstract
Conventional CD4+ and CD8+ T lymphocytes comprise a mixture of naive and memory cells. Generation and survival of these T-cell subsets is under strict homeostatic control and reflects contact with self-major histocompatibility complex (MHC) and certain cytokines. Naive T cells arise in the thymus via T-cell receptor (TCR)-dependent positive selection to self-peptide/MHC complexes and are then maintained in the periphery through self-MHC interaction plus stimulation via interleukin-7 (IL-7). By contrast, memory T cells are largely MHC-independent for their survival but depend strongly on stimulation via cytokines. Whereas typical memory T cells are generated in response to foreign antigens, some arise spontaneously through contact of naive precursors with self-MHC ligands; we refer to these cells as memory-phenotype (MP) T cells. In this review, we discuss the generation and homeostasis of naive T cells and these two types of memory T cells, focusing on their relative interaction with MHC ligands and cytokines.
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Affiliation(s)
- Takeshi Kawabe
- Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8575, Japan
| | - Jaeu Yi
- Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA
| | - Jonathan Sprent
- Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia
- St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2010, Australia
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25
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Qiu Y, Su M, Liu L, Tang Y, Pan Y, Sun J. Clinical Application of Cytokines in Cancer Immunotherapy. Drug Des Devel Ther 2021; 15:2269-2287. [PMID: 34079226 PMCID: PMC8166316 DOI: 10.2147/dddt.s308578] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/20/2021] [Indexed: 12/12/2022] Open
Abstract
Cytokines are key components of the immune system and play pivotal roles in anticancer immune response. Cytokines as either therapeutic agents or targets hold clinical promise for cancer precise treatment. Here, we provide an overview of the various roles of cytokines in the cancer immunity cycle, with a particular focus on the clinical researches of cytokine-based drugs in cancer therapy. We review 27 cytokines in 2630 cancer clinical trials registered with ClinicalTrials.gov that had completed recruitment up to January 2021 while summarizing important cases for each cytokine. We also discuss recent progress in methods for improving the delivery efficiency, stability, biocompatibility, and availability of cytokines in therapeutic applications.
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Affiliation(s)
- Yi Qiu
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Mengxi Su
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Leyi Liu
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Yiqi Tang
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Yuan Pan
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
| | - Jianbo Sun
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, People’s Republic of China
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26
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Delahaye MC, Salem KI, Pelletier J, Aurrand-Lions M, Mancini SJC. Toward Therapeutic Targeting of Bone Marrow Leukemic Niche Protective Signals in B-Cell Acute Lymphoblastic Leukemia. Front Oncol 2021; 10:606540. [PMID: 33489914 PMCID: PMC7820772 DOI: 10.3389/fonc.2020.606540] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 11/23/2020] [Indexed: 01/01/2023] Open
Abstract
B-cell acute lymphoblastic leukemia (B-ALL) represents the malignant counterpart of bone marrow (BM) differentiating B cells and occurs most frequently in children. While new combinations of chemotherapeutic agents have dramatically improved the prognosis for young patients, disease outcome remains poor after relapse or in adult patients. This is likely due to heterogeneity of B-ALL response to treatment which relies not only on intrinsic properties of leukemic cells, but also on extrinsic protective cues transmitted by the tumor cell microenvironment. Alternatively, leukemic cells have the capacity to shape their microenvironment towards their needs. Most knowledge on the role of protective niches has emerged from the identification of mesenchymal and endothelial cells controlling hematopoietic stem cell self-renewal or B cell differentiation. In this review, we discuss the current knowledge about B-ALL protective niches and the development of therapies targeting the crosstalk between leukemic cells and their microenvironment.
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27
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Panebra A, Kim WH, Hong YH, Lillehoj HS. Research Note: Characterization of monoclonal antibodies and development of sandwich ELISA for detecting chicken IL7. Poult Sci 2021; 100:100940. [PMID: 33652529 PMCID: PMC7936204 DOI: 10.1016/j.psj.2020.12.037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/11/2020] [Accepted: 12/15/2020] [Indexed: 11/18/2022] Open
Abstract
IL7 is a hematopoietic growth factor required for development and maintenance of lymphocytes including T cells, B cells, and natural killer cells. Recently, chicken IL7 (chIL7) has been cloned and studied in viral and parasite infection models. However, no monoclonal antibodies (mAb) that specifically detect chIL7 have been developed so far. In this study, recombinant chIL7 that expressed for immunization and mAb against chIL7 were developed and characterized to assess their immunologic properties. Five mAb exhibiting specific binding to chIL7 were generated and investigated for their applicability by Western blot, ELISA, and neutralization assays. A sandwich ELISA mAb pair that enables the measurement of chIL7 protein levels in biological samples from Eimeria-infected chickens was identified and several mAb neutralized chicken primary thymocyte proliferation mediated by chIL7. The mAb developed in this study will be valuable reagents for fundamental and applied immunological studies in poultry.
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Affiliation(s)
- Alfredo Panebra
- Animal Biosciences and Biotechnology Laboratory, Beltsville Agricultural Research Center, U.S. Department of Agriculture-ARS, Beltsville, MD 20705, USA
| | - Woo H Kim
- Animal Biosciences and Biotechnology Laboratory, Beltsville Agricultural Research Center, U.S. Department of Agriculture-ARS, Beltsville, MD 20705, USA
| | - Yeong H Hong
- Department of Animal Science and Technology, Chung-Ang University, Anseong-si, Gyeonggi-do 17546, Republic of Korea
| | - Hyun S Lillehoj
- Animal Biosciences and Biotechnology Laboratory, Beltsville Agricultural Research Center, U.S. Department of Agriculture-ARS, Beltsville, MD 20705, USA.
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28
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Otsuka H, Endo Y, Ohtsu H, Inoue S, Kuraoka M, Koh M, Yagi H, Nakamura M, Soeta S. Changes in histidine decarboxylase expression influence extramedullary hematopoiesis in postnatal mice. Anat Rec (Hoboken) 2020; 304:1136-1150. [PMID: 33034098 DOI: 10.1002/ar.24533] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 08/06/2020] [Accepted: 08/07/2020] [Indexed: 12/16/2022]
Abstract
Histidine decarboxylase (HDC), histamine synthase, is expressed in hematopoietic stem cells and in lineage-committed progenitors in the bone marrow (BM). However, the role of histamine in hematopoiesis is not well described. To evaluate the role of histamine in hematopoiesis, we analyzed the changes in HDC expression at hematopoietic sites, the BM, spleen, and liver of 2-, 3-, and 6-week-old wild-type mice. We also performed morphological analyses of the hematopoietic sites using HDC-deficient (HDC-KO) mice. In wild-type adults, HDC expression in the BM was higher than that in the spleen and liver and showed an age-dependent increase. Histological analysis showed no significant change in the adult BM and spleen of HDC-KO mice compared to wild-type mice. In the liver, HDC expression was temporarily increased at 3 weeks and decreased at 6 weeks of age. Morphological analysis of the liver revealed more numerous hematopoietic colonies and megakaryocytes in HDC-KO mice compared to wild-type mice at 2 and 3 weeks of age, whereas no changes were observed in adults. Most of these hematopoietic colonies consisted of B220-positive B-lymphocytes and TER119-positive erythroblasts and were positive for the cell proliferation marker PCNA. Notably, these hematopoietic colonies declined in HDC-KO mice upon N-acetyl histamine treatment. A significant increase in the expression of hematopoiesis-related cytokines, Il3, Il7, Epo, Gcsf, and Cxcl12 mRNA was observed in the liver of 3-week-old HDC-KO mice compared to wild-type mice. These results suggest that histamine-deficiency may maintain an microenvironment suitable for hematopoiesis by regulating hematopoiesis-related cytokine expression in the liver of postnatal mice.
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Affiliation(s)
- Hirotada Otsuka
- Laboratory of Veterinary Anatomy, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Yasuo Endo
- Division of Oral and Maxillofacial Surgery, Graduate School of Dentistry, Tohoku University, Sendai, Japan
| | - Hiroshi Ohtsu
- Tekiju Rehabilitation Hospital, Kobe-shi, Hyogo, Japan.,Tohoku University, Sendai, Japan
| | - Satoshi Inoue
- Department of Oral Anatomy and Developmental Biology, School of Dentistry, Showa University, Shinagawa-ku, Tokyo, Japan
| | - Mutsuki Kuraoka
- Laboratory of Experimental Animal Science, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Miki Koh
- Laboratory of Veterinary Anatomy, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
| | - Hideki Yagi
- Department of Pharmaceutical, Faculty of Pharmacy, International University of Health and Welfare, Otawara-shi, Tochigi, Japan
| | - Masanori Nakamura
- Department of Oral Anatomy and Developmental Biology, School of Dentistry, Showa University, Shinagawa-ku, Tokyo, Japan
| | - Satoshi Soeta
- Laboratory of Veterinary Anatomy, Nippon Veterinary and Life Science University, Musashino-shi, Tokyo, Japan
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29
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Facts and Challenges in Immunotherapy for T-Cell Acute Lymphoblastic Leukemia. Int J Mol Sci 2020; 21:ijms21207685. [PMID: 33081391 PMCID: PMC7589289 DOI: 10.3390/ijms21207685] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 10/13/2020] [Accepted: 10/14/2020] [Indexed: 12/12/2022] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL), a T-cell malignant disease that mainly affects children, is still a medical challenge, especially for refractory patients for whom therapeutic options are scarce. Recent advances in immunotherapy for B-cell malignancies based on increasingly efficacious monoclonal antibodies (mAbs) and chimeric antigen receptors (CARs) have been encouraging for non-responding or relapsing patients suffering from other aggressive cancers like T-ALL. However, secondary life-threatening T-cell immunodeficiency due to shared expression of targeted antigens by healthy and malignant T cells is a main drawback of mAb—or CAR-based immunotherapies for T-ALL and other T-cell malignancies. This review provides a comprehensive update on the different immunotherapeutic strategies that are being currently applied to T-ALL. We highlight recent progress on the identification of new potential targets showing promising preclinical results and discuss current challenges and opportunities for developing novel safe and efficacious immunotherapies for T-ALL.
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30
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Lee BM, Byun HK, Seong J. Significance of lymphocyte recovery from treatment-related lymphopenia in locally advanced pancreatic cancer. Radiother Oncol 2020; 151:82-87. [PMID: 32681928 DOI: 10.1016/j.radonc.2020.07.026] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 07/01/2020] [Accepted: 07/09/2020] [Indexed: 01/21/2023]
Abstract
BACKGROUND AND PURPOSE Radiation-induced lymphopenia is associated with poor prognosis in resected pancreatic cancer and locally advanced pancreatic cancer. However, whether lymphocyte recovery contributes to pancreatic cancer prognosis has not been well-investigated. MATERIALS AND METHODS We evaluated 497 locally advanced pancreatic cancer patients who underwent concurrent chemoradiotherapy (CCRT). Complete blood counts of patients were obtained before, during, and after CCRT until the 12-month follow-up visit. Patients were categorized into 3 groups according to the development of and recovery from acutte severe lymphopenia (ASL): no ASL (group A, n = 198), recovery from ASL (group B, n = 141), and no recovery from ASL (group C, n = 89). Prognostic factors of overall survival (OS) and progression-free survival (PFS) were determined using Cox regression analyses. RESULTS In groups A, B, and C, the 2-year OS rates were 40.4%, 31.9%, and 14.6%, respectively, and the 2-year PFS rates were 23.7%, 18.4%, and 10.1%, respectively. OS and PFS were comparable between Groups A and B, while group C had poor OS and PFS (p < 0.001). Recovery from ASL was associated with superior OS (HR 0.42, 95% CI: 0.32-0.55, p < 0.001) and PFS (HR 0.53, 95% CI: 0.41-0.70, p < 0.001). The baseline lymphocyte counts and target volume independently predicted development and recovery from ASL. CONCLUSION Recovery from ASL was associated with both superior OS and PFS in patients who received CCRT for locally advanced pancreatic cancer. Baseline lymphocyte counts and target volume were associated with both the development of and recovery from treatment-related ASL.
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Affiliation(s)
- Byung Min Lee
- Departments of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hwa Kyung Byun
- Departments of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jinsil Seong
- Departments of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
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31
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Ahn N, Kim K. Effects of Aerobic and Resistance Exercise on Myokines in High Fat Diet-Induced Middle-Aged Obese Rats. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:ijerph17082685. [PMID: 32295130 PMCID: PMC7215661 DOI: 10.3390/ijerph17082685] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 04/10/2020] [Accepted: 04/12/2020] [Indexed: 12/11/2022]
Abstract
The objective of this study was to analyze the effects of aerobic and resistance exercise on myokines expression in the skeletal muscle of middle-aged rats with high fat diet-induced obesity, to investigate the feasibility of using exercise training to reduce inflammation. Male 50-week-old Sprague Dawley rats were divided into normal diet, normal diet + exercise, high fat diet, and high fat diet + exercise groups. After six weeks on a high fat diet to induce obesity, a 12-week exercise program was implemented, which combined aerobic exercise (treadmill running) and resistance exercise (ladder climbing) three times a week for 75 min per session. We analyzed the protein levels of interleukins (IL) 6, 7, and 8, C-X-C motif chemokine receptor 2, and vascular endothelial growth factor in skeletal muscles by western blotting. Body weight decreased significantly during the 12-week exercise program in the exercise groups compared to the non-exercise groups (p < 0.05). The levels of all myokines analyzed were significantly lower in the skeletal muscle of the high fat diet group compared to the normal diet group (p < 0.05). After completing the 12-week exercise program, IL-7, IL-8, C-X-C motif chemokine receptor 2, and vascular endothelial growth factor expressions were significantly higher in the high fat diet + exercise group compared to the high fat diet group (p < 0.05). However, while IL-6 expression was significantly lower in the high fat diet and high fat diet + exercise groups compared to the normal diet group (p < 0.05), it was not significantly affected by exercise. In conclusion, high fat diet-induced obesity resulted in decreased myokines in the skeletal muscles, but combined exercise training of aerobic and resistance exercise increased myokines secretion in the skeletal muscle of obese rats, and is thought to help reduce inflammation.
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Affiliation(s)
| | - Kijin Kim
- Correspondence: ; Tel.: +82-53-580-5256
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32
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Abstract
Cytokines and hematopoietic growth factors have traditionally been thought of as regulators of the development and function of immune and blood cells. However, an ever-expanding number of these factors have been discovered to have major effects on bone cells and the development of the skeleton in health and disease (Table 1). In addition, several cytokines have been directly linked to the development of osteoporosis in both animal models and in patients. In order to understand the mechanisms regulating bone cells and how this may be dysregulated in disease states, it is necessary to appreciate the diverse effects that cytokines and inflammation have on osteoblasts, osteoclasts, and bone mass. This chapter provides a broad overview of this topic with extensive references so that, if desired, readers can access specific references to delve into individual topics in greater detail.
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Affiliation(s)
- Joseph Lorenzo
- Departments of Medicine and Orthopaedic Surgery, UConn Health, Farmington, CT, USA.
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33
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Leonard WJ, Lin JX, O'Shea JJ. The γ c Family of Cytokines: Basic Biology to Therapeutic Ramifications. Immunity 2019; 50:832-850. [PMID: 30995502 DOI: 10.1016/j.immuni.2019.03.028] [Citation(s) in RCA: 260] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 03/22/2019] [Accepted: 03/26/2019] [Indexed: 12/15/2022]
Abstract
The common cytokine receptor γ chain, γc, is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γc results in X-linked severe combined immunodeficiency in humans, and γc family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.
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Affiliation(s)
- Warren J Leonard
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674, USA.
| | - Jian-Xin Lin
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674, USA.
| | - John J O'Shea
- Molecular Immunology and Inflammation Branch, National Institute of Arthritis, Metabolic, and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1674, USA.
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34
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Leung GA, Cool T, Valencia CH, Worthington A, Beaudin AE, Forsberg EC. The lymphoid-associated interleukin 7 receptor (IL7R) regulates tissue-resident macrophage development. Development 2019; 146:146/14/dev176180. [PMID: 31332039 DOI: 10.1242/dev.176180] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 06/25/2019] [Indexed: 12/13/2022]
Abstract
The discovery of a fetal origin for tissue-resident macrophages (trMacs) has inspired an intense search for the mechanisms underlying their development. Here, we performed in vivo lineage tracing of cells with an expression history of IL7Rα, a marker exclusively associated with the lymphoid lineage in adult hematopoiesis. Surprisingly, we found that Il7r-Cre labeled fetal-derived, adult trMacs. Labeling was almost complete in some tissues and partial in others. The putative progenitors of trMacs, yolk sac (YS) erythromyeloid progenitors, did not express IL7R, and YS hematopoiesis was unperturbed in IL7R-deficient mice. In contrast, tracking of IL7Rα message levels, surface expression, and Il7r-Cre-mediated labeling across fetal development revealed dynamic regulation of Il7r mRNA expression and rapid upregulation of IL7Rα surface protein upon transition from monocyte to macrophage within fetal tissues. Fetal monocyte differentiation in vitro produced IL7R+ macrophages, supporting a direct progenitor-progeny relationship. Additionally, blockade of IL7R function during late gestation specifically impaired the establishment of fetal-derived trMacs in vivo These data provide evidence for a distinct function of IL7Rα in fetal myelopoiesis and identify IL7R as a novel regulator of trMac development.
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Affiliation(s)
- Gabriel A Leung
- Quantitative and Systems Biology Program, University of California-Merced, Merced, CA 95343, USA
| | - Taylor Cool
- Institute for the Biology of Stem Cells, University of California-Santa Cruz, Santa Cruz, CA 95064, USA.,Department of Biological Sciences, San Jose State University, San Jose, CA 95192, USA.,Department of Molecular, Cell, and Developmental Biology, University of California-Santa Cruz, Santa Cruz, CA 95064, USA
| | - Clint H Valencia
- Molecular and Cell Biology Department, School of Natural Sciences, University of California-Merced, Merced, CA 95343, USA
| | - Atesh Worthington
- Institute for the Biology of Stem Cells, University of California-Santa Cruz, Santa Cruz, CA 95064, USA.,Department of Molecular, Cell, and Developmental Biology, University of California-Santa Cruz, Santa Cruz, CA 95064, USA
| | - Anna E Beaudin
- Molecular and Cell Biology Department, School of Natural Sciences, University of California-Merced, Merced, CA 95343, USA
| | - E Camilla Forsberg
- Institute for the Biology of Stem Cells, University of California-Santa Cruz, Santa Cruz, CA 95064, USA .,Department of Biomolecular Engineering, University of California-Santa Cruz, Santa Cruz, CA 95064, USA
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35
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Baryawno N, Przybylski D, Kowalczyk MS, Kfoury Y, Severe N, Gustafsson K, Kokkaliaris KD, Mercier F, Tabaka M, Hofree M, Dionne D, Papazian A, Lee D, Ashenberg O, Subramanian A, Vaishnav ED, Rozenblatt-Rosen O, Regev A, Scadden DT. A Cellular Taxonomy of the Bone Marrow Stroma in Homeostasis and Leukemia. Cell 2019; 177:1915-1932.e16. [PMID: 31130381 DOI: 10.1016/j.cell.2019.04.040] [Citation(s) in RCA: 601] [Impact Index Per Article: 100.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 03/05/2019] [Accepted: 04/23/2019] [Indexed: 01/23/2023]
Abstract
Stroma is a poorly defined non-parenchymal component of virtually every organ with key roles in organ development, homeostasis, and repair. Studies of the bone marrow stroma have defined individual populations in the stem cell niche regulating hematopoietic regeneration and capable of initiating leukemia. Here, we use single-cell RNA sequencing (scRNA-seq) to define a cellular taxonomy of the mouse bone marrow stroma and its perturbation by malignancy. We identified seventeen stromal subsets expressing distinct hematopoietic regulatory genes spanning new fibroblastic and osteoblastic subpopulations including distinct osteoblast differentiation trajectories. Emerging acute myeloid leukemia impaired mesenchymal osteogenic differentiation and reduced regulatory molecules necessary for normal hematopoiesis. These data suggest that tissue stroma responds to malignant cells by disadvantaging normal parenchymal cells. Our taxonomy of the stromal compartment provides a comprehensive bone marrow cell census and experimental support for cancer cell crosstalk with specific stromal elements to impair normal tissue function and thereby enable emergent cancer.
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Affiliation(s)
- Ninib Baryawno
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Childhood Cancer Research Unit, Dep. of Children's and Women's Health, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Dariusz Przybylski
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Monika S Kowalczyk
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Youmna Kfoury
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Nicolas Severe
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Karin Gustafsson
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Konstantinos D Kokkaliaris
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Francois Mercier
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Marcin Tabaka
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Matan Hofree
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Danielle Dionne
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Ani Papazian
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA
| | - Dongjun Lee
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Department of Convergence Medical Science, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Orr Ashenberg
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Ayshwarya Subramanian
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | | | - Orit Rozenblatt-Rosen
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Aviv Regev
- Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Koch Institute of Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
| | - David T Scadden
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
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36
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Signalling circuits that direct early B-cell development. Biochem J 2019; 476:769-778. [PMID: 30842310 DOI: 10.1042/bcj20180565] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 02/11/2019] [Accepted: 02/15/2019] [Indexed: 12/23/2022]
Abstract
In mammals, the B-cell lineage arises from pluripotent progenitors in the bone marrow. During their development, B-cells undergo lineage specification and commitment, followed by expansion and selection. These processes are mediated by regulated changes in gene expression programmes, rearrangements of immunoglobulin (Ig) genes, and well-timed rounds of proliferation and apoptosis. Many of these processes are initiated by environmental factors including cytokines, chemokines, and cell-cell contacts. Developing B-cells process these environmental cues into stage-specific functions via signalling pathways including the PI3K, MAPK, or JAK-STAT pathway. The cytokines FLT3-Ligand and c-Kit-Ligand are important for the early expansion of the B-cell precursors at different developmental stages and conditions. Interleukin 7 is essential for commitment to the B-cell lineage and for orchestrating the Ig recombination machinery. After rearrangement of the immunoglobulin heavy chain, proliferation and apoptosis, and thus selection, are mediated by the clonal pre-B-cell receptor, and, following light chain rearrangement, by the B-cell receptor.
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Oliveira ML, Akkapeddi P, Ribeiro D, Melão A, Barata JT. IL-7R-mediated signaling in T-cell acute lymphoblastic leukemia: An update. Adv Biol Regul 2019; 71:88-96. [PMID: 30249539 PMCID: PMC6386770 DOI: 10.1016/j.jbior.2018.09.012] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 09/17/2018] [Accepted: 09/18/2018] [Indexed: 01/09/2023]
Abstract
Interleukin 7 (IL-7) and its receptor (IL-7R, a heterodimer of IL-7Rα and γc) are essential for normal lymphoid development. In their absence, severe combined immunodeficiency occurs. By contrast, excessive IL-7/IL-7R-mediated signaling can drive lymphoid leukemia development, disease acceleration and resistance to chemotherapy. IL-7 and IL-7R activate three main pathways: STAT5, PI3K/Akt/mTOR and MEK/Erk, ultimately leading to the promotion of leukemia cell viability, cell cycle progression and growth. However, the contribution of each of these pathways towards particular functional outcomes is still not completely known and appears to differ between normal and malignant states. For example, IL-7 upregulates Bcl-2 in a PI3K/Akt/mTOR-dependent and STAT5-independent manner in T-ALL cells. This is a 'symmetric image' of what apparently happens in normal lymphoid cells, where PI3K/Akt/mTOR does not impact on Bcl-2 and regulates proliferation rather than survival. In this review, we provide an updated summary of the knowledge on IL-7/IL-7R-mediated signaling in the context of cancer, focusing mainly on T-cell acute lymphoblastic leukemia, where this axis has been more extensively studied.
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Affiliation(s)
- Mariana L Oliveira
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal
| | - Padma Akkapeddi
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal
| | - Daniel Ribeiro
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal
| | - Alice Melão
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal
| | - João T Barata
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisboa, Portugal.
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Kim SY, Yeo A, Noh H, Ji YW, Song JS, Kim HC, Kim LK, Lee HK. Downregulation of IL-7 and IL-7R Reduces Membrane-Type Matrix Metalloproteinase 14 in Granular Corneal Dystrophy Type 2 Keratocyte. Invest Ophthalmol Vis Sci 2018; 59:5693-5703. [PMID: 30489629 DOI: 10.1167/iovs.18-25161] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose Granular corneal dystrophy type 2 (GCD2) is caused by a point mutation (R124H) in the TGF-β-induced gene (TGFBI). However, the mechanisms underlying the accumulation of TGF-β-induced protein (TGFBIp) are poorly understood. Therefore, we evaluated the signaling cascade affecting the expression of TGFBIp using patient-derived cells. Methods Keratocyte primary cultures were prepared from corneas from the eye bank or from heterozygous or homozygous patients with GCD2 after penetrating or lamellar keratoplasty. GCD2 diagnoses were based on the results of a DNA analysis for the R124H TGFβI mutation. Keratocytes were treated with various cytokines and then analyzed using quantitative PCR (qPCR) array, qPCR, flow cytometry, ELISA, and Western blotting. Results TGFBI expression was counterregulated by IL-7 in corneal fibroblasts. IL-7 expression was significantly reduced in corneal fibroblasts from patients with GCD2. TGF-β and TGFBI expression were reduced on IL-7 treatment in corneal fibroblasts. Interestingly, the interplay between TGF-β and IL-7 was regulated by the RANKL/RANK signaling cascade. Also, IL-7 regulates the expression of a membrane-type matrix metalloproteinase (MT-MMP), which plays a crucial role in migration and neovascularization in the cornea. Conclusions These studies demonstrate that impaired IL-7 expression in patients with GCD2 affects disease pathogenesis via a failure to control TGF-β expression. The RANKL/RANK axis regulates TGF-β and TGFBI expression via IL-7-mediated MT-MMP regulation in corneal fibroblasts. These findings improve our understanding of the pathogenesis of GCD2.
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Affiliation(s)
- So Young Kim
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea
| | - Areum Yeo
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea
| | - Hyemi Noh
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Woo Ji
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea
| | - Jong Suk Song
- Department of Ophthalmology, Korea University College of Medicine, Seoul, Korea
| | - Hyeon Chang Kim
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Lark Kyun Kim
- Severance Biomedical Science Institute and BK21 PLUS Project to Medical Sciences, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyung Keun Lee
- Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea.,Corneal Dystrophy Research Institute, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea
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Lin JX, Leonard WJ. The Common Cytokine Receptor γ Chain Family of Cytokines. Cold Spring Harb Perspect Biol 2018; 10:cshperspect.a028449. [PMID: 29038115 DOI: 10.1101/cshperspect.a028449] [Citation(s) in RCA: 133] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21 form a family of cytokines based on their sharing the common cytokine receptor γ chain (γc), which was originally discovered as the third receptor component of the IL-2 receptor, IL-2Rγ. The IL2RG gene is located on the X chromosome and is mutated in humans with X-linked severe combined immunodeficiency (XSCID). The breadth of the defects in XSCID could not be explained solely by defects in IL-2 signaling, and it is now clear that γc is a shared receptor component of the six cytokines noted above, making XSCID a disease of defective cytokine signaling. Janus kinase (JAK)3 associates with γc, and JAK3-deficient SCID phenocopies XSCID, findings that served to stimulate the development of JAK3 inhibitors as immunosuppressants. γc family cytokines collectively control broad aspects of lymphocyte development, growth, differentiation, and survival, and these cytokines are clinically important, related to allergic and autoimmune diseases and cancer as well as immunodeficiency. In this review, we discuss the actions of these cytokines, their critical biological roles and signaling pathways, focusing mainly on JAK/STAT (signal transducers and activators of transcription) signaling, and how this information is now being used in clinical therapeutic efforts.
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Affiliation(s)
- Jian-Xin Lin
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1674
| | - Warren J Leonard
- Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1674
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40
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Murine Bone Marrow Niches from Hematopoietic Stem Cells to B Cells. Int J Mol Sci 2018; 19:ijms19082353. [PMID: 30103411 PMCID: PMC6121419 DOI: 10.3390/ijms19082353] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 08/08/2018] [Accepted: 08/08/2018] [Indexed: 01/03/2023] Open
Abstract
After birth, the development of hematopoietic cells occurs in the bone marrow. Hematopoietic differentiation is finely tuned by cell-intrinsic mechanisms and lineage-specific transcription factors. However, it is now clear that the bone marrow microenvironment plays an essential role in the maintenance of hematopoietic stem cells (HSC) and their differentiation into more mature lineages. Mesenchymal and endothelial cells contribute to a protective microenvironment called hematopoietic niches that secrete specific factors and establish a direct contact with developing hematopoietic cells. A number of recent studies have addressed in mouse models the specific molecular events that are involved in the cellular crosstalk between hematopoietic subsets and their niches. This has led to the concept that hematopoietic differentiation and commitment towards a given hematopoietic pathway is a dynamic process controlled at least partially by the bone marrow microenvironment. In this review, we discuss the evolving view of murine hematopoietic–stromal cell crosstalk that is involved in HSC maintenance and commitment towards B cell differentiation.
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41
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Abusarah J, Khodayarian F, Cui Y, El-Kadiry AEH, Rafei M. Thymic Rejuvenation: Are We There Yet? Gerontology 2018. [DOI: 10.5772/intechopen.74048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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Terrazzini N, Mantegani P, Kern F, Fortis C, Mondino A, Caserta S. Interleukin-7 Unveils Pathogen-Specific T Cells by Enhancing Antigen-Recall Responses. J Infect Dis 2018; 217:1997-2007. [PMID: 29506153 PMCID: PMC5972594 DOI: 10.1093/infdis/jiy096] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 02/19/2018] [Indexed: 12/13/2022] Open
Abstract
Background Interleukin (IL)-7 promotes the generation, expansion, and survival of memory T cells. Previous mouse and human studies showed that IL-7 can support immune cell reconstitution in lymphopenic conditions, expand tumor-reactive T cells for adoptive immunotherapy, and enhance effector cytokine expression by autoreactive T cells. Whether pathogen-reactive T cells also benefit from IL-7 exposure remains unknown. Methods In this study, we investigated this issue in cultures of peripheral blood mononuclear cells (PBMCs) derived from patients infected with various endemic pathogens. After short-term exposure to IL-7, we measured PBMC responses to antigens derived from pathogens, such as Mycobacterium tuberculosis, Candida albicans, and cytomegalovirus, and to the superantigen Staphylococcus aureus enterotoxin B. Results We found that IL-7 favored the expansion and, in some instances, the uncovering of pathogen-reactive CD4 T cells, by promoting pathogen-specific interferon-γ, IL-2, and tumor necrosis factor recall responses. Conclusions Our findings indicate that IL-7 unveils and supports reactivation of pathogen-specific T cells with possible diagnostic, prognostic, and therapeutic significance of clinical value, especially in conditions of pathogen persistence and chronic infection.
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Affiliation(s)
- Nadia Terrazzini
- School of Pharmacy and Biomolecular Sciences, University of Brighton, United Kingdom
| | - Paola Mantegani
- Laboratory of Clinical Immunology, Clinic of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
| | - Florian Kern
- Brighton and Sussex Medical School, The University of Sussex, Falmer, East Sussex, United Kingdom
| | - Claudio Fortis
- Laboratory of Clinical Immunology, Clinic of Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
| | - Anna Mondino
- Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Caserta
- Brighton and Sussex Medical School, The University of Sussex, Falmer, East Sussex, United Kingdom
- Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
- School of Life Sciences, The University of Hull, United Kingdom
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Aiello FB, Guszczynski T, Li W, Hixon JA, Jiang Q, Hodge DL, Massignan T, Di Lisio C, Merchant A, Procopio AD, Bonetto V, Durum SK. IL-7-induced phosphorylation of the adaptor Crk-like and other targets. Cell Signal 2018; 47:131-141. [PMID: 29581031 DOI: 10.1016/j.cellsig.2018.03.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 03/20/2018] [Indexed: 12/16/2022]
Abstract
IL-7 is required for T cell differentiation and mature T cell homeostasis and promotes pro-B cell proliferation and survival. Tyrosine phosphorylation plays a central role in IL-7 signaling. We identified by two-dimensional electrophoresis followed by anti-phosphotyrosine immunoblotting and mass spectrometry sixteen tyrosine phosphorylated proteins from the IL-7-dependent cell line D1. IL-7 stimulation induced the phosphorylation of the proteins STI1, ATIC and hnRNPH, involved in pathways related to survival, proliferation and gene expression, respectively, and increased the phosphorylation of CrkL, a member of a family of adaptors including the highly homologous Crk isoforms CrkII and CrkI, important in multiple signaling pathways. We observed an increased phosphorylation of CrkL in murine pro-B cells and in murine and human T cells. In addition, IL-7 increased the association of CrkL with the transcription factor Stat5, essential for IL-7 pro-survival activity. The selective tyrosine kinase inhibitor Imatinib. counteracted the IL-7 pro-survival effect in D1 cells and decreased CrkL phosphorylation. These data suggested that CrkL could play a pro-survival role in IL-7-mediated signaling. We observed that pro-B cells also expressed, in addition to CrkL, the Crk isoforms CrkII and CrkI and therefore utilized pro-B cells conditionally deficient in all three to evaluate the role of these proteins. The observation that the IL-7 pro-survival effect was reduced in Crk/CrkL conditionally-deficient pro-B cells further pointed to a pro-survival role of these adaptors. To further evaluate the role of these proteins, gene expression studies were performed in Crk/CrkL conditionally-deficient pro-B cells. IL-7 decreased the transcription of the receptor LAIR1, which inhibits B cell proliferation, in a Crk/CrkL-dependent manner, suggesting that the Crk family of proteins may promote pro-B cell proliferation. Our data contribute to the understanding of IL-7 signaling and suggest the involvement of Crk family proteins in pathways promoting survival and proliferation.
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Affiliation(s)
- Francesca B Aiello
- Cancer and Inflammation Program, CCR, NCI, NIH, Bldg 560, Frederick, MD 21702, USA.
| | - Tad Guszczynski
- Molecular Targets Laboratory, FCRDC, Bldg 560, Frederick, MD 21702, USA.
| | - Wenqing Li
- Cancer and Inflammation Program, CCR, NCI, NIH, Bldg 560, Frederick, MD 21702, USA.
| | - Julie A Hixon
- Cancer and Inflammation Program, CCR, NCI, NIH, Bldg 560, Frederick, MD 21702, USA.
| | - Qiong Jiang
- Cancer and Inflammation Program, CCR, NCI, NIH, Bldg 560, Frederick, MD 21702, USA.
| | - Deborah L Hodge
- Laboratory of Experimental Medicine, FCRDC, Bldg 560, Frederick, MD 21702, USA.
| | - Tania Massignan
- Dulbecco Telethon Institute, IRCCS-Istituto di Ricerche Farmacologiche M. Negri, via La Masa 19, 20156 Milano, Italy
| | - Chiara Di Lisio
- Department of Medicine and Aging Sciences, University of Chieti-Pescara, via dei Vestini, 66013 Chieti, Italy.
| | - Anand Merchant
- Center for Cancer Research, NIH, Bethesda, MD 20892, USA.
| | - Antonio D Procopio
- Department of Clinical and Medical Sciences, Marche Polytechnic University, via Tronto 10, 60100 Ancona, Italy.
| | - Valentina Bonetto
- Dulbecco Telethon Institute, IRCCS-Istituto di Ricerche Farmacologiche M. Negri, via La Masa 19, 20156 Milano, Italy.
| | - Scott K Durum
- Cancer and Inflammation Program, CCR, NCI, NIH, Bldg 560, Frederick, MD 21702, USA.
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Brazvan B, Ebrahimi-Kalan A, Velaei K, Mehdipour A, Aliyari Serej Z, Ebrahimi A, Ghorbani M, Cheraghi O, Nozad Charoudeh H. Telomerase activity and telomere on stem progeny senescence. Biomed Pharmacother 2018; 102:9-17. [PMID: 29547744 DOI: 10.1016/j.biopha.2018.02.073] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2017] [Revised: 02/03/2018] [Accepted: 02/19/2018] [Indexed: 12/19/2022] Open
Abstract
The end of linear chromosomes is formed of a special nucleoprotein heterochromatin structure with repetitive TTAGGG sequences called telomere. Telomere length is regulated by a special enzyme called telomerase, a specific DNA polymerase that adds new telomeric sequences to the chromosome ends. Telomerase consists of two parts; the central protein part and the accessory part which is a RNA component transported by the central part. Regulation of telomere length by this enzyme is a multi-stage process. Telomere length elongation is strongly influenced by the level of telomerase and has a strong correlation with the activity of telomerase enzyme. Human Telomerase Reverse Transcriptase (hTERT) gene expression plays an important role in maintaining telomere length and high proliferative property of cells. Except a low activity of telomerase enzyme in hematopoietic and few types of stem cells, most of somatic cells didn't showed telomerase activity. Moreover, cytokines are secretory proteins that control many aspects of hematopoiesis, especially immune responses and inflammation. Also, the induction of hTERT gene expression by cytokines is organized through the PI3K/AKT and NF/kB signaling pathways. In this review we have tried to talk about effects of immune cell cytokines on telomerase expression/telomere length and the induction of telomerase expression by cytokines.
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Affiliation(s)
- Balal Brazvan
- Department of Basic Sciences, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Abbas Ebrahimi-Kalan
- Department of Neurosciences and Cognition, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Kobra Velaei
- Department of Anatomical Science, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ahmad Mehdipour
- Department of Tissue Engineering, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zeynab Aliyari Serej
- Applied Cell Sciences Department, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ayyub Ebrahimi
- Department of Molecular Biology and Genetic, Faculty of Arts and Sciences, Halic Uuniversity, Istanbul, Turkey
| | - Mohammad Ghorbani
- Department of Basic Sciences, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Omid Cheraghi
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran.
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de Oliveira FL, Dos Santos SN, Ricon L, da Costa TP, Pereira JX, Brand C, Fermino ML, Chammas R, Bernardes ES, El-Cheikh MC. Lack of galectin-3 modifies differentially Notch ligands in bone marrow and spleen stromal cells interfering with B cell differentiation. Sci Rep 2018; 8:3495. [PMID: 29472568 PMCID: PMC5823902 DOI: 10.1038/s41598-018-21409-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 01/29/2018] [Indexed: 12/30/2022] Open
Abstract
Galectin-3 (Gal-3) is a β-galactoside binding protein that controls cell-cell and cell-extracellular matrix interactions. In lymphoid organs, gal-3 inhibits B cell differentiation by mechanisms poorly understood. The B cell development is dependent on tissue organization and stromal cell signaling, including IL-7 and Notch pathways. Here, we investigate possible mechanisms that gal-3 interferes during B lymphocyte differentiation in the bone marrow (BM) and spleen. The BM of gal-3-deficient mice (Lgals3-/- mice) was evidenced by elevated numbers of B220+CD19+c-Kit+IL-7R+ progenitor B cells. In parallel, CD45- bone marrow stromal cells expressed high levels of mRNA IL-7, Notch ligands (Jagged-1 and Delta-like 4), and transcription factors (Hes-1, Hey-1, Hey-2 and Hey-L). The spleen of Lgals3-/- mice was hallmarked by marginal zone disorganization, high number of IgM+IgD+ B cells and CD138+ plasma cells, overexpression of Notch ligands (Jagged-1, Delta-like 1 and Delta-like 4) by stromal cells and Hey-1. Morever, IgM+IgD+ B cells and B220+CD138+ CXCR4+ plasmablasts were significantly increased in the BM and blood of Lgals3-/- mice. For the first time, we demonstrated that gal-3 inhibits Notch signaling activation in lymphoid organs regulating earlier and terminal events of B cell differentiation.
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Affiliation(s)
- Felipe Leite de Oliveira
- Laboratório de Proliferação e Diferenciação Celular, Instituto de Ciências Biomédicas (ICB), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | | | - Lauremilia Ricon
- Departamento de Clínica Médica, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brazil
| | - Thayse Pinheiro da Costa
- Laboratório de Proliferação e Diferenciação Celular, Instituto de Ciências Biomédicas (ICB), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.,Programa de Pós-Graduação em Ciências Morfológicas, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Jonathas Xavier Pereira
- Programa de Pós-Graduação em Anatomia Patológica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Camila Brand
- Laboratório de Proliferação e Diferenciação Celular, Instituto de Ciências Biomédicas (ICB), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.,Programa de Pós-Graduação em Ciências Morfológicas, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Marise Lopes Fermino
- Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil
| | - Roger Chammas
- Laboratório de Oncologia Experimental e Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina, São Paulo, Brazil
| | - Emerson Soares Bernardes
- Centro de Radiofarmácia, Instituto de Pesquisas Energéticas e Nucleares (IPEN), São Paulo, SP, Brazil
| | - Márcia Cury El-Cheikh
- Laboratório de Proliferação e Diferenciação Celular, Instituto de Ciências Biomédicas (ICB), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
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Cui D, Zhang J, Zuo Y, Huo S, Zhang Y, Wang L, Li X, Zhong F. Recombinant chicken interleukin-7 as a potent adjuvant increases the immunogenicity and protection of inactivated infectious bursal disease vaccine. Vet Res 2018; 49:10. [PMID: 29391066 PMCID: PMC5796573 DOI: 10.1186/s13567-017-0497-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 11/12/2017] [Indexed: 01/11/2023] Open
Abstract
Our previous work showed that a plasmid-based chicken interleukin-7 (chIL-7) gene expression vector possessed potent adjuvant activity for a VP2 DNA vaccine against chicken infectious bursal disease virus (IBDV). Whether recombinant chIL-7 prepared in procaryotic expression system has the adjuvant activity for inactivated IBDV vaccine remains unknown. Here, we prepared recombinant chIL-7 using an E. coli expression system and analyzed its adjuvant activity for the inactivated IBDV vaccine. The results show that the recombinant chIL-7 was successfully prepared in E. coli using the pET20b vector, which possessed biological activity to stimulate mouse B lymphocyte proliferation. Co-administration of the chIL-7 with inactivated IBDV vaccine significantly increased specific serum antibody titers against IBDV, enhanced lymphocyte proliferation and IFN-γ and IL-4 productions, and increased protection against virulent IBDV infection.
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Affiliation(s)
- Dan Cui
- Laboratory of Molecular Virology and Immunology, College of Veterinary Medicine/College of Animal Science and Technology, Agricultural University of Hebei, Baoding, 071000, Hebei, China.,Hebei Engineering and Technology Research Center of Veterinary Biotechnology, Baoding, 071000, Hebei, China
| | - Jianlou Zhang
- Laboratory of Molecular Virology and Immunology, College of Veterinary Medicine/College of Animal Science and Technology, Agricultural University of Hebei, Baoding, 071000, Hebei, China.,Hebei Engineering and Technology Research Center of Veterinary Biotechnology, Baoding, 071000, Hebei, China
| | - Yuzhu Zuo
- Laboratory of Molecular Virology and Immunology, College of Veterinary Medicine/College of Animal Science and Technology, Agricultural University of Hebei, Baoding, 071000, Hebei, China.,Hebei Engineering and Technology Research Center of Veterinary Biotechnology, Baoding, 071000, Hebei, China
| | - Shanshan Huo
- Laboratory of Molecular Virology and Immunology, College of Veterinary Medicine/College of Animal Science and Technology, Agricultural University of Hebei, Baoding, 071000, Hebei, China.,Hebei Engineering and Technology Research Center of Veterinary Biotechnology, Baoding, 071000, Hebei, China
| | - Yonghong Zhang
- Laboratory of Molecular Virology and Immunology, College of Veterinary Medicine/College of Animal Science and Technology, Agricultural University of Hebei, Baoding, 071000, Hebei, China.,Hebei Engineering and Technology Research Center of Veterinary Biotechnology, Baoding, 071000, Hebei, China
| | - Liyue Wang
- Laboratory of Molecular Virology and Immunology, College of Veterinary Medicine/College of Animal Science and Technology, Agricultural University of Hebei, Baoding, 071000, Hebei, China.,Hebei Engineering and Technology Research Center of Veterinary Biotechnology, Baoding, 071000, Hebei, China
| | - Xiujin Li
- Department of Biotechnology, College of Environmental and Chemical Engineering, Yanshan University, Qinhuangdao, 066004, Hebei, China.
| | - Fei Zhong
- Laboratory of Molecular Virology and Immunology, College of Veterinary Medicine/College of Animal Science and Technology, Agricultural University of Hebei, Baoding, 071000, Hebei, China. .,Hebei Engineering and Technology Research Center of Veterinary Biotechnology, Baoding, 071000, Hebei, China.
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Wrangle JM, Patterson A, Johnson CB, Neitzke DJ, Mehrotra S, Denlinger CE, Paulos CM, Li Z, Cole DJ, Rubinstein MP. IL-2 and Beyond in Cancer Immunotherapy. J Interferon Cytokine Res 2018; 38:45-68. [PMID: 29443657 PMCID: PMC5815463 DOI: 10.1089/jir.2017.0101] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 11/26/2017] [Indexed: 12/11/2022] Open
Abstract
The development of the T- and natural killer (NK) cell growth factor IL-2 has been a sentinel force ushering in the era of immunotherapy in cancer. With the advent of clinical grade recombinant IL-2 in the mid-1980s, oncologists could for the first time directly manipulate lymphocyte populations with systemic therapy. By itself, recombinant IL-2 can induce clinical responses in up to 15% of patients with metastatic cancer or renal cell carcinoma. When administered with adoptively transferred tumor-reactive lymphocytes, IL-2 promotes T cell engraftment and response rates of up to 50% in metastatic melanoma patients. Importantly, these IL-2-driven responses can yield complete and durable responses in a subset of patients. However, the use of IL-2 is limited by toxicity and concern of the expansion of T regulatory cells. To overcome these limitations and improve response rates, other T cell growth factors, including IL-15 and modified forms of IL-2, are in clinical development. Administering T cell growth factors in combination with other agents, such as immune checkpoint pathway inhibitors, may also improve efficacy. In this study, we review the development of T- and NK cell growth factors and highlight current combinatorial approaches based on these reagents.
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Affiliation(s)
- John M. Wrangle
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Alicia Patterson
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina
| | - C. Bryce Johnson
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina
| | - Daniel J. Neitzke
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina
| | - Shikhar Mehrotra
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina
| | - Chadrick E. Denlinger
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina
| | - Chrystal M. Paulos
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Zihai Li
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - David J. Cole
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina
| | - Mark P. Rubinstein
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
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Titanji K. Beyond Antibodies: B Cells and the OPG/RANK-RANKL Pathway in Health, Non-HIV Disease and HIV-Induced Bone Loss. Front Immunol 2017; 8:1851. [PMID: 29312334 PMCID: PMC5743755 DOI: 10.3389/fimmu.2017.01851] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Accepted: 12/06/2017] [Indexed: 12/13/2022] Open
Abstract
HIV infection leads to severe B cell dysfunction, which manifests as impaired humoral immune response to infection and vaccinations and is not completely reversed by otherwise effective antiretroviral therapy (ART). Despite its inability to correct HIV-induced B cell dysfunction, ART has led to significantly increased lifespans in people living with HIV/AIDS. This has in turn led to escalating prevalence of non-AIDS complications in aging HIV-infected individuals, including malignancies, cardiovascular disease, bone disease, and other end-organ damage. These complications, typically associated with aging, are a significant cause of morbidity and mortality and occur significantly earlier in HIV-infected individuals. Understanding the pathophysiology of these comorbidities and delineating clinical management strategies and potential cures is gaining in importance. Bone loss and osteoporosis, which lead to increase in fragility fracture prevalence, have in recent years emerged as important non-AIDS comorbidities in patients with chronic HIV infection. Interestingly, ART exacerbates bone loss, particularly within the first couple of years following initiation. The mechanisms underlying HIV-induced bone loss are multifactorial and complicated by the fact that HIV infection is linked to multiple risk factors for osteoporosis and fracture, but a very interesting role for B cells in HIV-induced bone loss has recently emerged. Although best known for their important antibody-producing capabilities, B cells also produce two cytokines critical for bone metabolism: the key osteoclastogenic cytokine receptor activator of NF-κB ligand (RANKL) and its physiological inhibitor osteoprotegerin (OPG). Dysregulated B cell production of OPG and RANKL was shown to be a major contributor to increased bone loss and fracture risk in animal models and HIV-infected humans. This review will summarize our current knowledge of the role of the OPG/RANK–RANKL pathway in B cells in health and disease, and the contribution of B cells to HIV-induced bone loss. Data from mouse studies indicate that RANKL and OPG may also play a role in B cell function and the implications of these findings for human B cell biology, as well as therapeutic strategies targeting the OPG/RANK–RANKL pathway, will be discussed.
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Affiliation(s)
- Kehmia Titanji
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States
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Bone Marrow-Derived Stem Cell Populations Are Differentially Regulated by Thyroid or/and Ovarian Hormone Loss. Int J Mol Sci 2017; 18:ijms18102139. [PMID: 29048335 PMCID: PMC5666821 DOI: 10.3390/ijms18102139] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 09/19/2017] [Accepted: 09/28/2017] [Indexed: 02/08/2023] Open
Abstract
Bone marrow-derived stem cells (BMDSCs) play an essential role in organ repair and regeneration. The molecular mechanisms by which hormones control BMDSCs proliferation and differentiation are unclear. Our aim in this study was to investigate how a lack of ovarian or/and thyroid hormones affects stem cell number in bone marrow lineage. To examine the effect of thyroid or/and ovarian hormones on the proliferative activity of BMDSCs, we removed the thyroid or/and the ovaries of adult female rats. An absence of ovarian and thyroid hormones was confirmed by Pap staining and Thyroid Stimulating Hormone (TSH) measurement, respectively. To obtain the stem cells from the bone marrow, we punctured the iliac crest, and aspirated and isolated cells by using a density gradient. Specific markers were used by cytometry to identify the different BMDSCs types: endothelial progenitor cells (EPCs), precursor B cells/pro-B cells, and mesenchymal stem cells (MSCs). Interestingly, our results showed that hypothyroidism caused a significant increase in the percentage of EPCs, whereas a lack of ovarian hormones significantly increased the precursor B cells/pro-B cells. Moreover, the removal of both glands led to increased MSCs. In conclusion, both ovarian and thyroid hormones appear to have key and diverse roles in regulating the proliferation of cells populations of the bone marrow.
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50
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Interleukin-7 Availability Is Maintained by a Hematopoietic Cytokine Sink Comprising Innate Lymphoid Cells and T Cells. Immunity 2017; 47:171-182.e4. [DOI: 10.1016/j.immuni.2017.07.005] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 05/05/2017] [Accepted: 07/05/2017] [Indexed: 01/09/2023]
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