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1
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Fang S, Cai C, Bai Y, Zhang L, Yang L. Early Pregnancy Regulates Expression of IkappaB Family in Ovine Spleen and Lymph Nodes. Int J Mol Sci 2023; 24:ijms24065156. [PMID: 36982231 PMCID: PMC10049502 DOI: 10.3390/ijms24065156] [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: 01/27/2023] [Revised: 03/03/2023] [Accepted: 03/06/2023] [Indexed: 03/30/2023] Open
Abstract
Early pregnancy modulates the maternal immune system, including the spleen and lymph nodes, which participate in maternal innate and adaptive immune responses. Methods: Ovine spleens and lymph nodes were sampled at day 16 of the estrous cycle, and at days 13, 16 and 25 of gestation, and qRT-PCR, Western blot and immunohistochemistry analysis were used to analyze the expression of the IκB family, including BCL-3, IκBα, IκBβ, IκBε, IKKγ, IκBNS and IκBζ. Early pregnancy induced expression of BCL-3, IκBα, IκBε, IKKγ and IκBζ, and expression of BCL-3, IκBβ and IκBNS peaked at day 16 of pregnancy in the spleen. However, early pregnancy suppressed the expression of BCL-3 and IκBNS, but stimulated the expression of IκBβ and IκBζ, and expression levels of IκBα, IκBβ, IκBε and IKKγ peaked in lymph nodes at days 13 and/or 16 of pregnancy. Early pregnancy changed the expression of the IκB family in the maternal spleen and lymph node in a tissue-specific manner, suggesting that the modulation of the IκB family may be involved in regulation of maternal functions of the spleen and lymph nodes, which are necessary for the establishment of maternal immune tolerance during early pregnancy in sheep.
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Affiliation(s)
- Shengya Fang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan 056038, China
| | - Chunjiang Cai
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan 056038, China
| | - Ying Bai
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan 056038, China
| | - Leying Zhang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan 056038, China
| | - Ling Yang
- School of Life Sciences and Food Engineering, Hebei University of Engineering, Handan 056038, China
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2
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Kapoor K, Eissa N, Tshikudi D, Bernstein CN, Ghia JE. Impact of intrarectal chromofungin treatment on dendritic cells-related markers in different immune compartments in colonic inflammatory conditions. World J Gastroenterol 2021; 27:8138-8155. [PMID: 35068859 PMCID: PMC8704268 DOI: 10.3748/wjg.v27.i47.8138] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/12/2021] [Accepted: 12/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Chromofungin (CHR: chromogranin-A 47-66) is a chromogranin-A derived peptide with anti-inflammatory and anti-microbial properties. Ulcerative colitis (UC) is characterized by a colonic decrease of CHR and a dysregulation of dendritic CD11c+ cells.
AIM To investigate the association between CHR treatment and dendritic cells (DCs)-related markers in different immune compartments in colitis.
METHODS A model of acute UC-like colitis using dextran sulphate sodium (DSS) was used in addition to biopsies collected from UC patients.
RESULTS Intrarectal CHR treatment reduced the severity of DSS-induced colitis and was associated with a significant decrease in the expression of CD11c, CD40, CD80, CD86 and interleukin (IL)-12p40 in the inflamed colonic mucosa and CD11c, CD80, CD86 IL-6 and IL-12p40 within the mesenteric lymph nodes and the spleen. Furthermore, CHR treatment decreased CD80 and CD86 expression markers of splenic CD11c+ cells and decreased NF-κB expression in the colon and of splenic CD11c+ cells. In vitro, CHR decreased CD40, CD80, CD86 IL-6 and IL-12p40 expression in naïve bone marrow-derived CD11c+ DCs stimulated with lipopolysaccharide. Pharmacological studies demonstrated an impact of CHR on the NF-κB pathway. In patients with active UC, CHR level was reduced and showed a negative linear relationship with CD11c and CD86.
CONCLUSION CHR has protective properties against intestinal inflammation via the regulation of DC-related markers and CD11c+ cells. CHR could be a potential therapy of UC.
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Affiliation(s)
- Kunal Kapoor
- Department of Immunology, University of Manitoba, Winnipeg R3E0T5, MB, Canada
| | - Nour Eissa
- Department of Immunology, University of Manitoba, Winnipeg R3E0T5, MB, Canada
- Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg R3E0T5, MB, Canada
- Section of Gastroenterology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg R3E0T5, MB, Canada
- University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg R3E0T5, MB, Canada
| | - Diane Tshikudi
- Department of Immunology, University of Manitoba, Winnipeg R3E0T5, MB, Canada
| | - Charles N Bernstein
- Section of Gastroenterology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg R3E0T5, MB, Canada
- University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg R3E0T5, MB, Canada
| | - Jean-Eric Ghia
- Department of Immunology, University of Manitoba, Winnipeg R3E0T5, MB, Canada
- Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg R3E0T5, MB, Canada
- Section of Gastroenterology, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg R3E0T5, MB, Canada
- University of Manitoba IBD Clinical and Research Centre, University of Manitoba, Winnipeg R3E0T5, MB, Canada
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3
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Buska-Mach K, Kedzierska AE, Lepczynski A, Herosimczyk A, Ozgo M, Karpinski P, Gomulkiewicz A, Lorek D, Slawek A, Dziegiel P, Chelmonska-Soyta A. Differential Signals From TNFα-Treated and Untreated Embryos in Uterine Tissues and Splenic CD4 + T Lymphocytes During Preimplantation Pregnancy in Mice. Front Vet Sci 2021; 8:641553. [PMID: 33763465 PMCID: PMC7982469 DOI: 10.3389/fvets.2021.641553] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 02/12/2021] [Indexed: 11/13/2022] Open
Abstract
The main aim of this study was to examine if a female mouse body in preimplantation pregnancy can distinguish between embryos of normal and impaired biological quality in the local and peripheral compartments. Normal (control group) and TNFα (tumor necrosis factor-α)-treated embryos (experimental group) at the morula stage were non-surgically transferred into the uteri of CD-1 strain [Crl:CD1(Icr)] female murine recipients. Twenty-four hours after the embryo transfer, females were euthanised, and uteri and spleens were dissected. In uterine tissues (local compartment), we assessed the expression of 84 genes comprising nine signal transduction pathways, using a modified RT2 Profiler PCR Array. In the spleen (peripheral compartment), we determined the proteome of splenic CD4+ lymphocytes using 2D protein electrophoresis with subsequent protein identification by mass spectrometry. Sample clustering and differential gene expression analyses within individual signal transduction pathways revealed differential expression of genes in the uteri of females after transplantation of normal vs. TNFα-treated embryos. The most affected signal transduction cascade was the NFKB (Nuclear factor NF-kappa-B) pathway, where 87.5% of the examined genes were significantly differentially expressed. Proteomic analysis of splenic CD4+ T lymphocytes revealed significant differential expression of 8 out of 132 protein spots. Identified proteins were classified as proteins influenced by cell stress, proteins engaged in the regulation of cytoskeleton stabilization and cell motility, and proteins having immunomodulatory function. These results support the hypothesis that even before embryo implantation, the body of pregnant female mice can sense the biological quality of an embryo both at the local and peripheral level.
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Affiliation(s)
- Katarzyna Buska-Mach
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Anna Ewa Kedzierska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Adam Lepczynski
- Department of Physiology, Cytobiology and Proteomics, West Pomeranian University of Technology, Szczecin, Poland
| | - Agnieszka Herosimczyk
- Department of Physiology, Cytobiology and Proteomics, West Pomeranian University of Technology, Szczecin, Poland
| | - Małgorzata Ozgo
- Department of Physiology, Cytobiology and Proteomics, West Pomeranian University of Technology, Szczecin, Poland
| | - Pawel Karpinski
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.,Department of Genetics, Wroclaw Medical University, Wrocław, Poland
| | - Agnieszka Gomulkiewicz
- Department of Human Morphology and Embryology, Wroclaw Medical University, Wrocław, Poland
| | - Daria Lorek
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Anna Slawek
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Piotr Dziegiel
- Department of Human Morphology and Embryology, Wroclaw Medical University, Wrocław, Poland
| | - Anna Chelmonska-Soyta
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland.,The Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, Wrocław, Poland
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4
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Cacicedo ML, Medina-Montano C, Kaps L, Kappel C, Gehring S, Bros M. Role of Liver-Mediated Tolerance in Nanoparticle-Based Tumor Therapy. Cells 2020; 9:E1985. [PMID: 32872352 PMCID: PMC7563539 DOI: 10.3390/cells9091985] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 08/26/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
In the last decades, the use of nanocarriers for immunotherapeutic purposes has gained a lot of attention, especially in the field of tumor therapy. However, most types of nanocarriers accumulate strongly in the liver after systemic application. Due to the default tolerance-promoting role of liver non-parenchymal cells (NPCs), Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), and hepatic stellate cells (HSCs), their potential role on the immunological outcome of systemic nano-vaccination approaches for therapy of tumors in the liver and in other organs needs to be considered. Concerning immunological functions, KCs have been the focus until now, but recent studies have elucidated an important role of LSECs and HSCs as well. Therefore, this review aims to summarize current knowledge on the employment of nanocarriers for immunotherapeutic therapy of liver diseases and the overall role of liver NPCs in the context of nano-vaccination approaches. With regard to the latter, we discuss strategies on how to address liver NPCs, aiming to exploit and modulate their immunological properties, and alternatively how to avoid unwanted engagement of nano-vaccines by liver NPCs for tumor therapy.
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Affiliation(s)
- Maximiliano L. Cacicedo
- Children’s Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany; (M.L.C.); (S.G.)
| | - Carolina Medina-Montano
- Department of Dermatology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (C.M.-M.); (C.K.)
| | - Leonard Kaps
- Department of Medicine, University Medical Center Mainz, I. Langenbeckstrasse 1, 55131 Mainz, Germany;
| | - Cinja Kappel
- Department of Dermatology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (C.M.-M.); (C.K.)
| | - Stephan Gehring
- Children’s Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany; (M.L.C.); (S.G.)
| | - Matthias Bros
- Department of Dermatology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany; (C.M.-M.); (C.K.)
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5
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Guzman-Genuino RM, Hayball JD, Diener KR. Regulatory B Cells: Dark Horse in Pregnancy Immunotherapy? J Mol Biol 2020; 433:166596. [PMID: 32693108 DOI: 10.1016/j.jmb.2020.07.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Revised: 07/13/2020] [Accepted: 07/15/2020] [Indexed: 12/20/2022]
Abstract
There are many unanswered questions surrounding the function of immune cells and how they interact with the reproductive system to support successful pregnancy or contribute to pregnancy pathologies. While the role of immune cells such as uterine natural killer and dendritic cells, and more recently regulatory T cells has been established, the role of another major immune cell population, the B cell, and particularly the regulatory B cells, is relatively poorly understood. This review outlines what is known about B-cell subsets in the context of pregnancy, what constitutes a regulatory B cell and what role they may play, particularly during early pregnancy. Lastly, we discuss why immunotherapies for the treatment of pregnancy disorders is not widely progressed clinically and speculate on the potential of functional regulatory B cells as the basis of novel immunotherapeutic approaches for the treatment of immune-based pregnancy pathologies.
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Affiliation(s)
- Ruth Marian Guzman-Genuino
- Experimental Therapeutics Laboratory, University of South Australia Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia
| | - John D Hayball
- Experimental Therapeutics Laboratory, University of South Australia Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia; Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Kerrilyn R Diener
- Experimental Therapeutics Laboratory, University of South Australia Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia; Robinson Research Institute and Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.
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6
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Kedzierska AE, Lorek D, Slawek A, Chelmonska-Soyta A. Tregitopes regulate the tolerogenic immune response and decrease the foetal death rate in abortion-prone mouse matings. Sci Rep 2020; 10:10531. [PMID: 32601347 PMCID: PMC7324366 DOI: 10.1038/s41598-020-66957-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Accepted: 05/27/2020] [Indexed: 12/22/2022] Open
Abstract
The imbalance in immune tolerance may cause the variety of reproductive failures. An intravenous immunoglobulin infusion (IVIg) therapy is used to improve the live birth rate in women suffering from recurrent pregnancy loss, recurrent spontaneous abortions and recurrent implantation failures. However, the results of IVIg studies are still inconclusive as IVIg infusion in women suffering from pregnancy loss is sometimes ineffective. One of the mechanisms of action of this treatment is inhibition of B cells differentiation and expansion of Tregs and secretion of interleukin 10. It was proposed that immunomodulatory effects of IVIg may be attributed to tregitopes - self-IgG-derived epitopes present in the structure of immunoglobulins. Similarly to IVIg, tregitopes cause the expansion of Tregs and secretion of antigen-specific effector cytokine response. Here, we studied whether the administration of mouse tregitope 167 and/or 289 can prevent abortions in mouse abortion-prone mouse matings. We revealed that tregitopes reduce the foetal death rate. This may be driven by observed higher pool of peripheral Tregs, increased production of IL-10 by Tregs and Bregs and/or maintaining the tolerogenic phenotype of antigen-presenting cells. We believe that our findings may indicate a potential alternative to IVIg for therapeutic intervention in case of pregnancy failures.
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Affiliation(s)
- Anna Ewa Kedzierska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland. .,Łukasiewicz Research Network - PORT Polish Center for Technology Development, Stablowicka 147 Str., Wroclaw, Poland.
| | - Daria Lorek
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Anna Slawek
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Anna Chelmonska-Soyta
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.,Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
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7
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Guzman-Genuino RM, Eldi P, Garcia-Valtanen P, Hayball JD, Diener KR. Uterine B Cells Exhibit Regulatory Properties During the Peri-Implantation Stage of Murine Pregnancy. Front Immunol 2019; 10:2899. [PMID: 31921160 PMCID: PMC6917594 DOI: 10.3389/fimmu.2019.02899] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 11/26/2019] [Indexed: 01/12/2023] Open
Abstract
A successful outcome to pregnancy is dependent on the ability of the maternal uterine microenvironment to regulate inflammation processes and establish maternal tolerance. Recently, B cells have been shown to influence pregnancy outcomes as aberrations in their numbers and functions are associated with obstetric complications. In this study, we aimed to comprehensively examine the population frequency and phenotypic profile of B cells over the course of murine pregnancy. Our results demonstrated a significant expansion in B cells within the uterus during the peri-implantation period, accompanied by alterations in B cell phenotype. Functional evaluation of uterine B cells purified from pregnant mice at day 5.5 post-coitus established their regulatory capacity as evidenced by effective suppression of proliferation and activation of syngeneic CD4+ T cells. Flow cytometric analysis revealed that the uterine B cell population has an expanded pool of IL-10-producing B cells bearing upregulated expression of co-stimulatory molecules CD80 and CD86 and activation marker CD27. Our investigations herein demonstrate that during the critical stages surrounding implantation, uterine B cells are amplified and phenotypically modified to act in a regulatory manner that potentially contributes toward the establishment of maternal immunological tolerance in early pregnancy.
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Affiliation(s)
- Ruth Marian Guzman-Genuino
- Experimental Therapeutics Laboratory, School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, Australia.,Adelaide Medical School, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
| | - Preethi Eldi
- Experimental Therapeutics Laboratory, School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, Australia
| | - Pablo Garcia-Valtanen
- Experimental Therapeutics Laboratory, School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, Australia
| | - John D Hayball
- Experimental Therapeutics Laboratory, School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, Australia.,Adelaide Medical School, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
| | - Kerrilyn R Diener
- Experimental Therapeutics Laboratory, School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, Australia.,Adelaide Medical School, Robinson Research Institute, The University of Adelaide, Adelaide, SA, Australia
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8
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Kordalivand N, Tondini E, Lau CYJ, Vermonden T, Mastrobattista E, Hennink WE, Ossendorp F, Nostrum CFV. Cationic synthetic long peptides-loaded nanogels: An efficient therapeutic vaccine formulation for induction of T-cell responses. J Control Release 2019; 315:114-125. [PMID: 31672626 DOI: 10.1016/j.jconrel.2019.10.048] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Revised: 10/23/2019] [Accepted: 10/26/2019] [Indexed: 12/18/2022]
Abstract
Recent studies have shown a high potency of protein-based vaccines for cell-mediated cancer immunotherapy. However, due to their poor cellular uptake, efficient immune responses with soluble protein antigens are often not observed. As a result of superior cellular uptake, nanogels loaded with antigenic peptides were investigated in this study as carrier systems for cancer immunotherapy. Different synthetic long peptides (SLPs) containing the CTL and CD4+ T-helper (Help) epitopes were synthesized and covalently conjugated via disulfide bonds to the polymeric network of cationic dextran nanogels. Cationic nanogels with a size of 210 nm, positive zeta potential (+24 mV) and high peptide loading content (15%) showed triggered release of the loaded peptides under reducing conditions. An in vitro study demonstrated the capability of cationic nanogels to maturate dendritic cells (DCs). Importantly, covalently SLP-loaded nanogels adjuvanted with poly(I:C) showed superior CD8+ T cell responses compared to soluble peptides and nanogel formulations with physically loaded peptides both in vitro and in vivo. In conclusion, covalently SLPs-loaded cationic nanogels are a promising system to provoke immune responses for therapeutic cancer vaccination.
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Affiliation(s)
- Neda Kordalivand
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
| | - Elena Tondini
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
| | - Chun Yin Jerry Lau
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
| | - Tina Vermonden
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
| | - Enrico Mastrobattista
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
| | - Wim E Hennink
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
| | - Ferry Ossendorp
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands
| | - Cornelus F van Nostrum
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
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9
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Lorek D, Kedzierska AE, Slawek A, Chelmonska-Soyta A. Expression of Toll-like receptors and costimulatory molecules in splenic B cells in a normal and abortion-prone murine pregnancy model. Am J Reprod Immunol 2019; 82:e13148. [PMID: 31134706 DOI: 10.1111/aji.13148] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 05/01/2019] [Accepted: 05/13/2019] [Indexed: 12/25/2022] Open
Abstract
PROBLEM The regulatory role of B lymphocytes in the pregnancy-induced maternal immune response is not well recognized. B lymphocytes function as antigen-presenting cells (APCs) and regulate Toll-like receptors and costimulatory molecule expression in response to intrinsic and extrinsic signals. Therefore, the aim of this study was to determine the expression of TLR2, TLR4, TLR9, and MHC class II and the costimulatory molecules CD80, CD86, and CD40 in splenic B cells in a normal and abortion-prone murine pregnancy model. METHODS OF STUDY The expression level of these molecules on female splenic B cells was investigated using real-time PCR and flow cytometry. The analysis was performed on the 3rd and 14th day of normal (CBA/JxBALB/c) and abortion-prone (CBA/JxDBA/2J) murine pregnancy. RESULTS The expression of Tlr9, Cd86, and H2-Ab1 in splenic B cells on the 3rd day after mating was upregulated, whereas Tlr2 was downregulated in abortion-prone females. On day 14, we observed lower expression levels of Tlr4 and Cd80 and higher expression levels of Cd86 in CBA/J females mated with DBA/2J males. At the protein level, the differences were observed only on day 3 of pregnancy. TLR4 and CD40 molecules were upregulated in splenic B cells, while TLR9 and CD86 were downregulated in abortion-prone mice. CONCLUSION Differential expression of TLRs and costimulatory molecules in splenic B cells in abortion-prone and normal pregnancies suggests the involvement of these cells in the regulation of the immune response at the periphery in pregnant females.
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Affiliation(s)
- Daria Lorek
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Anna Ewa Kedzierska
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.,Łukasiewicz Research Network - PORT Polish Center for Technology Development, Wroclaw, Poland
| | - Anna Slawek
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Anna Chelmonska-Soyta
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland.,Wroclaw University of Environmental and Life Sciences, Wroclaw, Poland
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10
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Han M, Hu R, Ma J, Zhang B, Chen C, Li H, Yang J, Huang G. Fas Signaling in Dendritic Cells Mediates Th2 Polarization in HDM-Induced Allergic Pulmonary Inflammation. Front Immunol 2018; 9:3045. [PMID: 30619373 PMCID: PMC6308134 DOI: 10.3389/fimmu.2018.03045] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 12/10/2018] [Indexed: 01/17/2023] Open
Abstract
Fas-Fas ligand (FasL) signaling plays an important role in the development of allergic inflammation, but the cellular and molecular mechanisms are still not well known. By using the bone marrow-derived dendritic cell (BMDC) transfer-induced pulmonary inflammation model, we found that house dust mite (HDM)-stimulated FAS-deficient BMDCs induced higher Th2-mediated allergic inflammation, associated with increased mucus production and eosinophilic inflammation. Moreover, FAS-deficient BMDCs promoted Th2 cell differentiation upon HDM stimulation in vitro. Compared to wild-type BMDCs, the Fas-deficient BMDCs had increased ERK activity and decreased IL-12 production upon HDM stimulation. Inhibition of ERK activity could largely increase IL-12 production, consequently restored the increased Th2 cytokine expression of OT-II CD4+ T cells activated by Fas-deficient BMDCs. Thus, our results uncover an important role of DC-specific Fas signaling in Th2 differentiation and allergic inflammation, and modulation of Fas signaling in DCs may offer a useful strategy for the treatment of allergic inflammatory diseases.
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Affiliation(s)
- Miaomiao Han
- Department of Otolaryngology-Head and Neck Surgery, Center for Allergic and Inflammatory Diseases, Affiliated Eye and ENT Hospital, Fudan University, Shanghai, China.,Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ran Hu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingyu Ma
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Baohua Zhang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ce Chen
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
| | - Huabin Li
- Department of Otolaryngology-Head and Neck Surgery, Center for Allergic and Inflammatory Diseases, Affiliated Eye and ENT Hospital, Fudan University, Shanghai, China
| | - Jun Yang
- Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Gonghua Huang
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
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11
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Li Y, Hao N, Zou S, Meng T, Tao H, Ming P, Li M, Ding H, Li J, Feng S, Wang X, Wu J. Immune Regulation of RAW264.7 Cells In Vitro by Flavonoids from Astragalus complanatus via Activating the NF- κB Signalling Pathway. J Immunol Res 2018; 2018:7948068. [PMID: 29850637 PMCID: PMC5907389 DOI: 10.1155/2018/7948068] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 02/06/2018] [Indexed: 12/28/2022] Open
Abstract
The current study aimed at investigating the effects of flavonoids from Astragalus complanatus (FAC) on the proliferation, the contents, and gene expression levels of cytokines, secretion of surface stimulating factors, cell cycle, and the expression level of the NF-κB signalling pathway in RAW264.7 cells. Our results revealed that compared with control group, the contents of IL-6, IL-1β, TNF-α, and NO and the mRNA expression levels of IL-6, IL-1β, TNF-α, and iNOS in FAC-treated groups significantly increased (p < 0.01). Moreover, FAC induced macrophage activation to release the above-mentioned mediators partly involved in NF-κB/MAPK signalling pathways. Therefore, FAC regulates immune function in RAW264.7 cells via activating the NF-κB signalling pathway. FAC could be applicable for agriculture, drug research, and food industry as a potent immune-modulatory agent.
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Affiliation(s)
- Yu Li
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Ning Hao
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Suping Zou
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Tingting Meng
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Huanqing Tao
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Pengfei Ming
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Manman Li
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Hongyan Ding
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Jinchun Li
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Shibin Feng
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Xichun Wang
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
| | - Jinjie Wu
- College of Animal Science and Technology, Anhui Agricultural University, Hefei 230036, China
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12
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Allen RP, Bolandparvaz A, Ma JA, Manickam VA, Lewis JS. Latent, Immunosuppressive Nature of Poly(lactic- co-glycolic acid) Microparticles. ACS Biomater Sci Eng 2018; 4:900-918. [PMID: 30555893 PMCID: PMC6290919 DOI: 10.1021/acsbiomaterials.7b00831] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Use of biomaterials to spatiotemporally control the activation of immune cells is at the forefront of biomedical engineering research. As more biomaterial strategies are employed for immunomodulation, understanding the immunogenicity of biodegradable materials and their byproducts is paramount in tailoring systems for immune activation or suppression. Poly(D,L-lactic-co-glycolic acid) (PLGA), one of the most commonly studied polymers in tissue engineering and drug delivery, has been previously described on one hand as an immune adjuvant, and on the other as a nonactivating material. In this study, the effect of PLGA microparticles (MPs) on the maturation status of murine bone marrow-derived dendritic cells (DCs), the primary initiators of adaptive immunity, was investigated to decipher the immunomodulatory properties of this biomaterial. Treatment of bone marrow-derived DCs from C57BL/6 mice with PLGA MPs led to a time dependent decrease in the maturation level of these cells, as quantified by decreased expression of the positive stimulatory molecules MHCII, CD80, and CD86 as well as the ability to resist maturation following challenge with lipopolysaccharide (LPS). Moreover, this immunosuppression was dependent on the molecular weight of the PLGA used to fabricate the MPs, as higher molecular weight polymers required longer incubation to produce comparable dampening of maturation molecules. These phenomena were correlated to an increase in lactic acid both intracellularly and extracellularly during DC/PLGA MP coculture, which is postulated to be the primary agent behind the observed immune inhibition. This hypothesis is supported by our results demonstrating that resistance to LPS stimulation may be due to the ability of PLGA MP-derived lactic acid to inhibit the phosphorylation of TAK1 and therefore prevent NF-κB activation. This work is significant as it begins to elucidate how PLGA, a prominent biomaterial with broad applications ranging from tissue engineering to pharmaceutics, could modulate the local immune environment and offers insight on engineering PLGA to exploit its evolving immunogenicity.
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Affiliation(s)
- Riley P. Allen
- Department of Biomedical Engineering, University of California Davis, 1 Shields Avenue, Davis, California 95616, United States
| | - Amir Bolandparvaz
- Department of Biomedical Engineering, University of California Davis, 1 Shields Avenue, Davis, California 95616, United States
| | - Jeffrey A. Ma
- Department of Biomedical Engineering, University of California Davis, 1 Shields Avenue, Davis, California 95616, United States
| | - Vishal A. Manickam
- Department of Biomedical Engineering, University of California Davis, 1 Shields Avenue, Davis, California 95616, United States
| | - Jamal S. Lewis
- Department of Biomedical Engineering, University of California Davis, 1 Shields Avenue, Davis, California 95616, United States
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13
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Dai J, Fang P, Saredy J, Xi H, Ramon C, Yang W, Choi ET, Ji Y, Mao W, Yang X, Wang H. Metabolism-associated danger signal-induced immune response and reverse immune checkpoint-activated CD40 + monocyte differentiation. J Hematol Oncol 2017; 10:141. [PMID: 28738836 PMCID: PMC5525309 DOI: 10.1186/s13045-017-0504-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 06/26/2017] [Indexed: 01/16/2023] Open
Abstract
Adaptive immunity is critical for disease progression and modulates T cell (TC) and antigen-presenting cell (APC) functions. Three signals were initially proposed for adaptive immune activation: signal 1 antigen recognition, signal 2 co-stimulation or co-inhibition, and signal 3 cytokine stimulation. In this article, we propose to term signal 2 as an immune checkpoint, which describes interactions of paired molecules leading to stimulation (stimulatory immune checkpoint) or inhibition (inhibitory immune checkpoint) of an immune response. We classify immune checkpoint into two categories: one-way immune checkpoint for forward signaling towards TC only, and two-way immune checkpoint for both forward and reverse signaling towards TC and APC, respectively. Recently, we and others provided evidence suggesting that metabolic risk factors (RF) activate innate and adaptive immunity, involving the induction of immune checkpoint molecules. We summarize these findings and suggest a novel theory, metabolism-associated danger signal (MADS) recognition, by which metabolic RF activate innate and adaptive immunity. We emphasize that MADS activates the reverse immune checkpoint which leads to APC inflammation in innate and adaptive immunity. Our recent evidence is shown that metabolic RF, such as uremic toxin or hyperhomocysteinemia, induced immune checkpoint molecule CD40 expression in monocytes (MC) and elevated serum soluble CD40 ligand (sCD40L) resulting in CD40+ MC differentiation. We propose that CD40+ MC is a novel pro-inflammatory MC subset and a reliable biomarker for chronic kidney disease severity. We summarize that CD40:CD40L immune checkpoint can induce TC and APC activation via forward stimulatory, reverse stimulatory, and TC contact-independent immune checkpoints. Finally, we modeled metabolic RF-induced two-way stimulatory immune checkpoint amplification and discussed potential signaling pathways including AP-1, NF-κB, NFAT, STAT, and DNA methylation and their contribution to systemic and tissue inflammation.
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Affiliation(s)
- Jin Dai
- Department of Cardiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian road, Hangzhou, 310006, Zhejiang, China.,Center for Metabolic Disease Research, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA
| | - Pu Fang
- Center for Metabolic Disease Research, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA
| | - Jason Saredy
- Center for Metabolic Disease Research, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA
| | - Hang Xi
- Center for Metabolic Disease Research, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA
| | - Cueto Ramon
- Center for Metabolic Disease Research, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA
| | - William Yang
- Center for Metabolic Disease Research, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA
| | - Eric T Choi
- Department of Surgery, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA
| | - Yong Ji
- Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, 210029, China
| | - Wei Mao
- Department of Cardiology, The First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian road, Hangzhou, 310006, Zhejiang, China.
| | - Xiaofeng Yang
- Center for Metabolic Disease Research, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.,Department of Pharmacology, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA
| | - Hong Wang
- Center for Metabolic Disease Research, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA. .,Department of Pharmacology, Temple University School of Medicine, 3500 N. Broad Street, Philadelphia, PA, 19140, USA.
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14
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Global decrease in the expression of signalling pathways’ genes in murine uterus during preimplantation pregnancy. Reprod Biol 2017; 17:89-96. [DOI: 10.1016/j.repbio.2017.01.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Revised: 12/12/2016] [Accepted: 01/04/2017] [Indexed: 01/25/2023]
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15
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Li D, Sun F, Bourajjaj M, Chen Y, Pieters EH, Chen J, van den Dikkenberg JB, Lou B, Camps MGM, Ossendorp F, Hennink WE, Vermonden T, van Nostrum CF. Strong in vivo antitumor responses induced by an antigen immobilized in nanogels via reducible bonds. NANOSCALE 2016; 8:19592-19604. [PMID: 27748778 DOI: 10.1039/c6nr05583d] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Cancer vaccines are at present mostly based on tumor associated protein antigens but fail to elicit strong cell-mediated immunity in their free form. For protein-based vaccines, the main challenges to overcome are the delivery of sufficient proteins into the cytosol of dendritic cells (DCs) and processing by, and presentation through, the MHC class I pathway. Recently, we developed a cationic dextran nanogel in which a model antigen (ovalbumin, OVA) is reversibly conjugated via disulfide bonds to the nanogel network to enable redox-sensitive intracellular release. In the present study, it is demonstrated that these nanogels, with the bound OVA, were efficiently internalized by DCs and were capable of maturating them. On the other hand, when the antigen was just physically entrapped in the nanogels, OVA was prematurely released before the particles were taken up by cells. When combined with an adjuvant (polyinosinic-polycytidylic acid, poly(I:C)), nanogels with conjugated OVA induced a strong protective and curative effect against melanoma in vivo. In a prophylactic vaccination setting, 90% of the mice vaccinated with nanogels with conjugated OVA + poly(I:C) did not develop a tumor. Moreover, in a therapeutic model, 40% of the mice showed clearance of established tumors and survived for the duration of the experiment (80 days) while the remaining mice showed substantial delay in tumor progression. In conclusion, our results demonstrate that conjugation of antigens to nanogels via reducible covalent bonds for intracellular delivery is a promising strategy to induce effective antigen-specific immune responses against cancer.
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Affiliation(s)
- Dandan Li
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584CG, The Netherlands.
| | - Feilong Sun
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584CG, The Netherlands.
| | - Meriem Bourajjaj
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584CG, The Netherlands.
| | - Yinan Chen
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584CG, The Netherlands.
| | - Ebel H Pieters
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584CG, The Netherlands.
| | - Jian Chen
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584CG, The Netherlands.
| | - Joep B van den Dikkenberg
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584CG, The Netherlands.
| | - Bo Lou
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584CG, The Netherlands.
| | - Marcel G M Camps
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333ZA, The Netherlands
| | - Ferry Ossendorp
- Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden 2333ZA, The Netherlands
| | - Wim E Hennink
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584CG, The Netherlands.
| | - Tina Vermonden
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584CG, The Netherlands.
| | - Cornelus F van Nostrum
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584CG, The Netherlands.
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16
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Stojić-Vukanić Z, Bufan B, Pilipović I, Vujnović I, Nacka-Aleksić M, Petrović R, Arsenović-Ranin N, Leposavić G. Estradiol enhances capacity of TLR-matured splenic dendritic cells to polarize CD4+ lymphocytes into IL-17/GM-CSF-producing cells in vitro. Int Immunopharmacol 2016; 40:244-253. [PMID: 27620506 DOI: 10.1016/j.intimp.2016.09.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 08/25/2016] [Accepted: 09/01/2016] [Indexed: 12/01/2022]
Abstract
There are little data on modulatory effects of estrogens on rat dendritic cell (DC) responses to inflammatory stimuli, and consequently their ability to activate and polarize CD4+ T lymphocyte-mediated immune responses. Splenic conventional DCs from young female Albino Oxford rats were activated in vitro with LPS (TLR4 agonist) or R848 (TLR7/8 agonist) in the presence and absence of 17β-estradiol (E2), and their allostimulatory and CD4+ lymphocyte polarizing ability in mixed leukocyte culture (MLC) were studied. Irrespective of the E2 presence, LPS and R848 up-regulated the expression of MHC II on DCs, so they exhibited enhanced allostimulatory capacity in co-culture with CD4+ lymphocytes. On the other hand, E2 promoted stimulatory action of both TLRs on OX62+ DC IL-23 production, augmented their stimulatory effects on IL-6 and IL-1β production, but diminished their enhancing effects on the expression IL-10 and IL-27 by DCs. Consequently, in MLC, OX62+ DCs activated/matured in the co-presence of E2 and either LPS or R848 increased the levels of IL-17, the signature Th17 cell cytokine, when compared with those activated/matured in the absence of E2. GM-CSF levels were also increased in these MLC. Given that the expression of IL-7 mRNA was diminished in DCs activated/matured in the co-presence of E2 and TLR, this increase most likely did not reflect enhanced differentiation of Th cells producing GM-CSF only (Th-GM). CONCLUSIONS E2 augments capacity of LPS- and R848-activated/matured DCs from young rat spleen to induce differentiation of IL-17- and GM-CSF-producing cells.
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Affiliation(s)
- Zorica Stojić-Vukanić
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Biljana Bufan
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Ivan Pilipović
- Immunology Research Center "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia
| | - Ivana Vujnović
- Immunology Research Center "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia
| | - Mirjana Nacka-Aleksić
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Raisa Petrović
- Immunology Research Center "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia
| | - Nevena Arsenović-Ranin
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Gordana Leposavić
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
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17
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Stojić-Vukanić Z, Nacka-Aleksić M, Bufan B, Pilipović I, Arsenović-Ranin N, Djikić J, Kosec D, Leposavić G. 17β-Estradiol influences in vitro response of aged rat splenic conventional dendritic cells to TLR4 and TLR7/8 agonists in an agonist specific manner. Int Immunopharmacol 2014; 24:24-35. [PMID: 25479725 DOI: 10.1016/j.intimp.2014.11.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 10/14/2014] [Accepted: 11/10/2014] [Indexed: 11/15/2022]
Abstract
This study was undertaken considering that, despite the broad use of the unopposed estrogen replacement therapy in elderly women, data on estrogen influence on the functional capacity of dendritic cells (DCs), and consequently immune response are limited. We examined the influence of 17β-estradiol on phenotype, cytokine secretory profile, and allostimulatory and polarizing capacity of splenic (OX62+) conventional DCs from 26-month-old (aged) Albino Oxford rats matured in vitro in the presence of LPS, a TLR4 agonist, and R848, a TLR7/8 agonist. In the presence of 17β-estradiol, DCs from aged rats exhibited an impaired ability to mature upon stimulation with LPS, as shown by the lower surface density of MHC II and costimulatory CD80 and CD86 molecules. 17β-Estradiol alone enhanced CD40 expression in OX62+ DCs without affecting the expression of other costimulatory molecules, thereby confirming that the expression of this molecule is regulated independently from the regulation of other costimulatory molecules. However, although R848 upregulated the expression of MHC II and CD80 and CD40 costimulatory molecules on DCs, 17β-estradiol diminished the effect of this TLR agonist only on MHC II expression. In conjunction, the previous findings suggest that LPS and R848 elicit changes in the expression of costimulatory molecules via triggering differential intracellular signaling pathways. Furthermore, 17β-estradiol diminished the stimulatory influence of both LPS- and R848-matured OX62+ DCs on allogeneic CD4+ T lymphocyte proliferation in a mixed lymphocyte reaction (MLR). Moreover, as shown in MLR, the exposure to 17β-estradiol during LPS- and R848-induced maturation diminished Th1- and enhanced Th17-driving capacity and reduced Th1-driving capacity of OX62+ DCs, respectively. This suggests that LPS and R848 affect not only the surface phenotype, but also functional characteristics of OX62+ DCs triggering distinct intracellular signaling pathways. Collectively, the findings indicate that estrogen directly acting on OX62+ DCs, may affect CD4+ lymphocyte-dependent immune response in aged female rats.
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Affiliation(s)
- Zorica Stojić-Vukanić
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Mirjana Nacka-Aleksić
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Biljana Bufan
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Ivan Pilipović
- Immunology Research Center "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia
| | - Nevena Arsenović-Ranin
- Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Jasmina Djikić
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
| | - Duško Kosec
- Immunology Research Center "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia
| | - Gordana Leposavić
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
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18
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CD80 and CD86 costimulatory molecules differentially regulate OT-II CD4⁺ T lymphocyte proliferation and cytokine response in cocultures with antigen-presenting cells derived from pregnant and pseudopregnant mice. Mediators Inflamm 2014; 2014:769239. [PMID: 24771983 PMCID: PMC3977523 DOI: 10.1155/2014/769239] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 01/10/2014] [Accepted: 02/13/2014] [Indexed: 12/17/2022] Open
Abstract
Immune phenomena during the preimplantation period of pregnancy are poorly understood. The aim of our study was to assess the capacity for antigen presentation of splenic antigen-presenting cells (APCs) derived from pregnant and pseudopregnant mice in in vitro conditions. Therefore, sorted CD11c+ dendritic cells and macrophages F4/80+ and CD11b+ presenting ovalbumin (OVA) were cocultured with CD4+ T cells derived from OT-II mice's (C57BL6/J-Tg(TcraTcrb)1100Mjb/J) spleen. After 132 hours of cell culture, proliferation of lymphocytes (ELISA-BrdU), activation of these cells (flow cytometry), cytokine profile (ELISA), and influence of costimulatory molecules blocking on these parameters were measured. We did not detect any differences in regulation of Th1/Th2 cytokine balance. CD86 seems to be the main costimulatory molecule involved in the proliferation response but CD80 is the main costimulatory molecule influencing cytokine secretion in pregnant mice. In conclusion, this study showed that CD80 and CD86 costimulatory molecules regulate OT-II CD4+ T lymphocyte proliferation and cytokine response in cocultures with antigen-presenting cells derived from pregnant and pseudopregnant mice. The implications of these changes still remain unclear.
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