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Lan X, Johnston E, Ning T, Chen G, Haglund L, Li J. Immunomodulatory bioadhesive technologies. Biomaterials 2025; 321:123274. [PMID: 40156979 DOI: 10.1016/j.biomaterials.2025.123274] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 02/20/2025] [Accepted: 03/17/2025] [Indexed: 04/01/2025]
Abstract
Bioadhesives have found significant use in medicine and engineering, particularly for wound care, tissue engineering, and surgical applications. Compared to traditional wound closure methods such as sutures and staples, bioadhesives offer advantages, including reduced tissue damage, enhanced healing, and ease of implementation. Recent progress highlights the synergy of bioadhesives and immunoengineering strategies, leading to immunomodulatory bioadhesives capable of modulating immune responses at local sites where bioadhesives are applied. They foster favorable therapeutic outcomes such as reduced inflammation in wounds and implants or enhanced local immune responses to improve cancer therapy efficacy. The dual functionalities of bioadhesion and immunomodulation benefit wound management, tissue regeneration, implantable medical devices, and post-surgical cancer management. This review delves into the interplay between bioadhesion and immunomodulation, highlighting the mechanobiological coupling involved. Key areas of focus include the modulation of immune responses through chemical and physical strategies, as well as the application of these bioadhesives in wound healing and cancer treatment. Discussed are remaining challenges such as achieving long-term stability and effectiveness, necessitating further research to fully harness the clinical potential of immunomodulatory bioadhesives.
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Affiliation(s)
- Xiaoyi Lan
- Department of Surgery, McGill University, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A3, Canada; Department of Mechanical Engineering, McGill University, 817 Sherbrooke St W, Montreal, Quebec, H3A 0C3, Canada
| | - Evan Johnston
- Department of Mechanical Engineering, McGill University, 817 Sherbrooke St W, Montreal, Quebec, H3A 0C3, Canada
| | - Tianqin Ning
- Department of Mechanical Engineering, McGill University, 817 Sherbrooke St W, Montreal, Quebec, H3A 0C3, Canada; Department of Biomedical Engineering, McGill University, 3775 Rue University, Montreal, Quebec, H3A 2B4, Canada
| | - Guojun Chen
- Department of Biomedical Engineering, McGill University, 3775 Rue University, Montreal, Quebec, H3A 2B4, Canada; Rosalind & Morris Goodman Cancer Institute, McGill University, 1160 Pine Ave W, Montreal, Quebec, H3A 1A3, Canada
| | - Lisbet Haglund
- Department of Surgery, McGill University, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A3, Canada; Shriners Hospital for Children, 1003 Decarie Blvd, Montreal, Quebec, H4A 0A9, Canada.
| | - Jianyu Li
- Department of Surgery, McGill University, 1650 Cedar Avenue, Montreal, Quebec, H3G 1A3, Canada; Department of Mechanical Engineering, McGill University, 817 Sherbrooke St W, Montreal, Quebec, H3A 0C3, Canada; Department of Biomedical Engineering, McGill University, 3775 Rue University, Montreal, Quebec, H3A 2B4, Canada.
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Kłósek M, Kurek-Górecka A, Balwierz R, Pietsz G, Czuba ZP. The Effect of Ethanolic Extract of Brazilian Green Propolis and Artepillin C on Cytokine Secretion by Stage IV Glioma Cells Under Hypoxic and Normoxic Conditions. Pharmaceuticals (Basel) 2025; 18:389. [PMID: 40143164 PMCID: PMC11944379 DOI: 10.3390/ph18030389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/05/2025] [Accepted: 03/07/2025] [Indexed: 03/28/2025] Open
Abstract
Background: The majority of gliomas are astrocytic in nature. Gliomas have the lowest survival rate among all tumors of the central nervous system (CNS), characterized by high aggressiveness and poor response to treatment. The tumor microenvironment is a source of cytokines such as IL-6, IFN-γ, VEGF, and PDGF-BB, secreted mainly by tumor and immune cells. These cytokines play a significant role in angiogenesis, invasion, and metastasis formation. In vitro and in vivo studies have shown that Brazilian green propolis, derived from Baccharis dracunculifolia DC and rich in artepillin C, exhibits anti-inflammatory, antimicrobial, chemopreventive, and anticancer activities. Additionally, it can penetrate the blood-brain barrier, demonstrating neuroprotective effects. The aim of the present study was to determine the concentration of selected cytokines produced by astrocytes of the CCF-STTG1 cell line, isolated from the brain of a patient with stage IV glioma (astrocytoma). Methods: The cytotoxicity of the EEP-B was evaluated using the MTT assay. Astrocytes were stimulated with LPS at a final concentration of 200 ng/mL and/or IFN-α at 100 U/mL, followed by incubation with EEP-B (25-50 µg/mL) and artepillin C (25-50 µg/mL) under 2-h hypoxia and normoxia conditions. Cytokine concentrations were measured using the xMAP Luminex Multiplex Immunoassay and the Multiplex Bead-Based Cytokine kit. Results: The absence of cytotoxic effects of EEP-B and artepillin C on human astrocytes of the CCF-STTG1 lineage was demonstrated. Stimulation with LPS, IFN-α, and their combination (LPS + IFN-α) significantly increased the secretion of the tested cytokines compared to the control cell line. The most pronounced and statistically significant reduction in cytokine levels, particularly IL-6 and VEGF, was observed following EEP-B treatment at both tested concentrations under both hypoxic and normoxic conditions. Conclusions: Brazilian green propolis may serve as a potential immunomodulator in combination therapies for gliomas of varying malignancy grades.
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Affiliation(s)
- Małgorzata Kłósek
- Department of Microbiology and Immunology, Faculty of Medical Sciences, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland; (A.K.-G.); (G.P.); (Z.P.C.)
| | - Anna Kurek-Górecka
- Department of Microbiology and Immunology, Faculty of Medical Sciences, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland; (A.K.-G.); (G.P.); (Z.P.C.)
| | - Radosław Balwierz
- Institute of Chemistry, University of Opole, Oleska 48, 45-052 Opole, Poland;
| | - Grażyna Pietsz
- Department of Microbiology and Immunology, Faculty of Medical Sciences, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland; (A.K.-G.); (G.P.); (Z.P.C.)
| | - Zenon P. Czuba
- Department of Microbiology and Immunology, Faculty of Medical Sciences, Medical University of Silesia in Katowice, Jordana 19, 41-808 Zabrze, Poland; (A.K.-G.); (G.P.); (Z.P.C.)
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Liu W, Zhao Z. Scupa: single-cell unified polarization assessment of immune cells using the single-cell foundation model. Bioinformatics 2025; 41:btaf090. [PMID: 39999031 PMCID: PMC11893155 DOI: 10.1093/bioinformatics/btaf090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 01/15/2025] [Accepted: 02/21/2025] [Indexed: 02/27/2025] Open
Abstract
MOTIVATION Immune cells undergo cytokine-driven polarization in response to diverse stimuli, altering their transcriptional profiles and functional states. This dynamic process is central to immune responses in health and diseases, yet a systematic approach to assess cytokine-driven polarization in single-cell RNA sequencing data has been lacking. RESULTS To address this gap, we developed single-cell unified polarization assessment (Scupa), the first computational method for comprehensive immune cell polarization assessment. Scupa leverages data from the Immune Dictionary, which characterizes cytokine-driven polarization states across 14 immune cell types. By integrating cell embeddings from the single-cell foundation model Universal Cell Embeddings, Scupa effectively identifies polarized cells across different species and experimental conditions. Applications of Scupa in independent datasets demonstrated its accuracy in classifying polarized cells and further revealed distinct polarization profiles in tumor-infiltrating myeloid cells across cancers. Scupa complements conventional single-cell data analysis by providing new insights into dynamic immune cell states, and holds potential for advancing therapeutic insights, particularly in cytokine-based therapies. AVAILABILITY AND IMPLEMENTATION The code is available at https://github.com/bsml320/Scupa.
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Affiliation(s)
- Wendao Liu
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, United States
- Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, United States
| | - Zhongming Zhao
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, United States
- Center for Precision Health, McWilliams School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX 77030, United States
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Singh A, Singh A, Saraswati SSK, Rana AK, Singh A, Verma C, Sinha V, Kalra K, Natarajan K. Suppressive effects of toll-like receptor 2, toll-like receptor 4, and toll-like receptor 7 on protective responses to Mycobacterium bovis BCG from epithelial cells. Microbes Infect 2025; 27:105428. [PMID: 39368609 DOI: 10.1016/j.micinf.2024.105428] [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: 03/01/2024] [Revised: 09/24/2024] [Accepted: 09/26/2024] [Indexed: 10/07/2024]
Abstract
Mycobacteria have several mechanisms for evasion of protective responses mounted by the host. In this study, we unravel yet another mechanism that is mediated by Toll-Like Receptors TLR2, TLR4, and TLR7 in epithelial cells. We show that mycobacterial infection of epithelial cells increases the expression of TLR2, TLR4, and TLR7. Stimulation of either TLR along with mycobacterial infection results in an inhibition of oxidative burst resulting in increased survival of mycobacteria inside epithelial cells. TLR stimulation along with mycobacterial infection also inhibits activation of epithelial cells for T cell responses by differentially regulating the activation of ERK-MAPK and p38-MAPK along with inhibition of co-stimulatory molecule CD86 expression. Furthermore, stimulation of either TLR inhibits the induction of apoptosis and autophagy. Knockdown of either TLR by specific siRNAs reverses the inhibition by ROS and apoptosis by mycobacteria and results in reduced intracellular survival of mycobacteria in a MyD88-dependent manner. These results point towards a negative role for TLR2, TLR4, and TLR7 in regulating protective responses to M. bovis BCG infection in epithelial cells.
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Affiliation(s)
- Aarti Singh
- Infectious Disease Immunology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India.
| | - Akshita Singh
- Infectious Disease Immunology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | | | - Ankush Kumar Rana
- Infectious Disease Immunology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - Aayushi Singh
- Infectious Disease Immunology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - Chaitenya Verma
- Infectious Disease Immunology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - Vishal Sinha
- Infectious Disease Immunology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - Kanika Kalra
- Infectious Disease Immunology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - Krishnamurthy Natarajan
- Infectious Disease Immunology Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India.
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Tang Q, Fan Y, Sun J, Fan W, Zhao B, Yin Z, Cao Y, Han Y, Su B, Yang C, Yu P, Ning C, Chen L. Remodel Heterogeneous Electrical Microenvironment at Nano-Scale Interface Optimizes Osteogenesis by Coupling of Immunomodulation and Angiogenesis. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2025; 21:e2406090. [PMID: 39692158 DOI: 10.1002/smll.202406090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 09/02/2024] [Indexed: 12/19/2024]
Abstract
Immunomodulation is essential for implants to regulate tissue regeneration, while bioelectricity plays a fundamental role in regulating immune activities. Under natural preferences, the bone matrix electrical microenvironment is heterogeneous in the nanoscale, which provides fundamental electrical cues to regulate bone immunity and regenerative repair. However, remodeling bone nanoscale heterogeneous electrical microenvironment remains a challenge, and the underlying immune modulation mechanism remains to be explored. In this research, in situ discretely distributed nano-heterojunctions are constructed on titanium oxide nanofibers to mimic the heterogeneous electrical microenvironment exhibited by bone collagen fibers. The material is identified to directly regulate calcium ion channeling for anti-inflammatory polarization of macrophages. Surprisingly, the highly biomimetic heterogeneous electrical microenvironment can induce a pro-angiogenic phenotypic transformation of macrophages, leading to enhanced neo-vascularization at the early stage of osteogenesis. Mechanistic exploration identifies that PI3K signaling pathway-mediated FGF2 secretion may partially explain for strengthened coupling of immunomodulation and angiogenesis, which optimizes subsequent bone regeneration. These findings highlight the significance of biomimetic heterogeneous electrical cues on immune-modulation and provide a design principle for future electroactive implant materials.
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Affiliation(s)
- Qingming Tang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Youzhun Fan
- School of Material Science and Engineering, National Engineering Research Center for Tissue Restoration and Reconstruction, Metallic Materials Surface Functionalization Engineering Research Center of Guangdong Province, South China University of Technology, Guangzhou, 510641, P. R. China
| | - Jiwei Sun
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Wenjie Fan
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Baoying Zhao
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Zhaoyi Yin
- Faculty of Materials Science and Engineering, Kunming University of Science and Technology, Kunming, 650093, China
| | - Yaru Cao
- Department of Neurobiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Yunyun Han
- Department of Neurobiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Bin Su
- State Key Laboratory of Materials Processing and Die & Mould Technology, School of Materials Science and Engineering, Huazhong University of Science and Technology, Wuhan, 430074, China
| | - Cheng Yang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
| | - Peng Yu
- School of Material Science and Engineering, National Engineering Research Center for Tissue Restoration and Reconstruction, Metallic Materials Surface Functionalization Engineering Research Center of Guangdong Province, South China University of Technology, Guangzhou, 510641, P. R. China
| | - Chengyun Ning
- School of Material Science and Engineering, National Engineering Research Center for Tissue Restoration and Reconstruction, Metallic Materials Surface Functionalization Engineering Research Center of Guangdong Province, South China University of Technology, Guangzhou, 510641, P. R. China
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- School of Stomatology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Hubei Province Key Laboratory of Oral and Maxillofacial Development and Regeneration, Wuhan, 430022, China
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Zhang J, Zhao X. Administration of fusion cytokines induces tumor regression and systemic antitumor immunity. MedComm (Beijing) 2021; 2:256-268. [PMID: 34766145 PMCID: PMC8491205 DOI: 10.1002/mco2.68] [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: 12/05/2020] [Revised: 03/16/2021] [Accepted: 03/18/2021] [Indexed: 12/24/2022] Open
Abstract
It is difficult to improve the curative effects of cancer immunotherapy on solid tumors. Cytokines, as powerful immune regulators, show potential in activating host antitumor immunity. We have previously found that the administration of certain cytokine combinations induces complete tumor clearance. Here, we constructed cognate fusion cytokines and evaluated their antitumor effects in various mouse tumor models. The in situ induction of the expression of the fusion cytokine IL12IL2GMCSF caused tumor eradication, including that of the tumors at advanced stages. An immune memory against unrelated syngeneic tumors was also elicited. Furthermore, flow cytometry analysis revealed that tumor‐infiltrating CD3+ cells were greatly increased in the treated tumors and were accompanied by an elevation of CD8+/CD4+ ratios. This fusion protein exhibited superior immune activating capability compared to that of cytokine mixtures, in the experiments done in vitro. We also induced tumor regression in various immunocompetent tumor models via intratumoral injection. To improve its translational potential for clinical application, a systemically‐administered immunocytokine, IL12IL2DiaNFGMCSF, was constructed by inserting a tumor‐targeting diabody in the fusion protein. This protein also displayed good immune stimulating activities in vitro. Intravenous infusion of IL12IL2DiaNFGMCSF induced tumor‐infiltrating immune cell alterations like IL12IL2GMCSF, with moderate serum IFNγ increment. Therapeutic effects were observed in the various tumor models after systemic administration of IL12IL2DiaNFGMCSF, but with slight toxicity. These results show the feasibility of developing a versatile cancer immunotherapy.
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Affiliation(s)
| | - Xuan Zhao
- Institute for Immunology and School of Medicine Tsinghua University Beijing China
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Shu C, Sun P, Xie H, Huang W, Qi J, Ma Y. Virus-Like Particles Presenting the FGF-2 Protein or Identified Antigenic Peptides Promoted Antitumor Immune Responses in Mice. Int J Nanomedicine 2020; 15:1983-1996. [PMID: 32308382 PMCID: PMC7146011 DOI: 10.2147/ijn.s237182] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2019] [Accepted: 02/25/2020] [Indexed: 01/29/2023] Open
Abstract
Background Fibroblast growth factor (FGF)-2 is overexpressed in various tumor tissues. It affects tumor cell proliferation, invasion and survival, promotes tumor angiogenesis and is tightly involved in the development of systemic and local immunosuppressive tumor mechanisms. Purpose This study aimed to develop an effective vaccine against FGF-2 and to investigate the effects of anti-FGF-2 immunization on tumor growth and antitumor immune responses. Methods A set of thirteen synthesized overlapping peptides covering all possible linear B-cell epitopes of murine FGF-2 and a recombinant FGF-2 protein were conjugated to virus-like particles (VLPs) of recombinant hepatitis B core antigen (HBcAg). The VLPs were immunized through a preventive or therapeutic strategy in a TC-1 or 4T1 grafted tumor model. Results Immunization with FGF-2 peptides or full-length protein-coupled VLPs produced FGF-2-specific antibodies with a high titer. Peptide 12, which is located in the heparin-binding site of FGF-2, or protein-conjugated VLPs presented the most significant effects on the suppression of TC-1 tumor growth. The levels of IFN-γ-expressing splenocytes and serum IFN-γ were significantly elevated; further, the immune effector cells CD8+ IFN-γ+ cytotoxic T lymphocytes (CTLs) and CD4+ IFN-γ+ Th1 cells were significantly increased, whereas the immunosuppressive cells CD4+ CD25+ FOXP3+ Treg cells and Gr-1+ CD11b+ myeloid-derived suppressor cells (MDSCs) were decreased in the immunized mice. In addition, VLP immunization significantly suppressed tumor vascularization and promoted tumor cell apoptosis. In mice bearing 4T1 breast tumor, preventive immunization with FGF-2-conjugated VLPs suppressed tumor growth and lung metastasis, and increased effector cell responses. Conclusion Active immunization against FGF-2 is a new possible strategy for tumor immunotherapy.
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Affiliation(s)
- Congyan Shu
- Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming 650118, People's Republic of China.,Sichuan Institute for Food and Drug Control, Chengdu 611731, People's Republic of China
| | - Pengyan Sun
- Yunnan Center for Disease Control and Prevention, Kunming 650022, People's Republic of China
| | - Hanghang Xie
- Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming 650118, People's Republic of China
| | - Weiwei Huang
- Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming 650118, People's Republic of China
| | - Jialong Qi
- Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming 650118, People's Republic of China
| | - Yanbing Ma
- Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming 650118, People's Republic of China
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Transgenerational effects of maternal bisphenol: a exposure on offspring metabolic health. J Dev Orig Health Dis 2018; 10:164-175. [PMID: 30362448 DOI: 10.1017/s2040174418000764] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Exposure to the endocrine disruptor bisphenol A (BPA) is ubiquitous and associated with health abnormalities that persist in subsequent generations. However, transgenerational effects of BPA on metabolic health are not widely studied. In a maternal C57BL/6J mice (F0) exposure model using BPA doses that are relevant to human exposure levels (10 μg/kg/day, LowerB; 10 mg/kg/day, UpperB), we showed male- and dose-specific effects on pancreatic islets of the first (F1) and second generation (F2) offspring relative to controls (7% corn oil diet; control). In this study, we determined the transgenerational effects (F3) of BPA on metabolic health and pancreatic islets in our model. Adult F3 LowerB and UpperB male offspring had increased body weight relative to Controls, however glucose tolerance was similar in the three groups. F3 LowerB, but not UpperB, males had reduced β-cell mass and smaller islets which was associated with increased glucose-stimulated insulin secretion. Similar to F1 and F2 BPA male offspring, staining for markers of T-cells and macrophages (CD3 and F4/80) was increased in pancreas of F3 LowerB and UpperB male offspring, which was associated with changes in cytokine levels. In contrast to F3 BPA males, LowerB and UpperB female offspring had comparable body weight, glucose tolerance and insulin secretion as Controls. Thus, maternal BPA exposure resulted in fewer metabolic defects in F3 than F1 and F2 offspring, and these were sex- and dose-specific.
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Bansal A, Rashid C, Xin F, Li C, Polyak E, Duemler A, van der Meer T, Stefaniak M, Wajid S, Doliba N, Bartolomei MS, Simmons RA. Sex- and Dose-Specific Effects of Maternal Bisphenol A Exposure on Pancreatic Islets of First- and Second-Generation Adult Mice Offspring. ENVIRONMENTAL HEALTH PERSPECTIVES 2017; 125:097022. [PMID: 29161229 PMCID: PMC5915189 DOI: 10.1289/ehp1674] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 07/26/2017] [Accepted: 07/26/2017] [Indexed: 05/17/2023]
Abstract
BACKGROUND Exposure to the environmental endocrine disruptor bisphenol A (BPA) is ubiquitous and associated with the increased risk of diabetes and obesity. However, the underlying mechanisms remain unknown. We recently demonstrated that perinatal BPA exposure is associated with higher body fat, impaired glucose tolerance, and reduced insulin secretion in first- (F1) and second-generation (F2) C57BL/6J male mice offspring. OBJECTIVE We sought to determine the multigenerational effects of maternal bisphenol A exposure on mouse pancreatic islets. METHODS Cellular and molecular mechanisms underlying these persistent changes were determined in F1 and F2 adult offspring of F0 mothers exposed to two relevant human exposure levels of BPA (10μg/kg/d-LowerB and 10mg/kg/d-UpperB). RESULTS Both doses of BPA significantly impaired insulin secretion in male but not female F1 and F2 offspring. Surprisingly, LowerB and UpperB induced islet inflammation in male F1 offspring that persisted into the next generation. We also observed dose-specific effects of BPA on islets in males. UpperB exposure impaired mitochondrial function, whereas LowerB exposure significantly reduced β-cell mass and increased β-cell death that persisted in the F2 generation. Transcriptome analyses supported these physiologic findings and there were significant dose-specific changes in the expression of genes regulating inflammation and mitochondrial function. Previously we observed increased expression of the critically important β-cell gene, Igf2 in whole F1 embryos. Surprisingly, increased Igf2 expression persisted in the islets of male F1 and F2 offspring and was associated with altered DNA methylation. CONCLUSION These findings demonstrate that maternal BPA exposure has dose- and sex-specific effects on pancreatic islets of adult F1 and F2 mice offspring. The transmission of these changes across multiple generations may involve either mitochondrial dysfunction and/or epigenetic modifications. https://doi.org/10.1289/EHP1674.
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Affiliation(s)
- Amita Bansal
- Center for Research on Reproduction and Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Cetewayo Rashid
- Center for Research on Reproduction and Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Frances Xin
- Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Changhong Li
- Division of Endocrinology and Diabetes, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Erzsebet Polyak
- Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Anna Duemler
- Center for Research on Reproduction and Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Eberly College of Science, Pennsylvania State University, University Park, Pennsylvania, USA
| | - Tom van der Meer
- Center for Research on Reproduction and Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Pediatrics, University of Groningen, Groningen, Netherlands
| | - Martha Stefaniak
- Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sana Wajid
- Exposure Biology Informatics Core, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Nicolai Doliba
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Marisa S Bartolomei
- Center for Research on Reproduction and Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rebecca A Simmons
- Center for Research on Reproduction and Women's Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Center of Excellence in Environmental Toxicology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
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Bioactive Nutrients and Nutrigenomics in Age-Related Diseases. Molecules 2017; 22:molecules22010105. [PMID: 28075340 PMCID: PMC6155887 DOI: 10.3390/molecules22010105] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 12/20/2016] [Accepted: 01/03/2017] [Indexed: 01/10/2023] Open
Abstract
The increased life expectancy and the expansion of the elderly population are stimulating research into aging. Aging may be viewed as a multifactorial process that results from the interaction of genetic and environmental factors, which include lifestyle. Human molecular processes are influenced by physiological pathways as well as exogenous factors, which include the diet. Dietary components have substantive effects on metabolic health; for instance, bioactive molecules capable of selectively modulating specific metabolic pathways affect the development/progression of cardiovascular and neoplastic disease. As bioactive nutrients are increasingly identified, their clinical and molecular chemopreventive effects are being characterized and systematic analyses encompassing the "omics" technologies (transcriptomics, proteomics and metabolomics) are being conducted to explore their action. The evolving field of molecular pathological epidemiology has unique strength to investigate the effects of dietary and lifestyle exposure on clinical outcomes. The mounting body of knowledge regarding diet-related health status and disease risk is expected to lead in the near future to the development of improved diagnostic procedures and therapeutic strategies targeting processes relevant to nutrition. The state of the art of aging and nutrigenomics research and the molecular mechanisms underlying the beneficial effects of bioactive nutrients on the main aging-related disorders are reviewed herein.
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Preliminary Studies of the Immunomodulator Effect of the Bougainvillea xbuttiana Extract in a Mouse Model. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:479412. [PMID: 25861362 PMCID: PMC4378339 DOI: 10.1155/2015/479412] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Revised: 02/02/2015] [Accepted: 02/04/2015] [Indexed: 01/29/2023]
Abstract
Bougainvillea xbuttiana is used as an analgesic in folk medicine in Mexico. The purpose of the present study was to determine the effects of the ethanolic extract from B. xbuttiana on macrophages activities. The phytochemical screening was performed for determine the presence of alkaloids, flavonoids, triterpenes, and saponins. The effects of B. xbuttiana were analyzed using the macrophages activities as determined by the H2O2 release, spreading and phagocytic index, vacuoles formation percentage, and mediators production. The viability percentage was determined in live cells after fixing and staining with crystal violet. The presence of H2O2 in macrophages was performed by using the peroxidase-phenol red solution. The cytokine production was determined by two assays, ELISA for detection of IL-6, IL-10, and IFN-γ and biological assay for TNF detection. The results showed that the Bxb extract dose-dependent manner produces (a) an increase in levels of H2O2 and spreading and vacuoles formation percentages, (b) a decrease in phagocytic index and in the amounts of TNF, IL-6, and IFN-γ, and (c) an increase significant in IL-10 and NO production. This study indicates that the ethanolic extract from Bougainvillea xbuttiana was able to activate macrophages. The combination of these results suggests that this extract has an immunomodulator effect.
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Hayes MD, Ovcinnikovs V, Smith AG, Kimber I, Dearman RJ. The aryl hydrocarbon receptor: differential contribution to T helper 17 and T cytotoxic 17 cell development. PLoS One 2014; 9:e106955. [PMID: 25203682 PMCID: PMC4159274 DOI: 10.1371/journal.pone.0106955] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 08/11/2014] [Indexed: 12/30/2022] Open
Abstract
The aryl hydrocarbon receptor (AhR) has been shown to be required for optimal Thelper (Th) 17 cell activation. Th17 cells provide immunity against extracellular pathogens and are implicated in autoimmune diseases. Herein, the role of the AhR in cytokine production by Th17, and by the analogous population of T cytotoxic (Tc)17 cells, has been examined. Lymph node Tc (CD8(+)) and Th (CD4(+)) cells were isolated by negative selection from naive AhR(+/-) and AhR(-/-) mice and polarised to Tc1/Th1 or Tc17/Th17 phenotypes with appropriate cytokines. Cell differentiation was assessed as a function of mRNA and protein (ELISA and flow cytometry) expression for interferon (IFN)-γ and for key Th17 cytokines. In AhR(+/-) mice, Th17 cells displayed an exclusive IL-17 profile, which was markedly inhibited by a selective AhR antagonist to levels observed in AhR knockout mice. Addition of the natural AhR agonist 6-formylindolo[3,2-b]carbazole (FICZ) markedly enhanced Th17 cell activity in the heterozygotes. In contrast, Tc17 cells polarised into 3 distinct subsets: producing either IL-17 or IFN-γ alone, or both cytokines. Blocking AhR was also detrimental to Tc17 development, with reduced responses recorded in AhR(-/-) mice and antagonist-mediated reduction of IL-17 expression in the heterozygotes. However, Tc17 cells were largely refractory to exogenous FICZ, presumably because Tc17 cells express baseline AhR mRNA, but unlike Th17 cells, there is no marked up-regulation during polarisation. Thus, Th17 cell development is more dependent upon AhR activation than is Tc17 cell development, suggesting that endogenous AhR ligands play a much greater role in driving Th17 cell responses.
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Affiliation(s)
- Mark D. Hayes
- Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom
| | - Vitalijs Ovcinnikovs
- Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom
| | - Andrew G. Smith
- MRC Toxicology Unit, The University of Leicester, Leicester, United Kingdom
| | - Ian Kimber
- Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom
| | - Rebecca J. Dearman
- Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom
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Jung M, Shin YJ, Kim J, Cha SB, Lee WJ, Shin MK, Shin SW, Yang MS, Jang YS, Kwon TH, Yoo HS. Induction of immune responses in mice and pigs by oral administration of classical swine fever virus E2 protein expressed in rice calli. Arch Virol 2014; 159:3219-30. [PMID: 25091740 DOI: 10.1007/s00705-014-2182-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2014] [Accepted: 07/15/2014] [Indexed: 12/19/2022]
Abstract
Classical swine fever (CSF), caused by the CSF virus (CSFV), is a highly contagious disease in pigs. In Korea, vaccination using a live-attenuated strain (LOM strain) has been used to control the disease. However, parenteral vaccination using a live-attenuated strain still faces a number of problems related to storage, cost, injection stress, and differentiation of CSFV infected and vaccinated pigs. Therefore, two kinds of new candidates for oral vaccination have been developed based on the translation of the E2 gene of the SW03 strain, which was isolated from an outbreak of CSF in 2002 in Korea, in transgenic rice calli (TRCs) from Oriza sativa L. cv. Dongjin to express a recombinant E2 protein (rE2-TRCs). The expression of the recombinant E2 protein (rE2) in rE2-TRCs was confirmed using Northern blot, SDS-PAGE, and Western blot analysis. Immune responses to the rE2-TRC in mice and pigs were investigated after oral administration. The administration of rE2-TRCs increased E2-specific antibodies titers and antibody-secreting cells when compared to animals receiving the vector alone (p < 0.05 and p < 0.01). In addition, mice receiving rE2-TRCs had a higher level of CD8+ lymphocytes and Th1 cytokine immune responses to purified rE2 (prE2) in vitro than the controls (p < 0.05 and p < 0.01). Pigs receiving rE2-TRCs also showed an increase in IL-8, CCL2, and the CD8+ subpopulation in response to stimulation with prE2. These results suggest that oral administration of rE2-TRCs can induce E2-specific immune responses.
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Affiliation(s)
- Myunghwan Jung
- Department of Infectious diseases, College of Veterinary Medicine, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul, 151-742, Korea
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van den Bogaart E, Talha ABA, Straetemans M, Mens PF, Adams ER, Grobusch MP, Nour BYM, Schallig HDFH. Cytokine profiles amongst Sudanese patients with visceral leishmaniasis and malaria co-infections. BMC Immunol 2014; 15:16. [PMID: 24886212 PMCID: PMC4024313 DOI: 10.1186/1471-2172-15-16] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2013] [Accepted: 04/16/2014] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The immune system plays a critical role in the development of co-infections, promoting or preventing establishment of multiple infections and shaping the outcome of pathogen-host interactions. Its ability to mediate the interplay between visceral leishmaniasis (VL) and malaria has been suggested, but poorly documented. The present study investigated whether concomitant infection with Leishmania donovani complex and Plasmodium falciparum in naturally co-infected patients altered the immunological response elicited by the two pathogens individually. RESULTS Circulating levels of interferon (IFN)-γ, interleukin (IL)-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, IL-17A and tumor necrosis factor (TNF) were assessed in sera of patients infected with active VL and/or malaria and healthy individuals from Gedarif State, Sudan. Comparative analysis of cytokine profiles from co- and mono-infected patients highlighted significant differences in the immune response mounted upon co-infection, confirming the ability of L. donovani and P. falciparum to mutually interact at the immunological level. Progressive polarization towards type-1 and pro-inflammatory cytokine patterns characterized the co-infected patients, whose response partly reflected the effect elicited by VL (IFN-γ, TNF) and malaria (IL-2, IL-13), and partly resulted from a synergistic interaction of the two diseases upon each other (IL-17A). Significantly reduced levels of P. falciparum parasitaemia (P <0.01) were detected in the co-infected group as opposed to the malaria-only patients, suggesting either a protective or a non-detrimental effect of the co-infection against P. falciparum infection. CONCLUSIONS These findings suggest that a new immunological scenario may occur when L. donovani and P. falciparum co-infect the same patient, with potential implications on the course and resolution of these diseases.
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Affiliation(s)
- Erika van den Bogaart
- Department of Biomedical Research, Royal Tropical Institute (KIT), Amsterdam, The Netherlands.
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Umehara H, Tanaka M, Sawaki T, Jin ZX, Huang CR, Dong L, Kawanami T, Karasawa H, Masaki Y, Fukushima T, Hirose Y, Okazaki T. Fractalkine in rheumatoid arthritis and allied conditions. Mod Rheumatol 2014. [DOI: 10.3109/s10165-006-0471-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Perié L, Aru J, Kourilsky P, Slotine JJ. Does a quorum sensing mechanism direct the behavior of immune cells? C R Biol 2013; 336:13-6. [PMID: 23537765 DOI: 10.1016/j.crvi.2013.01.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Revised: 01/28/2013] [Accepted: 01/29/2013] [Indexed: 10/27/2022]
Abstract
Quorum sensing is a decision-making process used by decentralized groups such as colonies of bacteria to trigger a coordinated behavior. The existence of decentralized coordinated behavior has also been suggested in the immune system. In this paper, we explore the possibility for quorum sensing mechanisms in the immune response. Cytokines are good candidates as inducer of quorum sensing effects on migration, proliferation and differentiation of immune cells. The existence of a quorum sensing mechanism should be explored experimentally. It may provide new perspectives into immune responses and could lead to new therapeutic strategies.
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Affiliation(s)
- Leïla Perié
- Collège de France, Chair of molecular immunology, 11, place Marcelin-Berthelot, 75005 Paris, France.
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Coriolano MC, de Melo CML, Santos AJG, Pereira VRA, Coelho LCBB. Rachycentron canadum (cobia) lectin promoted mitogenic response in mice BALB/c splenocytes. Scand J Immunol 2013; 76:567-72. [PMID: 22946764 DOI: 10.1111/j.1365-3083.2012.02774.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
The mitogenic lectins are invaluable tools to study the biochemical changes associated with lymphocyte activation and proliferation of various immune cells. Rachycentron canadum lectin (RcaL) was detected and purified from serum of cobia fish. The aim of this study was to evaluate the proliferative response and cytokine production in splenocytes of mice in vitro stimulated with RcaL lectin; Canavalia ensiformis lectin (Con A) was used as positive control. A high proliferation index was induced by RcaL in relation to control cells. Furthermore, RcaL induced higher IL-2 and IL-6 production in relation to control. The cell viability was 90% in splenocytes treated with RcaL lectin, but RcaL promoted significant late apoptosis after 24 and 48 h in relation to control. RcaL induced proliferative responses suggesting that this lectin can be used as a mitogenic agent in immunostimulatory assays.
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Affiliation(s)
- M C Coriolano
- Departamento de Bioquímica, Laboratório de Glicoproteínas da Universidade Federal de Pernambuco-UFPE, Recife, Brazil
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Shimato S, Maier LM, Maier R, Bruce JN, Anderson RCE, Anderson DE. Profound tumor-specific Th2 bias in patients with malignant glioma. BMC Cancer 2012. [PMID: 23186108 PMCID: PMC3537750 DOI: 10.1186/1471-2407-12-561] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Background Vaccination against tumor-associated antigens is one promising approach to immunotherapy against malignant gliomas. While previous vaccine efforts have focused exclusively on HLA class I-restricted peptides, class II-restricted peptides are necessary to induce CD4+ helper T cells and sustain effective anti-tumor immunity. In this report we investigated the ability of five candidate peptide epitopes derived from glioma-associated antigens MAGE and IL-13 receptor α2 to detect and characterize CD4+ helper T cell responses in the peripheral blood of patients with malignant gliomas. Methods Primary T cell responses were determined by stimulating freshly isolated PBMCs from patients with primary glioblastoma (GBM) (n = 8), recurrent GBM (n = 5), meningioma (n = 7), and healthy controls (n = 6) with each candidate peptide, as well as anti-CD3 monoclonal antibody (mAb) and an immunodominant peptide epitope derived from myelin basic protein (MBP) serving as positive and negative controls, respectively. ELISA was used to measure IFN-γ and IL-5 levels, and the ratio of IFN-γ/IL-5 was used to determine whether the response had a predominant Th1 or Th2 bias. Results We demonstrate that novel HLA Class-II restricted MAGE-A3 and IL-13Rα2 peptides can detect T cell responses in patients with GBMs as well as in healthy subjects. Stimulation with a variety of peptide antigens over-expressed by gliomas is associated with a profound reduction in the IFN-γ/IL-5 ratio in GBM patients relative to healthy subjects. This bias is more pronounced in patients with recurrent GBMs. Conclusions Therapeutic vaccine strategies to shift tumor antigen-specific T cell response to a more immunostimulatory Th1 bias may be needed for immunotherapeutic trials to be more successful clinically.
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Affiliation(s)
- Shinji Shimato
- Department of Neurosurgery, Gabriele Bartoli Brain Tumor Research Laboratory, Columbia University, New York City, NY, USA
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19
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Izsepi E, Himer L, Szilagyi O, Hajdu P, Panyi G, Laszlo G, Matko J. Membrane microdomain organization, calcium signal, and NFAT activation as an important axis in polarized Th cell function. Cytometry A 2012. [DOI: 10.1002/cyto.a.22234] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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20
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Immunomodulatory response of mice splenocytes induced by RcaL, a lectin isolated from cobia fish (Rachycentron canadum) serum. Appl Biochem Biotechnol 2012; 168:1335-48. [PMID: 22941310 DOI: 10.1007/s12010-012-9861-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Accepted: 08/21/2012] [Indexed: 01/05/2023]
Abstract
This work reports the isolation of a serum lectin from cobia fish (Rachycentron canadum) named RcaL. Immunomodulatory activity on mice splenocyte experimental cultures through cytotoxic assays and cytokine production were also performed. RcaL was obtained through precipitation with ammonium sulphate and affinity chromatography on a Concanavalin A-Sepharose 4B column. The ammonium sulphate fraction F3 showed the highest specific hemagglutinating activity and was applied to affinity chromatography. The lectin was eluted with methyl-α-D-mannopyranoside. RcaL showed highest affinity for methyl-α-D-mannopyranoside and D-mannose; eluted fractions of RcaL agglutinated rabbit erythrocytes (titre, 128(-1)) retained 66 % of chromatographed lectin activity, and the obtained purification factor was 1.14. Under reducing conditions, a polypeptide band of 19.2 kDa was revealed in sodium dodecyl sulphate polyacrylamide gel electrophoresis (PAGE). PAGE confirmed RcaL as an acidic protein revealed in a single band. Cytotoxic and immunomodulatory assays with RcaL in mice splenocyte cultures showed that the lectin was not cytotoxic and induced higher interferon gamma and nitric oxide production in splenocyte cultures. Purified RcaL induced preferential Th1 response, suggesting that it acts as an immunomodulatory compound.
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Abstract
This paper is a shortened English transcription of a lecture given on 13 February 2012 at the College de France. The lecture concluded a series of talks delivered the same year on the theme: "Immunity: the game of chance and specificity". The article comprises four parts: I. The game of chance and specificity. II. About the future of research in immunology. III. On the future of the applications of research in immunology. IV. The social conditions of the evolution of research and its applications.
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Gene expression profiling of hybridoma cells after bursal-derived bioactive factor BP5 treatment. Amino Acids 2012; 43:2443-56. [DOI: 10.1007/s00726-012-1323-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2011] [Accepted: 05/15/2012] [Indexed: 12/25/2022]
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Turner AK, Begon M, Jackson JA, Paterson S. Evidence for selection at cytokine loci in a natural population of field voles (Microtus agrestis). Mol Ecol 2012; 21:1632-46. [PMID: 22364125 DOI: 10.1111/j.1365-294x.2012.05501.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Individuals in natural populations are frequently exposed to a wide range of pathogens. Given the diverse profile of gene products involved in responses to different types of pathogen, this potentially results in complex pathogen-specific selection pressures acting on a broad spectrum of immune system genes in wild animals. Thus far, studies into the evolution of immune genes in natural populations have focused almost exclusively on the Major Histocompatibility Complex (MHC). However, the MHC represents only a fraction of the immune system and there is a need to broaden research in wild species to include other immune genes. Here, we examine the evidence for natural selection in a range of non-MHC genes in a natural population of field voles (Microtus agrestis). We concentrate primarily on genes encoding cytokines, signalling molecules critical in eliciting and mediating immune responses and identify signatures of natural selection acting on several of these genes. In particular, genetic diversity within Interleukin 1 beta and Interleukin 2 appears to have been maintained through balancing selection. Taken together with previous findings that polymorphism within these genes is associated with variation in resistance to multiple pathogens, this suggests that pathogen-mediated selection may be an important force driving genetic diversity at cytokine loci in voles and other natural populations. These results also suggest that, along with the MHC, preservation of genetic variation within cytokine genes should be a priority for the conservation genetics of threatened wildlife populations.
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Affiliation(s)
- Andrew K Turner
- Institute of Integrative Biology, Biosciences Building, University of Liverpool, Crown Street, Liverpool L69 7ZB, UK
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24
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Mejri N, Müller J, Gottstein B. Intraperitoneal murine Echinococcus multilocularis infection induces differentiation of TGF-β-expressing DCs that remain immature. Parasite Immunol 2011; 33:471-82. [PMID: 21609335 DOI: 10.1111/j.1365-3024.2011.01303.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Intraperitoneal larval infection (alveolar echinococcosis, AE) with Echinococcus multilocularis in mice impairs host immunity. Metacestode metabolites may modulate immunity putatively via dendritic cells. During murine AE, a relative increase of peritoneal DCs (pe-DCs) in infected mice (AE-pe-DCs; 4% of total peritoneal cells) as compared to control mice (naïve pe-DCs; 2%) became apparent in our study. The differentiation of AE-pe-DCs into TGF-β-expressing cells and the higher level of IL-4 than IFN-γ/IL-2 mRNA expression in AE-CD4+pe-T cells indicated a Th2 orientation. Analysis of major accessory molecule expression on pe-DCs from AE-infected mice revealed that CD80 and CD86 were down-regulated on AE-pe-DCs, while ICAM-1(CD54) remained practically unchanged. Moreover, AE-pe-DCs had a weaker surface expression of MHC class II (Ia) molecules as compared to naïve pe-DCs. The gene expression level of molecules involved in MHC class II (Ia) synthesis and formation of MHC class II (Ia)-peptide complexes were down-regulated. In addition, metacestodes excreted/secreted (E/S) or vesicle-fluid (V/F) antigens were found to alter MHC class II molecule expression on the surface of BMDCs. Finally, conversely to naïve pe-DCs, an increasing number of AE-pe-DCs down-regulated Con A-induced proliferation of naïve CD4+pe-T cells. These findings altogether suggested that TGF-β-expressing immature AE-pe-DCs might play a significant role in the generation of a regulatory immune response within the peritoneal cavity of AE-infected mice.
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Affiliation(s)
- N Mejri
- Institute of Parasitology, University of Berne, Bern, Switzerland
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Turner AK, Begon M, Jackson JA, Bradley JE, Paterson S. Genetic diversity in cytokines associated with immune variation and resistance to multiple pathogens in a natural rodent population. PLoS Genet 2011; 7:e1002343. [PMID: 22039363 PMCID: PMC3197692 DOI: 10.1371/journal.pgen.1002343] [Citation(s) in RCA: 74] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2011] [Accepted: 08/26/2011] [Indexed: 12/31/2022] Open
Abstract
Pathogens are believed to drive genetic diversity at host loci involved in immunity to infectious disease. To date, studies exploring the genetic basis of pathogen resistance in the wild have focussed almost exclusively on genes of the Major Histocompatibility Complex (MHC); the role of genetic variation elsewhere in the genome as a basis for variation in pathogen resistance has rarely been explored in natural populations. Cytokines are signalling molecules with a role in many immunological and physiological processes. Here we use a natural population of field voles (Microtus agrestis) to examine how genetic diversity at a suite of cytokine and other immune loci impacts the immune response phenotype and resistance to several endemic pathogen species. By using linear models to first control for a range of non-genetic factors, we demonstrate strong effects of genetic variation at cytokine loci both on host immunological parameters and on resistance to multiple pathogens. These effects were primarily localized to three cytokine genes (Interleukin 1 beta (Il1b), Il2, and Il12b), rather than to other cytokines tested, or to membrane-bound, non-cytokine immune loci. The observed genetic effects were as great as for other intrinsic factors such as sex and body weight. Our results demonstrate that genetic diversity at cytokine loci is a novel and important source of individual variation in immune function and pathogen resistance in natural populations. The products of these loci are therefore likely to affect interactions between pathogens and help determine survival and reproductive success in natural populations. Our study also highlights the utility of wild rodents as a model of ecological immunology, to better understand the causes and consequences of variation in immune function in natural populations including humans.
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Affiliation(s)
- Andrew K Turner
- Institute of Integrative Biology, Biosciences Building, University of Liverpool, Liverpool, United Kingdom.
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Hawley DM, Altizer SM. Disease ecology meets ecological immunology: understanding the links between organismal immunity and infection dynamics in natural populations. Funct Ecol 2011. [DOI: 10.1111/j.1365-2435.2010.01753.x] [Citation(s) in RCA: 259] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Dana M. Hawley
- Department of Biology, Virginia Tech, Blacksburg, Virginia 24061, USA
| | - Sonia M. Altizer
- Odum School of Ecology, University of Georgia, Athens, Georgia 30602, USA
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de Melo CML, Melo H, Correia MTS, Coelho LCBB, da Silva MB, Pereira VRA. Mitogenic Response and Cytokine Production Induced by Cramoll 1,4 Lectin in Splenocytes of Inoculated Mice. Scand J Immunol 2011; 73:112-21. [DOI: 10.1111/j.1365-3083.2010.02490.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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de Melo CML, de Castro MCAB, de Oliveira AP, Gomes FOS, Pereira VRA, Correia MTS, Coelho LCBB, Paiva PMG. Immunomodulatory response of Cramoll 1,4 lectin on experimental lymphocytes. Phytother Res 2010; 24:1631-6. [DOI: 10.1002/ptr.3156] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Szulc L, Boratynska A, Martyniszyn L, Niemialtowski MG. Antigen presenting and effector cell cluster formation in BALB/c mice during mousepox: model studies*. J Appl Microbiol 2010; 109:1817-28. [PMID: 20666870 DOI: 10.1111/j.1365-2672.2010.04813.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
AIMS The objective of this study was to access APC-effector cell cluster formation in genetically susceptible BALB/c (H-2(d) ) mice infected with highly virulent Moscow strain of ectromelia virus (ECTV-MOS) and estimate of lymphocyte activation based upon expression of CD62L and CD44 molecules. METHODS AND RESULTS APC-effector cell clusters were obtained by enzymatic digestion from draining lymph nodes (DLNs) and spleens of BALB/c mice. We found that APCs infected with ECTV-MOS form unstable clusters with effector cells, and thus may diminish T-cell activation at the early stage of mousepox. Different types of effector cells including T-cell subsets (CD4(+) and CD8(+) ), B cells and polymorphonuclear cells colocalize within individual clusters. Increase in CD19(+) B cells within APC-effector cell clusters during severe clinical mousepox may reflect B-cell activation. CONCLUSIONS Our studies indicated vigorous changes in APC-effector cell cluster formation in genetically susceptible BALB/c mice during mousepox (up to 2 weeks). ECTV-MOS can modulate APC interactions with effector cells and consequently may impair T-cell activation probably owing to unstable cluster formation and/or subsequent weak stimulation by infected APCs at the early stages of mousepox. SIGNIFICANCE AND IMPACT OF THE STUDY This is the first report of APC-effector cell cluster formation in BALB/c mice during mousepox. It gives us a new light on the mutual cell-cell interactions and development of the immune response during ECTV-MOS infection.
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Affiliation(s)
- L Szulc
- Division of Immunology, Department of Preclinical Sciences, Faculty of Veterinary Medicine, Warsaw University of Life Sciences - SGGW, Warsaw, Poland
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Kim S, Kim HJ, Jeon NL. Biological applications of microfluidic gradient devices. Integr Biol (Camb) 2010; 2:584-603. [DOI: 10.1039/c0ib00055h] [Citation(s) in RCA: 277] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
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Giavina-Bianchi P, Aun MV, Bisaccioni C, Agondi R, Kalil J. Difficult-to-control asthma management through the use of a specific protocol. Clinics (Sao Paulo) 2010; 65:905-18. [PMID: 21049219 PMCID: PMC2954742 DOI: 10.1590/s1807-59322010000900014] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2010] [Revised: 05/18/2010] [Accepted: 06/02/2010] [Indexed: 12/21/2022] Open
Abstract
The present study is a critical review of difficult-to-control asthma, highlighting the characteristics and severity of the disease. It also presents a protocol for the management of patients with this asthma phenotype. The protocol, which was based on relevant studies in the literature, is described and analyzed.
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IFNalpha kinoid vaccine-induced neutralizing antibodies prevent clinical manifestations in a lupus flare murine model. Proc Natl Acad Sci U S A 2009; 106:5294-9. [PMID: 19279210 DOI: 10.1073/pnas.0900615106] [Citation(s) in RCA: 70] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
A major involvement of IFNalpha in the etiopathogenesis of systemic lupus erythematosus has been suggested by clinical observations, including the increase of serum levels of this cytokine in patients with active disease. Supporting this hypothesis, we have shown that expression of IFNalpha from a recombinant adenovirus (IFNalpha Adv) precipitates lupus manifestations in genetically susceptible New Zealand Black (NZB) x New Zealand White (NZW)F(1) mice (NZB/W) but not in BALB/c mice. In the present investigation, we have prepared an IFNalpha immunogen, termed IFNalpha kinoid, which, appropriately adjuvanted, induces transient neutralizing antibodies (Abs) but no cellular immune response to the cytokine and without apparent side effects. Using this preparation, we also showed that, in kinoid-vaccinated NZB/W mice, lupus manifestations, including proteinuria, histological renal lesions, and death triggered by IFNalpha Adv challenge were delayed/prevented as long as an effective threshold of anti-IFNalpha inhibitory capacity was present in the serum.
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Goncharova LB, Tarakanov AO. Molecular networks of brain and immunity. ACTA ACUST UNITED AC 2007; 55:155-66. [PMID: 17408562 DOI: 10.1016/j.brainresrev.2007.02.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2006] [Revised: 02/13/2007] [Accepted: 02/14/2007] [Indexed: 11/22/2022]
Abstract
Exciting complexity of natural phenomena can be based on rather simple biophysical principles. For example, the genetic code is based on a double-helix of DNA formed by planar geometry of weak hydrogen bounds. On the examples of cytokine networks, immune synapse, psychoneuroimmunology and systems biology, this review paper attempts to show how molecular networks both in brain and immunity can be studied using common principles of protein-protein interactions.
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Affiliation(s)
- Larisa B Goncharova
- Institute Pasteur of St. Petersburg, ul. Mira 14, St. Petersburg 197101, Russia
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Ma Y, HayGlass KT, Becker AB, Fan Y, Yang X, Basu S, Srinivasan G, Simons FER, Halayko AJ, Peng Z. Novel recombinant interleukin-13 peptide-based vaccine reduces airway allergic inflammatory responses in mice. Am J Respir Crit Care Med 2007; 176:439-45. [PMID: 17556715 DOI: 10.1164/rccm.200610-1405oc] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
RATIONALE Interleukin (IL)-13 plays a pivotal role in the pathogenesis of allergic asthma. Passive administration of its monoclonal antibody or soluble receptor to block overproduced IL-13 has been proven to be effective in controlling airway allergic responses in animal models, but these approaches have disadvantages of short half-lives, high costs, and possible adverse effects. OBJECTIVES We sought to develop a novel therapeutic strategy through constructing an IL-13 peptide-based vaccine for blocking IL-13 on a persistent effect basis and to evaluate its in vivo effects using a murine model. METHODS To break self-tolerance, truncated hepatitis B core antigen was used as a carrier. Vaccine was prepared by inserting a peptide derived from the receptor binding site of mouse IL-13 into the immunodominant epitope region of the carrier using gene recombination methods. Mice received vaccine subcutaneously three times, and then subjected to intraperitoneal sensitization and intranasal challenge with ovalbumin. Control animals received carrier or saline in place of vaccine. MEASUREMENTS AND MAIN RESULTS The vaccine presented as virus-like particles and induced sustained and high titered IL-13-specific IgG without the use of conventional adjuvant. Vaccination significantly suppressed ovalbumin-induced inflammatory cell number, and IL-13 and IL-5 levels in bronchoalveolar lavage fluids. Serum total and ovalbumin-specific IgE were also significantly inhibited. Moreover, allergen-induced goblet cell hyperplasia, lung tissue inflammatory cell infiltration, and pulmonary hyperresponsiveness to inhaled methacholine were significantly suppressed in vaccinated mice. CONCLUSIONS Our data indicate that IL-13 peptide-based vaccines could be an effective therapeutic approach in the treatment of asthma.
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Affiliation(s)
- Yanbing Ma
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, Manitoba, Canada
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Graham AL, Cattadori IM, Lloyd-Smith JO, Ferrari MJ, Bjørnstad ON. Transmission consequences of coinfection: cytokines writ large? Trends Parasitol 2007; 23:284-91. [PMID: 17466597 DOI: 10.1016/j.pt.2007.04.005] [Citation(s) in RCA: 94] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Coinfection of a host by multiple parasite species is commonly observed and recent epidemiological work indicates that coinfection can enhance parasite transmission. This article proposes an immunoepidemiological framework to understand how within-host interactions during coinfection might affect between-host transmission. Cytokines, immune signalling molecules with a fundamental role in the amplification of antiparasitic effector mechanisms, provide a useful way to simplify immunological complexity for this endeavour--focusing on cytokines offers analytical tractability without sacrificing realism. Testable predictions about the epidemiological consequences of coinfection are generated by this conceptual framework.
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Affiliation(s)
- Andrea L Graham
- Institutes of Evolution, Immunology & Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, UK.
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Riganò R, Buttari B, Profumo E, Ortona E, Delunardo F, Margutti P, Mattei V, Teggi A, Sorice M, Siracusano A. Echinococcus granulosus antigen B impairs human dendritic cell differentiation and polarizes immature dendritic cell maturation towards a Th2 cell response. Infect Immun 2007; 75:1667-78. [PMID: 17210662 PMCID: PMC1865679 DOI: 10.1128/iai.01156-06] [Citation(s) in RCA: 115] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2006] [Revised: 09/03/2006] [Accepted: 01/02/2007] [Indexed: 01/04/2023] Open
Abstract
Despite inducing a strong host cellular and humoral immune response, the helminth Echinococcus granulosus is a highly successful parasite that develops, progresses, and ultimately causes chronic disease. Although surgery remains the preferred therapeutic option, pharmacological research now envisages antihelminthic strategies. To understand the mechanisms that E. granulosus uses to escape host immunosurveillance and promote chronic infection, we investigated how two hydatid cyst components, purified antigen B (AgB) and sheep hydatid fluid (SHF), act on host dendritic cell (DC) differentiation from monocyte precursors and how they influence maturation of DC that have already differentiated. We evaluated the immunomodulatory potential of these antigens by performing immunochemical and cytofluorimetric analyses of monocyte-derived DCs from healthy human donors. During monocyte differentiation, AgB and SHF downmodulated CD1a expression and upregulated CD86 expression. Compared with immature DCs differentiated in medium alone (iDCs), AgB- and SHF-differentiated cells stimulated with lipopolysaccharide included a significantly lower percentage of CD83(+) cells (P < 10(-4)) and had weaker costimulatory molecule expression. When stimulated with AgB and SHF, iDCs matured and primed lymphocytes towards the Th2 response typical of E. granulosus infection. SHF and particularly AgB reduced the production of interleukin-12p70 (IL-12p70) and tumor necrosis factor alpha in lipopolysaccharide-stimulated iDCs. Anti-IL-10 antibodies increased the levels of IL-12p70 secretion in AgB- and SHF-matured DCs. AgB and SHF induced interleukin-1 receptor-associated kinase phosphorylation and activated nuclear factor-kappaB, suggesting that Toll-like receptors could participate in E. granulosus-stimulated DC maturation. These results suggest that E. granulosus escapes host immunosurveillance in two ways: by interfering with monocyte differentiation and by modulating DC maturation.
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Affiliation(s)
- Rachele Riganò
- Dipartimento di Malattie Infettive, Parassitarie ed Immunomediate, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
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Ma XJ, Tian DY, Xu D, Yang DF, Zhu HF, Liang ZH, Zhang ZG. Uric acid enhances T cell immune responses to hepatitis B surface antigen-pulsed-dendritic cells in mice. World J Gastroenterol 2007; 13:1060-6. [PMID: 17373740 PMCID: PMC4146868 DOI: 10.3748/wjg.v13.i7.1060] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the induction of T cellular immune responses in BALB/c mice immunized with uric acid and dendritic cells (DCs) pulsed with hepatitis B virus surface antigen (HBsAg).
METHODS: DCs were generated from bone-marrow cells of BABL/c mice, and then pulsed or unpulsed with HBsAg protein (HBsAg-pulsed-DCs or unpulsed-DCs) in vitro. BABL/c mice were immunized with HBsAg-pulsed-DCs (1 × 106) and uric acid, injected through the tail vein of each mouse. The mice in control groups were immunized with HBsAg-pulsed-DCs alone, unpulsed-DCs alone or 200 μg uric acid alone or PBS alone. The immunization was repeated 7 d later. Cytotoxic T lymphocytes (CTLs) in vivo were determined by the CFSE labeled spleen lysis assay. Spleen cells or spleen T cells were isolated, and re-stimulated in vitro with HBsAg for 120 h or 72 h. Production of IFN-γ and IL-4 secreted by spleen cells were determined by ELISA method; proliferation of spleen T cells were detected by flow cytometry.
RESULTS: The cytotoxicities of HBsAg-specific-CTLs, generated after immunization of HBsAg-pulsed-DCs and uric acid, were 68.63% ± 11.32% and significantly stronger than that in the control groups (P < 0.01). Compared with control groups, in mice treated with uric acid and HBsAg-pulsed-DCs, the spleen T cell proliferation to HBsAg re-stimulation was stronger (1.34 ± 0.093 vs 1.081 ± 0.028, P < 0.01), the level of IFN-γ secreted by splenocytes was higher (266.575 ± 51.323 vs 135.223 ± 32.563, P < 0.01) , and IL-4 level was lower (22.385 ± 2.252 vs 40.598 ± 4.218, P < 0.01).
CONCLUSION: Uric acid can strongly enhance T cell immune responses induced by HBsAg-pulsed-DCs vaccine. Uric acid may serve as an effective adjuvant of DC vaccine against HBV infection.
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Affiliation(s)
- Xiao-Jun Ma
- Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue 1095,Wuhan 430030, Hubei Province, China
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Kanai N, Min WP, Ichim TE, Wang H, Zhong R. Th1/Th2 xenogenic antibody responses are associated with recipient dendritic cells. Microsurgery 2007; 27:234-9. [PMID: 17477419 DOI: 10.1002/micr.20342] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
We characterized dendritic cells (DC) phenotypically and functionally between C57BL/6 (Th1-prone) and BALB/c (Th2-prone) mouse recipients in an in vivo sensitization model. Two strains of mice were presensitized with Lewis rat splenocytes as xenogeneic antigens. We found that BALB/c recipients mounted a significantly higher total IgG response to the xeno-antigens when compared with C57BL/6 recipients, 10 days after rat splenocyte infusion. A Th2-mediated antibody response with high ratio of IgG1/IgG2a was seen in the BALB/c recipients, while a Th1 antibody response with low ratio of IgG1/IgG2a was detected in C57BL/6 recipients. CD11c(+)DC isolated from C57BL/6 recipients possessed increased expression of CD8alpha(+) (DC-1 type). The administration of bone marrow derived-DC from IL-12 knockout mice into C57BL/6 recipients induced a shift of Th-mediated anti-xenogeneic antibody responses from Th1 to Th2 domain. Our findings suggest that DC could play an important role to regulate the balance of Th1/Th2 cytokine profiles and rejection patterns in xenotransplantation.
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Abstract
Ulcerative colitis (UC) and Crohn’s disease (CD) are the major forms of idiopathic inflammatory bowel disease (IBD). Both UC and CD are debilitating chronic disorders that afflict millions of individuals throughout the world with symptoms which impair function and quality of life. The etiology of IBD is inadequately understood and therefore, drug therapy has been empirical instead of being based on sound understanding of IBD pathogenesis. This is a major factor for poor drug efficacy and drug related side effects that often add to the disease complexity. The development of biologicals notably infliximab to intercept tumor necrosis factor (TNF)-α reflects some progress, albeit major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD seems to be perpetuated by inflammatory cytokines like TNF-α, interleukin (IL)-1β, IL-6 and IL-8 for which activated peripheral granulocytes and monocytes/macrophages (GM) are major sources. Further, in IBD, peripheral GMs are elevated with activation behavior, increased survival time and are found in vast numbers within the inflamed intestinal mucosa; they are suspected to be major factors in the immunopathogenesis of IBD. Hence, peripheral blood GMs should be appropriate targets of therapy. The Adacolumn is a medical device developed for selective depletion of GM by receptor-mediated adsorption (GMA). Clinical data show GMA, in patients with steroid dependent or steroid refractory UC, is associated with up to 85% efficacy and tapering or discontinuation of steroids, while in steroid naïve patients (the best responders), GMA spares patients from exposure to steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse suppresses relapse thus sparing the patients from the morbidity associated with IBD relapse. Further, GMA appears to reduce the number of patients being submitted to colectomy or exposure to unsafe immunosupressants. First UC episode, steroid naivety and short disease duration appear good predictors of response to GMA and based on the available data, GMA seems to have an excellent safety profile.
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Affiliation(s)
- Hiroyuki Hanai
- Center for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, 26 Shirowacho, Hamamatsu 4300846, Japan
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Umehara H, Tanaka M, Sawaki T, Jin ZX, Huang CR, Dong L, Kawanami T, Karasawa H, Masaki Y, Fukushima T, Hirose Y, Okazaki T. Fractalkine in rheumatoid arthritis and allied conditions. Mod Rheumatol 2006; 16:124-30. [PMID: 16767549 DOI: 10.1007/s10165-006-0471-9] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2006] [Accepted: 03/14/2006] [Indexed: 10/24/2022]
Abstract
Leukocyte adhesion and trafficking at the endothelium requires both adhesion molecules and chemotactic factors. Fractalkine (CX3C) is a unique chemokine, and is expressed on tumor necrosis factor-alpha- and interleukin-1-activated endothelial cells (ECs). Fractalkine receptor, CX3CR1, is expressed on NK cells, monocytes, and some portion of CD4- and CD8-positive T cells. Interactions between fractalkine and CX3CR1 can mediate not only chemotaxis, but also cell adhesion in the absence of substrates for other adhesion molecules. Furthermore, fractalkine activates NK cells, leading to increased cytotoxicity and interferon-gamma production. Recently, accumulating evidence has shown that fractalkine is involved in the pathogenesis of rheumatoid arthritis and allied conditions. This review examines new concepts underlying fractalkine-mediated leukocyte migration and tissue damage, focusing primarily on the pathophysiological roles of fractalkine in rheumatic diseases.
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Affiliation(s)
- Hisanori Umehara
- Division of Hematology and Immunology, Department of Internal Medicine, Kanazawa Medical University, Daigaku, Uchinada-machi, Kahoku-gun, Ishikawa, 920-0293, Japan.
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Hanai H, Iida T, Yamada M, Sato Y, Takeuchi K, Tanaka T, Kondo K, Kikuyama M, Maruyama Y, Iwaoka Y, Nakamura A, Hirayama K, Saniabadi AR, Watanabe F. Effects of adacolumn selective leukocytapheresis on plasma cytokines during active disease in patients with active ulcerative colitis. World J Gastroenterol 2006; 12:3393-9. [PMID: 16733857 PMCID: PMC4087871 DOI: 10.3748/wjg.v12.i21.3393] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between ulcerative colitis (UC) clinical activity index (CAI) and circulating levels of IL-1ra, IL-10, IL-6 and IL-18.
METHODS: Blood levels of IL-1ra, IL-10, IL-6 and IL-18 were measured in 31 patients with active UC, the mean CAI was 11.1, ranging from 5-25; and 12 healthy individuals as controls. Patients were given granulocyte and monocyte adsorptive apheresis (GMA) with Adacolumn. Leucocytes which bear the FcγR and complement receptors were adsorbed to the column leucocytapheresis carriers. Each patient could receive up to 11 GMA sessions over 8 wk.
RESULTS: We found strong correlations between CAI and IL-10 (r = 0.827, P < 0.001), IL-6 (r = 0.785, P < 0.001) and IL-18 (r = 0.791, P < 0.001). IL-1ra was not correlated with CAI. Following GMA therapy, 24 of the 31 patients achieved remission and the levels of all 4 cytokines fell to the levels in healthy controls. Further, blood levels of IL-1ra and IL-10 increased at the column outflow and inflow at 60 min suggesting release from leucocytes that adhered to the carriers.
CONCLUSION: Elevated blood levels of IL-6 and IL-18 together with peripheral blood granulocytes and monocytes/macrophages in patients with active UC show activative behaviour and increased survival time can be pro-inflammatory and the targets of GMA therapy.
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Affiliation(s)
- Hiroyuki Hanai
- Hamamatsu South Hospital, Center for Gastroenterology and IBD Research, Japan.
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Raymond CR, Sidahmed AME, Wilkie BN. Effects of antigen and recombinant porcine cytokines on pig dendritic cell cytokine expression in vitro. Vet Immunol Immunopathol 2006; 111:175-85. [PMID: 16476491 DOI: 10.1016/j.vetimm.2005.12.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2005] [Revised: 10/18/2005] [Accepted: 12/22/2005] [Indexed: 11/17/2022]
Abstract
To evaluate variables influencing in vitro immune response induction, pig monocyte-derived DCs (moDCs) were treated with putative type-1 and type-2 antigens (Ags, killed Mycobacterium tuberculosis (Mtb) and hen egg white lysozyme (HEWL)) and recombinant porcine cytokines (IL-6, IL-10, IL-12, IFN-gamma and TNF-alpha). Responses were measured as moDC cytokine mRNA expression. Treatment of moDCs with HEWL increased IL-13 but not IL-12, IFN-gamma or IL-10 mRNA, suggesting a DC2 phenotype. Addition of TNF-alpha, IFN-gamma or IL-12 to HEWL-treated moDCs increased IL-12p35 and reduced IL-13 mRNA; suggesting a DC1 phenotype. Mtb increased moDC IL-12p35, IFN-gamma and to a lesser extent IL-13 mRNA. This DC1 bias was enhanced by TNF-alpha, IFN-gamma or IL-12, which increased IL-12p35 and to a lesser extent IL-10 mRNA but reduced IL-13 mRNA. Addition of IL-10 to Mtb-pulsed moDCs reduced IL-12p35, IFN-gamma and IL-13, but increased IL-10 mRNA, suggesting diversion from DC1 to DC2. Thus porcine moDCs treated with Ag and/or cytokines alter moDC cytokine expression confirming their likely ability to initiate and steer acquired immune response.
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Affiliation(s)
- Claudine R Raymond
- Department of Pathobiology, University of Guelph, Guelph, Ont., NIG-2W1, Canada.
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Bekker-Mendez VC, Pérez-Castillo VL, Rico-Rosillo MG, Pérez-Rodríguez M, Arellano-Blanco J, Kretschmer-Schmid RR, Talamás-Rohana P. Downregulation of Selected Cytokines in Amebiasis. Arch Med Res 2006; 37:556-8. [PMID: 16624659 DOI: 10.1016/j.arcmed.2005.09.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2005] [Accepted: 09/26/2005] [Indexed: 11/28/2022]
Abstract
A 220-kDa E. histolytica lectin is capable of downregulating some inflammatory cytokines (IL-5, IL-6, INF-gamma and TNF-alpha) and thus of inducing an overall anti-inflammatory Th-phenotype in leucocytes of selected, perhaps constitutionally predisposed, individuals irrespective of their HLA-DR3 profile (i.e., in this study patients long recovered from amebic abscess of the liver). This probably inhibited cytokine response pattern could increase the risk for developing amebic abscess of the liver in the course of invasive intestinal amebiasis.
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Ji MJ, Su C, Wang Y, Wu HW, Cai XP, Li GF, Zhu X, Wang XJ, Zhang ZS, Wu GL. Characterization of CD4+ T cell responses in mice infected with Schistosoma japonicum. Acta Biochim Biophys Sin (Shanghai) 2006; 38:327-34. [PMID: 16680373 DOI: 10.1111/j.1745-7270.2006.00169.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
To better understand the interaction between Schistosoma japonicum and its murine host, we characterized the immune response of CD4+ T cells generated during an experimental S. japonicum infection based on different key aspects, from gene expression to cell behavior. Mouse oligonucleotide microarrays were used to compare gene expression profiles of CD4+ T cells from spleens of mice at 0, 3, 6 and 13 weeks post-infection. Flow cytometry analysis was used to determine type 1 and type 2 cytokine-secreting CD4+ T cells, to test apoptosis of CD4+ T cells and to count CD4+CD25+ T cells, a kind of regulatory subpopulation of CD4+ T cells. The percentage of interleukin-4-producing CD4+ T cells was found to be much higher than that of gamma-interferon-producing cells, especially after stimulation with S. japonicum egg antigen, which was consistent with type 1 and type 2 cytokine gene expression in the genechip. Microarray data also showed that S. japonicum induced the increased expression of Th2 response-related genes, whereas some transcripts related to the Th1 responsive pathway were depressed. Flow cytometry analysis showed a marked increase in the apoptotic CD4+ T cells from 6 weeks post-infection and in the ratio of CD4+CD25+ to CD4+ T cells in infected mice after 13 weeks. We therefore concluded that experimental infection of mice with S. japonicum resulted in a Th2-skewed immune response, which was to a great extent monitored by the immune regulatory network, including cytokine cross-modulation, cell apoptosis and the subpopulation of regulatory cells.
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Affiliation(s)
- Min-Jun Ji
- Department of Pathogen Biology, Nanjing Medical University, Nanjing 210029, China
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Saniabadi AR, Hanai H, Suzuki Y, Ohmori T, Sawada K, Yoshimura N, Saito Y, Takeda Y, Umemura K, Kondo K, Ikeda Y, Fukunaga K, Nakashima M, Beretta A, Bjarnason I, Lofberg R. Adacolumn for selective leukocytapheresis as a non-pharmacological treatment for patients with disorders of the immune system: an adjunct or an alternative to drug therapy? J Clin Apher 2005; 20:171-84. [PMID: 15892107 DOI: 10.1002/jca.20046] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Inflammatory and/or autoimmune diseases like ulcerative colitis (UC) or Crohn's disease (CD) are debilitating chronic disorders that poorly respond to pharmacological interventions. Further, drug therapy has adverse effects that add to disease complications. The current thinking is that disorders like inflammatory bowel disease (IBD) reflect an over exuberant immune activation driven by cytokines including TNF-alpha. Major sources of cytokines include myeloid leukocytes (granulocytes, monocytes/macrophages), which in IBD are elevated with activation behavior and are found in vast numbers within the inflamed intestinal mucosa. Accordingly, myeloid cells should be the targets of therapy. Adacolumn is filled with cellulose acetate beads that selectively adsorb and deplete myeloid cells and a small fraction of lymphocytes (FcgammaR and complement receptors bearing cells). In one study, 20 steroid naive patients with moderate (n = 14) or severe (n = 6) UC according to Rachmilewitz despite 1.5-2.25 g/day of 5-aminosalicylic acid received 6 to 10 Adacolumn sessions at 2 sessions/week. Efficacy was assessed 1 week after the last session. The majority of patients responded to 6 sessions, 17 (85%) achieved remission. In 2 of the 3 non-responders, CAI was 8 and 12 in 1; all 3 had deep colonic ulcers at study initiation. Decreases were seen in total leukocytes (P = 0.003), % neutrophils (P = 0.003), % monocytes (P = 0.004), an increase in lymphocytes (P = 0.001), decreases in C-reactive protein (P = 0.0002), and rises in blood levels of soluble TNF-alpha receptors I (P = 0.0007), II (P = 0.0045). In a separate study, a case with very severe steroid refractory UC who received up to 11 sessions responded well and avoided colectomy. Further, myeloid cell purging with Adacolumn has been associated with the release of IL-1 receptor antagonist, suppression of TNF-alpha, IL-1beta, IL-6, IL-8, down-modulation of L-selectin and the chemokine receptor CXCR3. In conclusion, selective depletion of myeloid cells appears to induce anti-inflammatory effects and represents a non-pharmacological treatment for patients with active IBD. The treatment has a clear drug-sparing role. Changes in blood levels of inflammatory and anti-inflammatory factors are thought to contribute to the efficacy of this procedure.
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Affiliation(s)
- Abbi R Saniabadi
- Japan Immunoresearch Laboratories, Nishiyokote Machi, Takasaki, Japan.
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Cox K, North M, Burke M, Singhal H, Renton S, Aqel N, Islam S, Knight SC. Plasmacytoid dendritic cells (PDC) are the major DC subset innately producing cytokines in human lymph nodes. J Leukoc Biol 2005; 78:1142-52. [PMID: 16260587 DOI: 10.1189/jlb.1103532] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Plasmacytoid dendritic cells (PDC) constitute a distinct subset of DC found in human peripheral lymph nodes (LN), but little is known about their function. Cell suspensions were prepared from tumor draining LN (n=20) and control LN (n=11) of women undergoing surgical resection for primary breast cancer and elective surgery for benign conditions, respectively. Using four-color flow cytometry, human leukocyte antigen-DR+ DC subsets were identified phenotypically. The proportions and numbers of cells innately producing interleukin (IL)-4, IL-10, IL-12, and interferon-gamma (IFN-gamma) were also measured from intracellular accumulation of cytokine after blocking with monensin. All flow cytometry data were collected without compensation and were compensated off-line using the Winlist algorithm (Verity software). This package also provided the subtraction program to calculate percentage positive cells and intensity of staining. PDC (CD11c-, CD123+) expressed more cytokines than did myeloid DC (CD11c+) or CD1a+ putative "migratory" DC (P<0.001). LN PDC from patients with a good prognosis (px; n=11) demonstrated a relative increase in IL-12 and IFN-gamma expression (median IL-10:IL-12 ratio=0.78 and median IL-4:IFN-gamma ratio=0.7), and PDC from LN draining poor px cancer (n=9) showed a relative increase in IL-10 and IL-4 expression (median IL-10:IL-12 ratio=1.31 and median IL-4:IFN-gamma ratio=2.6). The difference in IL-4:IFN-gamma expression between good and poor px cancer groups was significant (P<0.05). Thus, PDC innately producing cytokines were identified in cell suspensions from human LN, and the character of PDC cytokine secretion may differ between two breast cancer prognostic groups. We speculate that a shift towards PDC IL-10 and IL-4 expression could promote tumor tolerance in LN draining poor px breast cancer.
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Affiliation(s)
- Karina Cox
- Antigen Presentation Research Group, Faculty of Medicine, Imperial College London, Northwick Park and St. Marks Campus, Harrow, Middlesex, United Kingdom
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Fazal N, Raziuddin S, Khan M, Al-Ghoul WM. Antigen presenting cells (APCs) from thermally injured and/or septic rats modulate CD4+ T cell responses of naive rat. Biochim Biophys Acta Mol Basis Dis 2005; 1762:46-53. [PMID: 16257513 DOI: 10.1016/j.bbadis.2005.07.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2004] [Revised: 07/25/2005] [Accepted: 07/26/2005] [Indexed: 12/26/2022]
Abstract
Regulation of immune response is marked by complex interactions among the cells that recognize and present antigens. Antigen presenting cells (APCs), the antigen presenting cell component of the innate immune response plays an important role in effector CD4+ T cell response. Thermal injury and/or superimposed sepsis in rats' leads to suppressed CD4+ T cell functions. We investigated modulations of CD4+ T cell function by APCs (purified non-T cells) from thermally injured and/or septic rats. Rats were subjected to 30% total body surface area scald burn or exposed to 37 degrees C water (Sham burn) and sepsis was induced by cecal-ligation and puncture (CLP) method. At day 3 post-injury animals were sacrificed and CD4+ T cells and APCs from mesenteric lymph nodes (MLN) were obtained using magnetic microbead isolation procedure. APCs from injured rats were co-cultured with sham rat MLN CD4+ T cells and proliferative responses (thymidine incorporation), phenotypic changes (Flow cytometry), IL-2 production (ELISA) and CTLA-4 mRNA (RT-PCR) were determined in naive rat CD4+ T cells. The data indicate that APCs from thermally injured and/or septic rats when co-cultured with CD4+ T cells suppressed CD4+ T cell effector functions. This lack of CD4+ T cell activation was accompanied with altered co-stimulatory molecules, i.e., CD28 and/or CTLA-4 (CD152). In conclusion, our studies indicated that defective APCs from thermally injured and/or septic rats modulate CD4+ T cell functions via changes in co-stimulatory molecules expressed on naive CD4+ T cells. This altered APC: CD4+ T cell interaction leads to suppressed CD4+ T cell activation of healthy animals.
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Affiliation(s)
- Nadeem Fazal
- Burn and Shock Trauma Institute, Department of Surgery, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
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Latchumanan VK, Balkhi MY, Sinha A, Singh B, Sharma P, Natarajan K. Regulation of immune responses to Mycobacterium tuberculosis secretory antigens by dendritic cells. Tuberculosis (Edinb) 2005; 85:377-83. [PMID: 16246624 DOI: 10.1016/j.tube.2005.08.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Towards elucidating the immune responses induced by antigens from the Mycobacterium tuberculosis (M. tb) RD-1 region, we have been characterizing their interactions with dendritic cells (DCs) and their precursors. We have shown that incubation of bone marrow DC precursors with M. tb antigens induces the differentiation of DC precursors and also the maturation of various DC subsets. While MTSA differentiated DCs were immature, MTSA matured DCs were terminally mature. However, regardless of their maturation status M. tb secretory antigen-activated DCs down-regulated pro-inflammatory T helper cell responses to a subsequent challenge with M. tb cell extract (CE) while increasing regulatory responses. Investigations into the underlying mechanisms showed that stimulation with M. tb CE changed the polarization of antigen-activated DCs from DC1 to DC2. This resulted in secretion of high levels of IL-10 and TGF-beta together with increased surface expression of CD86. Blocking either IL-10 or TGF-beta or CD86 restored Th1 responses to CE antigens. Conversely, treatment of antigen-activated DCs with IL-12 and/or IFN-gamma fully restored Th1 responses of CE antigens. These results indicate that M. tb strategically secretes antigens from infected macrophages to down-regulate pro-inflammatory immune responses at sites of infection.
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Affiliation(s)
- Vinoth K Latchumanan
- Immunology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India
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Abstract
Evidence suggests that amelioration of childhood immune thrombocytopenic purpura and some other autoimmune states by intravenous normal IgG is due to the following chain of events: (1) cross-linking of Fcgamma-receptors on blood effector cells; (2) release of mediators from these cells, often yielding an infusion-related reaction; (3) mediator-induced development of a cytokine field characterized by a mutually stabilizing Th2 polarization of CD4 T lymphocytes and alternative activation of macrophages; (4) selective quiescence of these macrophages towards targets coated with IgG autoantibody, due to increased expression of the macrophage Fcgamma-receptor IIB. In this paper it is postulated that in the field of antibody therapy of tumor, an undesirable delayed or absent subsidence of antibody-coated tumor is due to immunomodulation of the same type as yields amelioration of autoimmunity, and arising from a similar chain of events. If the postulate is correct the chain could usefully be broken at the level of mediator action, possibly by blocking that increased synthesis of prostaglandin E(2) which is catalyzed by the enzyme cyclooxygenase-2.
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Affiliation(s)
- George T Stevenson
- Tenovus Research Laboratory, Southampton University Hospitals, Southampton SO16 6YD, UK
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