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Anwar S, Turienzo CF, Tsang L, Smith SG, Fletcher H, Toulza F, Cliff JM, Brown M, Dockrell HM. Impact of helminth co-infection and treatment on mycobacterial growth inhibition in UK migrants with TB infection. IJTLD OPEN 2025; 2:217-223. [PMID: 40226135 PMCID: PMC11984527 DOI: 10.5588/ijtldopen.24.0528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 12/21/2024] [Indexed: 04/15/2025]
Abstract
BACKGROUND TB and helminth infections are co-endemic in many parts of the world. This has led to the hypothesis that immunomodulation due to helminth infections could adversely affect the ability to control Mycobacterium tuberculosis infection. Anti-helminthic treatment has been associated with improved anti-mycobacterial cellular responses and decreases in the frequency of regulatory T-cells. We therefore investigated how control of mycobacterial growth and anti-mycobacterial immune responses are modulated in helminth and TB co-infected individuals using a mycobacterial growth inhibition assay (MGIA). METHODS Migrants with eosinophilia or suspected/diagnosed helminth infection and/or TB infection (TBI) were recruited when attending University College London Hospitals (London, UK) and followed up after completing anti-helminthic treatment. Mycobacterial growth inhibition was assessed using the BACTEC™ MGIT™ system after 72 hours of co-culture of peripheral blood mononuclear cells (PBMC) with M. bovis bacille Calmette-Guérin (BCG) or M. tuberculosis Erdman. RESULTS Anti-helminthic treatment reduced total and helminth-specific antibodies in helminth-infected and TBI-helminth co-infected individuals. Helminth-infected individuals displayed lower growth inhibition in the MGIA than those without helminth infections, and mycobacterial growth inhibition improved after anti-helminthic treatment. Blocking interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) improved mycobacterial growth inhibition, while blocking interferon-gamma (IFN-γ) did not alter growth inhibition. CONCLUSION Infection with helminths such as Schistosoma mansoni and Strongyloides spp. may reduce the ability to control mycobacterial growth.
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Affiliation(s)
- S Anwar
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
- Department of Microbiology & Immunology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - C F Turienzo
- University College London Hospital, London, UK
- King's College London, London, UK
| | - L Tsang
- University College London Hospital, London, UK
- The North West London Hospital NHS Trust, Northwick Park Hospital, London, UK
| | - S G Smith
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
- Brunel University, London, UK
| | - H Fletcher
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
- Johnson&Johnson, London, UK
| | - F Toulza
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
- Guys and St Thomas NHS Trust, London, UK
| | - J M Cliff
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
- Brunel University, London, UK
| | - M Brown
- University College London Hospital, London, UK
- Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, UK
| | - H M Dockrell
- Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK
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Jheng MJ, Kita H. Control of Asthma and Allergy by Regulatory T Cells. Int Arch Allergy Immunol 2024; 186:87-102. [PMID: 39154634 PMCID: PMC11729466 DOI: 10.1159/000540407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 07/15/2024] [Indexed: 08/20/2024] Open
Abstract
BACKGROUND Epithelial barriers, such as the lungs and skin, face the challenge of providing the tissues' physiological function and maintaining tolerance to the commensal microbiome and innocuous environmental factors while defending the host against infectious microbes. Asthma and allergic diseases can result from maladaptive immune responses, resulting in exaggerated and persistent type 2 immunity and tissue inflammation. SUMMARY Among the diverse populations of tissue immune cells, CD4+ regulatory T cells (Treg cells) are central to controlling immune responses and inflammation and restoring tissue homeostasis. Humans and mice that are deficient in Treg cells experience extensive inflammation in their mucosal organs and skin. During past decades, major progress has been made toward understanding the immunobiology of Treg cells and the molecular and cellular mechanisms that control their differentiation and function. It is now clear that Treg cells are not a single cell type and that they demonstrate diversity and plasticity depending on their differentiation stages and tissue environment. They could also take on a proinflammatory phenotype in certain conditions. KEY MESSAGES Treg cells perform distinct functions, including the induction of immune tolerance, suppression of inflammation, and promotion of tissue repair. Subsets of Treg cells in mucosal tissues are regulated by their differentiation stage and tissue inflammatory milieu. Treg cell dysfunction likely plays roles in persistent immune responses and tissue inflammation in asthma and allergic diseases.
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Affiliation(s)
- Min-Jhen Jheng
- Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic Arizona, Scottsdale, AZ
| | - Hirohito Kita
- Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic Arizona, Scottsdale, AZ
- Department of Immunology, Mayo Clinic Arizona, Scottsdale, AZ
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Guo X, Qin Y, Feng Z, Li H, Yang J, Su K, Mao R, Li J. Investigating the anti-inflammatory effects of icariin: A combined meta-analysis and machine learning study. Heliyon 2024; 10:e35307. [PMID: 39170422 PMCID: PMC11336647 DOI: 10.1016/j.heliyon.2024.e35307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 07/24/2024] [Accepted: 07/25/2024] [Indexed: 08/23/2024] Open
Abstract
Objective The objectives of this study were to define the superiority of icariin and its derivatives' anti-inflammatory activities and to create a reference framework for evaluating preclinical evidence. This method combines machine learning and meta-analysis to identify underlying biological pathways. Methods Data came from PubMed, Embase, Web of Science, and the Cochrane Library. SYRCLE was used to evaluate the risk of bias in a subset of research. Meta-analysis and detailed subgroup analyses, categorized by species, genders, disease type, dosage, and treatment duration, were performed using R and STATA 15.0 software to derive nuanced insights. Employing R software (version 4.2.3) and the tidymodels package, the analysis focused on constructing a model and selecting features, with TNF-α as the dependent variable. This approach aims to identify significant predictors of drug efficacy. An in-depth literature facilitated the synthesis of anti-inflammatory mechanisms attributed to icariin and its constituent compounds. Results Following a meticulous search and selection process, 19 studies, involving 370 and 260 animals were included in the meta-analysis and machine-learning assessment, respectively. The findings revealed that icariin and its derivatives markedly reduced inflammation markers, including TNF-α and IL-1β. Additionally, machine-learning outcomes, with TNF-α as the target variable, indicated enhanced anti-inflammatory effects of icariin across respiratory, urological, neurological, and digestive disease types. These effects were more pronounced at doses exceeding 27.52 mg/kg/day and treatment durations beyond 31.22 days. Conclusion Strong anti-inflammatory effects are exhibited by icariiin and its derivatives, which are especially beneficial in the management of digestive, neurological, pulmonary, and urinary conditions. Effective for periods longer than 31.22 days and at dosages more than 27.52 mg/kg/day. Subsequent research will involve more targeted animal experiments and safety assessments to obtain more comprehensive preclinical evidence.
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Affiliation(s)
- Xiaochuan Guo
- Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
- The First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
- Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases By Henan and Education Ministry of PR China, Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan province, China
| | - Yanqin Qin
- Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases By Henan and Education Ministry of PR China, Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan province, China
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
| | - Zhenzhen Feng
- Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
- Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases By Henan and Education Ministry of PR China, Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan province, China
| | - Haibo Li
- Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases By Henan and Education Ministry of PR China, Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan province, China
| | - Jingfan Yang
- Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases By Henan and Education Ministry of PR China, Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan province, China
| | - Kailin Su
- Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
- The First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
- Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases By Henan and Education Ministry of PR China, Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan province, China
| | - Ruixiao Mao
- Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
- The First Clinical Medical College, Henan University of Chinese Medicine, Zhengzhou 450046, Henan Province, China
- Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases By Henan and Education Ministry of PR China, Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan province, China
| | - Jiansheng Li
- Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, Henan Province, China
- Co-construction Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases By Henan and Education Ministry of PR China, Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Zhengzhou 450046, Henan province, China
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Karwig L, Moore PF, Alber G, Eschke M. Distinct characteristics of unique immunoregulatory canine non-conventional TCRαβ pos CD4 negCD8α neg double-negative T cell subpopulations. Front Immunol 2024; 15:1439213. [PMID: 39185407 PMCID: PMC11341405 DOI: 10.3389/fimmu.2024.1439213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/12/2024] [Indexed: 08/27/2024] Open
Abstract
Conventional CD4pos regulatory T (Treg) cells characterized by expression of the key transcription factor forkhead box P3 (FoxP3) are crucial to control immune responses, thereby maintaining homeostasis and self-tolerance. Within the substantial population of non-conventional T cell receptor (TCR)αβpos CD4negCD8αneg double-negative (dn) T cells of dogs, a novel FoxP3pos Treg-like subset was described that, similar to conventional CD4pos Treg cells, is characterized by high expression of CD25. Noteworthy, human and murine TCRαβpos regulatory dn T cells lack FoxP3. Immunosuppressive capacity of canine dn T cells was hypothesized based on expression of inhibitory molecules (interleukin (IL)-10, cytotoxic T-lymphocyte associated protein 4, CTLA4). Here, to verify their regulatory function, the dnCD25pos (enriched for FoxP3pos Treg-like cells) and the dnCD25neg fraction, were isolated by fluorescence-activated cell sorting from peripheral blood mononuclear cells (PBMC) of Beagle dogs and analyzed in an in vitro suppression assay in comparison to conventional CD4posCD25pos Treg cells (positive control) and CD4posCD25neg T cells (negative control). Canine dnCD25pos T cells suppressed the Concanavalin A-driven proliferation of responder PBMC to a similar extent as conventional CD4posCD25pos Treg cells. Albeit to a lesser extent than FoxP3-enriched dn and CD4posCD25pos populations, even dnCD25neg T cells reduced the proliferation of responder cells. This is remarkable, as dnCD25neg T cells have a FoxP3neg phenotype comparable to non-suppressive CD4posCD25neg T cells. Both, CD25pos and CD25neg dn T cells, can mediate suppression independent of cell-cell contact and do not require additional signals from CD4posCD25neg T cells to secrete inhibitory factors in contrast to CD4posCD25pos T cells. Neutralization of IL-10 completely abrogated the suppression by dnCD25pos and CD4posCD25pos Treg cells in a Transwell™ system, while it only partially reduced suppression by dnCD25neg T cells. Taken together, unique canine non-conventional dnCD25pos FoxP3pos Treg-like cells are potent suppressor cells in vitro. Moreover, inhibition of proliferation of responder T cells by the dnCD25neg fraction indicates suppressive function of a subset of dn T cells even in the absence of FoxP3. The identification of unique immunoregulatory non-conventional dn T cell subpopulations of the dog in vitro is of high relevance, given the immunotherapeutic potential of manipulating regulatory T cell responses in vivo.
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Affiliation(s)
- Laura Karwig
- Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | - Peter F. Moore
- Department of Veterinary Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
| | - Gottfried Alber
- Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
| | - Maria Eschke
- Institute of Immunology/Molecular Pathogenesis, Center for Biotechnology and Biomedicine, Faculty of Veterinary Medicine, Leipzig University, Leipzig, Germany
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Salama RAA, Patni MAMF, Ba-Hutair SNM, Wadid NA, Akikwala MS. Exploring Novel Treatment Modalities for Type 1 Diabetes Mellitus: Potential and Prospects. Healthcare (Basel) 2024; 12:1485. [PMID: 39120188 PMCID: PMC11311856 DOI: 10.3390/healthcare12151485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 07/24/2024] [Indexed: 08/10/2024] Open
Abstract
Despite the effectiveness of insulin injections in managing hyperglycemia in type 1 diabetes mellitus (T1DM), they fall short in addressing autoimmunity and regenerating damaged islets. This review aims to explore the potential and prospects of emerging treatment modalities for T1DM, including mesenchymal stem cells (MSCs), MSC-derived exosomes, gene therapy, islet allotransplantation, pancreatic islet cell transplantation, and teplizumab. We review emerging treatment modalities for T1DM, highlighting several promising strategies with varied mechanisms and outcomes. Mesenchymal stem cells demonstrate potential in modulating the immune response and preserving or restoring beta-cell function, although variability in sources and administration routes necessitates further standardization. Similarly, MSC-derived exosomes show promise in promoting beta-cell regeneration and immune regulation, supported by early-stage studies showing improved glucose homeostasis in animal models, albeit with limited clinical data. Gene therapy, utilizing techniques like CRISPR-Cas9, offers targeted correction of genetic defects and immune modulation; however, challenges in precise delivery and ensuring long-term safety persist. Islet allotransplantation and pancreatic islet cell transplantation have achieved some success in restoring insulin independence, yet challenges such as donor scarcity and immunosuppression-related complications remain significant. Teplizumab, an anti-CD3 monoclonal antibody, has demonstrated potential in delaying T1DM onset by modulating immune responses and preserving beta-cell function, with clinical trials indicating prolonged insulin production capability. Despite significant progress, standardization, long-term efficacy, and safety continue to pose challenges across these modalities. Conclusion: While these therapies demonstrate significant potential, challenges persist. Future research should prioritize optimizing these treatments and validating them through extensive clinical trials to enhance T1DM management and improve patient outcomes.
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Affiliation(s)
- Rasha Aziz Attia Salama
- Department of Community Medicine, College of Medicine, Ras Al Khaimah Medical and Health Science University, Ras Al Khaimah 11172, United Arab Emirates; (R.A.A.S.); (N.A.W.)
- Kasr El Aini Faculty of Medicine, Cairo University, Giza 12525, Egypt
| | - Mohamed Anas Mohamed Faruk Patni
- Department of Community Medicine, College of Medicine, Ras Al Khaimah Medical and Health Science University, Ras Al Khaimah 11172, United Arab Emirates; (R.A.A.S.); (N.A.W.)
| | - Shadha Nasser Mohammed Ba-Hutair
- Department of Obstetrics and Gynecology, College of Medicine, Ras Al Khaimah Medical and Health Science University, Ras Al Khaimah 11172, United Arab Emirates;
| | - Nihal Amir Wadid
- Department of Community Medicine, College of Medicine, Ras Al Khaimah Medical and Health Science University, Ras Al Khaimah 11172, United Arab Emirates; (R.A.A.S.); (N.A.W.)
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LeGuern C, Markmann JF. Regulatory CD4 + T cells: permanent or temporary suppressors of immunity. Front Immunol 2024; 15:1293892. [PMID: 38404584 PMCID: PMC10890821 DOI: 10.3389/fimmu.2024.1293892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 01/26/2024] [Indexed: 02/27/2024] Open
Affiliation(s)
- Christian LeGuern
- Center for Transplantation Sciences, Massachusetts General Brigham, Harvard Medical School, Boston, MA, United States
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Zhang Z, Zhu T, Zhang L, Xing Y, Yan Z, Li Q. Critical influence of cytokines and immune cells in autoimmune gastritis. Autoimmunity 2023; 56:2174531. [PMID: 36762543 DOI: 10.1080/08916934.2023.2174531] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023]
Abstract
Gastric cancer (GC) is a type of the most common cancers. Autoimmune gastritis (AIG) and infection with Helicobacter pylori (HP) are the risk factors of triggering GC. With the emphasis on the treatment of HP, the incidence and prevalence of HP infection in population is decreasing. However, AIG lacks accurate diagnosis and treatment methods, which occupies high cancer risk factors. AIG is controlled by the immune environment of the stomach, including immune cells, inflammatory cells, and infiltrating intercellular material. Various immune cells or cytokines play a central role in the process of regulating gastric parietal cells. Abnormal expression levels of cytokines involved in immunity are bound to face the risk of tumorigenesis. Therefore, it is particularly important for preventing or treating AIG and avoiding the risk of gastric cancer to clarify the confirmed action mode of immune cells and cytokines in the gastric system. Herein, we briefly reviewed the role of the immune environment under AIG, focussing on describing these double-edged effects between immune cells and cytokines, and pointing out potential research challenges.
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Affiliation(s)
- Zepeng Zhang
- Kunshan Hospital of Chinese Medicine, Suzhou, Jiangsu, China
| | - Tongtong Zhu
- Kunshan Hospital of Traditional Chinese and Western Medicine, Suzhou, Jiangsu, China
| | - Lei Zhang
- Kunshan Hospital of Chinese Medicine, Suzhou, Jiangsu, China
| | - Yanchao Xing
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Zhiqiang Yan
- Kunshan Hospital of Chinese Medicine, Suzhou, Jiangsu, China
| | - Qingsong Li
- Kunshan Hospital of Chinese Medicine, Suzhou, Jiangsu, China
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Association of Increased Programmed Death Ligand 1 Expression and Regulatory T Cells Infiltration with Higher Hepatocellular Carcinoma Recurrence in Patients with Hepatitis B Virus Pre-S2 Mutant after Curative Surgical Resection. Viruses 2022; 14:v14061346. [PMID: 35746817 PMCID: PMC9229682 DOI: 10.3390/v14061346] [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: 04/02/2022] [Revised: 06/03/2022] [Accepted: 06/18/2022] [Indexed: 01/27/2023] Open
Abstract
Although surgical resection is available as a potentially curative therapy for hepatocellular carcinoma (HCC), high recurrence of HCC after surgery remains a serious obstacle for long-term patient survival. Therefore, the discovery of valuable prognostic biomarkers for HCC recurrence is urgently needed. Pre-S2 mutant is a mutant form of hepatitis B virus (HBV) large surface protein which is expressed from the HBV surface gene harboring deletion mutations spanning the pre-S2 gene segment. Pre-S2 mutant-positive HCC patients have been regarded as a high-risk population of HCC recurrence after resection surgery and display increased immune checkpoint programmed death ligand 1 (PD-L1) expression and pro-tumor regulatory T cells (Tregs) infiltration in tumor tissues. In this study, the association of higher levels of PD-L1 expression and Tregs infiltration in tumor tissues with post-operative HCC recurrence in pre-S2 mutant-positive HCC patients was evaluated. We found that patients with pre-S2 mutant in combination with higher levels of PD-L1 expression and Tregs infiltration in tumor tissues were independently associated with a higher risk of HCC recurrence (hazard ratio, 4.109; p value = 0.0011) and poorer recurrence-free survival (median, 8.2 versus 18.0 months; p value = 0.0004) than those of patients with either one or two of these three biomarkers. Furthermore, a combination of pre-S2 mutant, intra-tumoral PD-L1 expression, and tumor-infiltrating Tregs exhibited superior performance in identifying patients at a higher risk of HCC recurrence (area under the receiver operating characteristic curve, 0.8400). Collectively, this study suggests that higher levels of PD-L1 expression and Tregs infiltration in tumor tissues predicted a higher risk of HCC recurrence in pre-S2 mutant-positive HCC patients after curative surgical resection.
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Hall BM, Verma ND, Tran GT, Hodgkinson SJ. Transplant Tolerance, Not Only Clonal Deletion. Front Immunol 2022; 13:810798. [PMID: 35529847 PMCID: PMC9069565 DOI: 10.3389/fimmu.2022.810798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 02/23/2022] [Indexed: 11/13/2022] Open
Abstract
The quest to understand how allogeneic transplanted tissue is not rejected and how tolerance is induced led to fundamental concepts in immunology. First, we review the research that led to the Clonal Deletion theory in the late 1950s that has since dominated the field of immunology and transplantation. At that time many basic mechanisms of immune response were unknown, including the role of lymphocytes and T cells in rejection. These original observations are reassessed by considering T regulatory cells that are produced by thymus of neonates to prevent autoimmunity. Second, we review "operational tolerance" induced in adult rodents and larger animals such as pigs. This can occur spontaneously especially with liver allografts, but also can develop after short courses of a variety of rejection inhibiting therapies. Over time these animals develop alloantigen specific tolerance to the graft but retain the capacity to reject third-party grafts. These animals have a "split tolerance" as peripheral lymphocytes from these animals respond to donor alloantigen in graft versus host assays and in mixed lymphocyte cultures, indicating there is no clonal deletion. Investigation of this phenomenon excludes many mechanisms, including anti-donor antibody blocking rejection as well as anti-idiotypic responses mediated by antibody or T cells. This split tolerance is transferred to a second immune-depleted host by T cells that retain the capacity to effect rejection of third-party grafts by the same host. Third, we review research on alloantigen specific inhibitory T cells that led to the first identification of the CD4+CD25+T regulatory cell. The key role of T cell derived cytokines, other than IL-2, in promoting survival and expansion of antigen specific T regulatory cells that mediate transplant tolerance is reviewed. The precise methods for inducing and diagnosing operational tolerance remain to be defined, but antigen specific T regulatory cells are key mediators.
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Affiliation(s)
- Bruce M. Hall
- Immune Tolerance Laboratory, School of Medicine, University of New South Wales (UNSW) Sydney, Ingham Institute, and Renal Service and Multiple Sclerosis Clinic, Liverpool Hospital, Liverpool, NSW, Australia
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Sadanandan P, Payne NL, Sun G, Ashokan A, Gowd SG, Lal A, Satheesh KMK, Pulakkat S, Nair SV, Menon KN, Bernard CCA, Koyakutty M. Exploiting the preferential phagocytic uptake of nanoparticle-antigen conjugates for the effective treatment of autoimmunity. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2021; 40:102481. [PMID: 34748963 DOI: 10.1016/j.nano.2021.102481] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 06/09/2021] [Accepted: 10/23/2021] [Indexed: 10/19/2022]
Abstract
Tolerance induction is central to the suppression of autoimmunity. Here, we engineered the preferential uptake of nano-conjugated autoantigens by spleen-resident macrophages to re-introduce self-tolerance and suppress autoimmunity. The brain autoantigen, myelin oligodendrocyte glycoprotein (MOG), was conjugated to 200 or 500 nm silica nanoparticles (SNP) and delivered to the spleen and liver-resident macrophages of experimental autoimmune encephalomyelitis (EAE) mice model of multiple sclerosis. MOG-SNP conjugates significantly reduced signs of EAE at a very low dose (50 μg) compared to the higher dose (>800 μg) of free-MOG. This was associated with reduced proliferation of splenocytes and pro-inflammatory cytokines secretion, decreased spinal cord inflammation, demyelination and axonal damage. Notably, biodegradable porous SNP showed an enhanced disease suppression assisted by elevated levels of regulatory T cells and programmed-death ligands (PD-L1/2) in splenic and lymph node cells. Our results demonstrate that targeting nano-conjugated autoantigens to tissue-resident macrophages in lymphoid organs can effectively suppress autoimmunity.
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Affiliation(s)
- Prashant Sadanandan
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India; Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Natalie L Payne
- Australian Regenerative Medicine Institute, Monash University, Clayton, Australia
| | - Guizhi Sun
- Australian Regenerative Medicine Institute, Monash University, Clayton, Australia
| | - Anusha Ashokan
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Siddaramana G Gowd
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Arsha Lal
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Kumar M K Satheesh
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Sreeranjini Pulakkat
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Shantikumar V Nair
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India
| | - Krishnakumar N Menon
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India.
| | - Claude C A Bernard
- Australian Regenerative Medicine Institute, Monash University, Clayton, Australia.
| | - Manzoor Koyakutty
- Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, Kerala, India.
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Vergani D, Terziroli Beretta-Piccoli B, Mieli-Vergani G. A reasoned approach to the treatment of autoimmune hepatitis. Dig Liver Dis 2021; 53:1381-1393. [PMID: 34162505 DOI: 10.1016/j.dld.2021.05.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/15/2021] [Accepted: 05/27/2021] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis on histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to analyse AIH therapeutic interventions with reference to our knowledge of the pathogenesis of AIH. Standard treatment, based on steroids and azathioprine, leads to disease remission in 80-90% of patients. Alternative first-line treatment with budesonide is effective in adults, but less so in the juvenile form of AIH; first-line treatment with ciclosporin does not provide convincing advantages compared to standard treatment. Second-line treatments are needed for patients not responding or intolerant to first-line standard management. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but is teratogenic. Only few and heterogeneous data on calcineurin inhibitors and m-TOR inhibitors are available. Biologicals, including anti-tumour necrosis factor- α and anti-CD20 monoclonal antibodies, have given ambivalent results and may have severe side-effects. Clinical trials with new therapeutic options aiming at targeting B lymphocytes and proinflammatory cytokines, or expanding regulatory T cells to restore tolerance are ongoing.
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Affiliation(s)
- Diego Vergani
- King's College London Faculty of Life Sciences & Medicine, London, UK; Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; Epatocentro Ticino, Lugano, Switzerland
| | - Benedetta Terziroli Beretta-Piccoli
- Institute of Liver Studies, MowatLabs, King's College Hospital, London, UK; Epatocentro Ticino, Lugano, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Switzerland
| | - Giorgina Mieli-Vergani
- King's College London Faculty of Life Sciences & Medicine, London, UK; Epatocentro Ticino, Lugano, Switzerland; Paediatric Liver, GI and Nutrition Centre, MowatLabs, King's College Hospital, London, UK.
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12
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Lutz MB, Backer RA, Clausen BE. Revisiting Current Concepts on the Tolerogenicity of Steady-State Dendritic Cell Subsets and Their Maturation Stages. THE JOURNAL OF IMMUNOLOGY 2021; 206:1681-1689. [PMID: 33820829 DOI: 10.4049/jimmunol.2001315] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 01/11/2021] [Indexed: 12/25/2022]
Abstract
The original concept stated that immature dendritic cells (DC) act tolerogenically whereas mature DC behave strictly immunogenically. Meanwhile, it is also accepted that phenotypically mature stages of all conventional DC subsets can promote tolerance as steady-state migratory DC by transporting self-antigens to lymph nodes to exert unique functions on regulatory T cells. We propose that in vivo 1) there is little evidence for a tolerogenic function of immature DC during steady state such as CD4 T cell anergy induction, 2) all tolerance as steady-state migratory DC undergo common as well as subset-specific molecular changes, and 3) these changes differ by quantitative and qualitative markers from immunogenic DC, which allows one to clearly distinguish tolerogenic from immunogenic migratory DC.
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Affiliation(s)
- Manfred B Lutz
- Institute for Virology and Immunobiology, University of Würzburg, 97070 Würzburg, Germany; and
| | - Ronald A Backer
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55122 Mainz, Germany
| | - Björn E Clausen
- Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, 55122 Mainz, Germany
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13
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Exploring the Pathogenic Role and Therapeutic Implications of Interleukin 2 in Autoimmune Hepatitis. Dig Dis Sci 2021; 66:2493-2512. [PMID: 32833154 DOI: 10.1007/s10620-020-06562-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 08/12/2020] [Indexed: 12/11/2022]
Abstract
Interleukin 2 is essential for the expansion of regulatory T cells, and low-dose recombinant interleukin 2 has improved the clinical manifestations of diverse autoimmune diseases in preliminary studies. The goals of this review are to describe the actions of interleukin 2 and its receptor, present preliminary experiences with low-dose interleukin 2 in the treatment of diverse autoimmune diseases, and evaluate its potential as a therapeutic intervention in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Interleukin 2 is critical for the thymic selection, peripheral expansion, induction, and survival of regulatory T cells, and it is also a growth factor for activated T cells and natural killer cells. Interleukin 2 activates the signal transducer and activator of transcription 5 after binding with its trimeric receptor on regulatory T cells. Immune suppressor activity is increased; anti-inflammatory interleukin 10 is released; pro-inflammatory interferon-gamma is inhibited; and activation-induced apoptosis of CD8+ T cells is upregulated. Preliminary experiences with cyclic injections of low-dose recombinant interleukin 2 in diverse autoimmune diseases have demonstrated increased numbers of circulating regulatory T cells, preserved regulatory function, improved clinical manifestations, and excellent tolerance. Similar improvements have been recognized in one of two patients with refractory autoimmune hepatitis. In conclusion, interferon 2 has biological actions that favor the immune suppressor functions of regulatory T cells, and low-dose regimens in preliminary studies encourage its rigorous investigation in autoimmune hepatitis.
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14
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Treg-Resistant Cytotoxic CD4 + T Cells Dictate T Helper Cells in Their Vicinity: TH17 Skewing and Modulation of Proliferation. Int J Mol Sci 2021; 22:ijms22115660. [PMID: 34073458 PMCID: PMC8198086 DOI: 10.3390/ijms22115660] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/19/2021] [Accepted: 05/23/2021] [Indexed: 12/31/2022] Open
Abstract
Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell−cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.
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15
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Lin YT, Jeng LB, Chan WL, Su IJ, Teng CF. Hepatitis B Virus Pre-S Gene Deletions and Pre-S Deleted Proteins: Clinical and Molecular Implications in Hepatocellular Carcinoma. Viruses 2021; 13:v13050862. [PMID: 34066744 PMCID: PMC8151789 DOI: 10.3390/v13050862] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/29/2021] [Accepted: 05/07/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent and fatal human cancers worldwide and its development and prognosis are intimately associated with chronic infection with hepatitis B virus (HBV). The identification of genetic mutations and molecular mechanisms that mediate HBV-induced tumorigenesis therefore holds promise for the development of potential biomarkers and targets for HCC prevention and therapy. The presence of HBV pre-S gene deletions in the blood and the expression of pre-S deleted proteins in the liver tissues of patients with chronic hepatitis B and HBV-related HCC have emerged as valuable biomarkers for higher incidence rates of HCC development and a higher risk of HCC recurrence after curative surgical resection, respectively. Moreover, pre-S deleted proteins are regarded as important oncoproteins that activate multiple signaling pathways to induce DNA damage and promote growth and proliferation in hepatocytes, leading to HCC development. The signaling molecules dysregulated by pre-S deleted proteins have also been validated as potential targets for the prevention of HCC development. In this review, we summarize the clinical and molecular implications of HBV pre-S gene deletions and pre-S deleted proteins in HCC development and recurrence and highlight their potential applications in HCC prevention and therapy.
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Affiliation(s)
- Yueh-Te Lin
- Cancer Genome Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
| | - Long-Bin Jeng
- Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan;
| | - Wen-Ling Chan
- Department of Bioinformatics and Medical Engineering, Asia University, Taichung 413, Taiwan;
- Epigenome Research Center, China Medical University Hospital, Taichung 404, Taiwan
| | - Ih-Jen Su
- Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan 710, Taiwan;
| | - Chiao-Fang Teng
- Organ Transplantation Center, China Medical University Hospital, Taichung 404, Taiwan;
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung 404, Taiwan
- Correspondence: ; Tel.: +886-4-2205-2121
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16
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Small organic molecules accelerate the expansion of regulatory T cells. Bioorg Chem 2021; 111:104908. [PMID: 33895604 DOI: 10.1016/j.bioorg.2021.104908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 04/04/2021] [Accepted: 04/07/2021] [Indexed: 11/21/2022]
Abstract
The regulatory T cells (Treg cells) expressing CD4 + CD25 + FOXP3 + markers are indispensable for the initiation of immune homeostasis and tolerance to self-antigens in both mice and humans. A decrease in regulatory T cells leads to various autoimmune pathologies. Herein, we report three low molecular weight, small organic molecules as a new series of Treg proliferators TRP-1-3. These small molecules were tested for their proliferative effect on regulatory T cells. It was found that TRP-1 (Oleracein E) strongly accelerates the Treg proliferation in vitro in a concentration-dependent manner. The effect was evident for all subsets of Treg cells tested, including naturally occurring, thymus-derived and peripherally-induced or adaptive Treg, indicating an effect independent of the maturation site. Importantly, increased Treg cells numbers by TRP-1 correlated with improved CD4 + CD25 + FOXP3 + expression in vitro, while propidium iodide-based staining showed low TRP-1-induced cytotoxicity. Molecular docking plus simulation studies of these TRP-1-3 with IL-2R, mTOR and TCR receptors suggest a TCR-based Treg cells activation mechanism. Because of its high Treg cells activities and low cellular cytotoxicity, TRP-1-3 may be useful in stimulating ex-vivo/in-vivo, Treg cell-specific responses for therapeutic applications.
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17
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Liu S, Liang J, Liu Z, Zhang C, Wang Y, Watson AH, Zhou C, Zhang F, Wu K, Zhang F, Lu Y, Wang X. The Role of CD276 in Cancers. Front Oncol 2021; 11:654684. [PMID: 33842369 PMCID: PMC8032984 DOI: 10.3389/fonc.2021.654684] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Accepted: 03/02/2021] [Indexed: 02/05/2023] Open
Abstract
Objective Aberrant expression of the immune checkpoint molecule, CD276, also known as B7-H3, is associated with tumorigenesis. In this review, we aim to comprehensively describe the role of CD276 in malignancies and its potential therapeutic effect. Data Sources Database including PubMed, EMbase, Cochrane Library, CNKI, and Clinical Trails.gov were searched for eligible studies and reviews. Study selection: Original studies and review articles on the topic of CD276 in tumors were retrieved. Results CD276 is an immune checkpoint molecule in the epithelial mesenchymal transition (EMT) pathway. In this review, we evaluated the available evidence on the expression and regulation of CD276. We also assessed the role of CD276 within the immune micro-environment, effect on tumor progression, and the potential therapeutic effect of CD276 targeted therapy for malignancies. Conclusion CD276 plays an essential role in cell proliferation, invasion, and migration in malignancies. Results from most recent studies indicate CD276 could be a promising therapeutic target for malignant tumors.
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Affiliation(s)
- Shengzhuo Liu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China.,William Harvey Research Institute, Queen Mary University of London, London, United Kingdom
| | - Jiayu Liang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhihong Liu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Chi Zhang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Yang Wang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Alice Helen Watson
- Clinical Science and Services, Royal Veterinary College, University of London, London, United Kingdom
| | - Chuan Zhou
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Fan Zhang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Kan Wu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Fuxun Zhang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Yiping Lu
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
| | - Xianding Wang
- Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, China
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18
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Kuczma MP, Szurek EA, Cebula A, Ngo VL, Pietrzak M, Kraj P, Denning TL, Ignatowicz L. Self and microbiota-derived epitopes induce CD4 + T cell anergy and conversion into CD4 +Foxp3 + regulatory cells. Mucosal Immunol 2021; 14:443-454. [PMID: 33139845 PMCID: PMC7946630 DOI: 10.1038/s41385-020-00349-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 08/31/2020] [Accepted: 09/23/2020] [Indexed: 02/04/2023]
Abstract
The physiological role of T cell anergy induction as a key mechanism supporting self-tolerance remains undefined, and natural antigens that induce anergy are largely unknown. In this report, we used TCR sequencing to show that the recruitment of CD4+CD44+Foxp3-CD73+FR4+ anergic (Tan) cells expands the CD4+Foxp3+ (Tregs) repertoire. Next, we report that blockade in peripherally-induced Tregs (pTregs) formation due to mutation in CNS1 region of Foxp3 or chronic exposure to a selecting self-peptide result in an accumulation of Tan cells. Finally, we show that microbial antigens from Akkermansia muciniphila commensal bacteria can induce anergy and drive conversion of naive CD4+CD44-Foxp3- T (Tn) cells to the Treg lineage. Overall, data presented here suggest that Tan induction helps the Treg repertoire to become optimally balanced to provide tolerance toward ubiquitous and microbiome-derived epitopes, improving host ability to avert systemic autoimmunity and intestinal inflammation.
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Affiliation(s)
- Michal P Kuczma
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Edyta A Szurek
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Anna Cebula
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Vu L Ngo
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Maciej Pietrzak
- Mathematical Biosciences Institute, Ohio State University, Columbus, OH, USA
| | - Piotr Kraj
- Department of Biological Sciences, Old Dominion University, Norfolk, VA, USA
| | - Timothy L Denning
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA
| | - Leszek Ignatowicz
- Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA.
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19
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Increased infiltration of regulatory T cells in hepatocellular carcinoma of patients with hepatitis B virus pre-S2 mutant. Sci Rep 2021; 11:1136. [PMID: 33441885 PMCID: PMC7807072 DOI: 10.1038/s41598-020-80935-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 12/28/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a frequent and deadly human cancer worldwide that is intimately associated with chronic hepatitis B virus (HBV) infection. Pre-S2 mutant is a HBV oncoprotein that plays important roles in HCC development and is linked to poor prognosis in HCC patients. However, the profiles of tumor-infiltrating lymphocytes in HCC tissues of pre-S2 mutant-positive patients remain unknown. In this study, we performed fluorescent immunohistochemistry staining to detect the infiltration of 'anti-tumor' cytotoxic T lymphocytes (CTLs) and 'pro-tumor' regulatory T cells (Tregs) in pre-S2 mutant-positive and -negative HCC patients. We showed that pre-S2 mutant-positive patients had a significantly higher infiltration of CD4+CD25+ cells and forkhead box P3 (Foxp3)-expressing cells but similar CTLs and lower granzyme B-expressing cells in HCC tissues compared with pre-S2 mutant-negative patients. Moreover, the percentage of pre-S2 plus pre-S1 + pre-S2 deletion (pre-S2 mutant) was positively correlated with the density of CD4+CD25+ cells and Foxp3-expressing cells but negatively with granzyme B-expressing cells in HCC tissues. Considering that increased intratumoral Tregs have been shown to promote tumor immune evasion, our data may provide new insights into the pathogenesis of HBV pre-S2 mutant-induced HCC and suggest that therapeutics targeting Tregs may be a promising strategy for treating pre-S2 mutant-positive high-risk patient population.
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20
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McGee MC, August A, Huang W. TCR/ITK Signaling in Type 1 Regulatory T cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1278:115-124. [PMID: 33523446 DOI: 10.1007/978-981-15-6407-9_7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Type 1 regulatory T (Tr1) cells can modulate inflammation through multiple direct and indirect molecular and cellular mechanisms and have demonstrated potential for anti-inflammatory therapies. Tr1 cells do not express the master transcription factor of conventional regulatory T cells, Foxp3, but express high levels of the immunomodulatory cytokine, IL-10. IL-2-inducible T-cell kinase (ITK) is conserved between mouse and human and is highly expressed in T cells. ITK signaling downstream of the T-cell receptor (TCR) is critical for T-cell subset differentiation and function. Upon activation by TCR, ITK is critical for Ras activation, leading to downstream activation of MAPKs and upregulation of IRF4, which further enable Tr1 cell differentiation and suppressive function. We summarize here the structure, signaling pathway, and function of ITK in T-cell lineage designation, with an emphasis on Tr1 cell development and function.
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Affiliation(s)
- Michael C McGee
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA
| | - Avery August
- Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
| | - Weishan Huang
- Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA. .,Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA.
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21
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Dafni U, Martín-Lluesma S, Balint K, Tsourti Z, Vervita K, Chenal J, Coukos G, Zaman K, Sarivalasis A, Kandalaft LE. Efficacy of cancer vaccines in selected gynaecological breast and ovarian cancers: A 20-year systematic review and meta-analysis. Eur J Cancer 2020; 142:63-82. [PMID: 33221598 DOI: 10.1016/j.ejca.2020.10.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/29/2020] [Accepted: 10/08/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND Therapeutic cancer vaccination is an area of interest, even though promising efficacy has not been demonstrated so far. DESIGN A systematic review and meta-analysis was conducted to evaluate vaccines' efficacy on breast cancer (BC) and ovarian cancer (OC) patients. Our search was based on the PubMed electronic database, from 1st January 2000 to 4th February 2020. OBJECTIVE response rate (ORR) was the primary end-point of interest, while progression-free survival (PFS), overall survival (OS) and toxicity were secondary end-points. Analysis was performed separately for BC and OC patients. Pooled ORRs were estimated by fixed or random effects models, depending on the detected degree of heterogeneity, for all studies with more than five patients. Subgroup analyses by vaccine type and treatment schema as well as sensitivity analyses, were implemented. RESULTS Among 315 articles initially identified, 67 were eligible for our meta-analysis (BC: 46, 1698 patients; OC: 32, 426 patients; where both BC/OC in 11). Dendritic-cell and peptide vaccines were found in more studies, 6/10 BC and 10/13 OC studies, respectively. In our primary BC analysis (21 studies; 428 patients), the pooled ORR estimate was 9% (95%CI[5%,13%]). The primary OC analysis (12 studies; 182 patients), yielded pooled ORR estimate of 4% (95%CI[1%,7%]). Similar were the results derived in sensitivity analyses. No statistically significant differences were detected by vaccine type or treatment schema. Median PFS was 2.6 months (95% confidence interval (CI)[1.9,2.9]) and 13.0 months (95%CI[8.5,16.3]) for BC and OC respectively, while corresponding median OS was 24.8 months (95%CI[15.0,46.0]) and 39.0 months (95%CI[31.0,49.0]). In almost all cases, the observed toxicity was only moderate. CONCLUSION Despite their modest results in terms of ORR, therapeutic vaccines in the last 20 years display relatively long survival rates and low toxicity. Since a plethora of different approaches have been tested, a better understanding of the underlying mechanisms is needed in order to further improve vaccine efficacy.
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Affiliation(s)
- U Dafni
- Department of Oncology, CHUV, University of Lausanne, Lausanne, Switzerland; Faculty of Nursing, National and Kapodistrian University of Athens, Athens, Greece
| | - S Martín-Lluesma
- Departamento de Ciencias Médicas Básicas, Facultad de Medicina, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla Del Monte, Madrid, 28668, Spain
| | - K Balint
- Department of Oncology, CHUV, University of Lausanne, Lausanne, Switzerland
| | - Z Tsourti
- Scientific Research Consulting Hellas, Statistics Center, Athens, Greece
| | - K Vervita
- Scientific Research Consulting Hellas, Statistics Center, Athens, Greece
| | - J Chenal
- Department of Oncology, CHUV, University of Lausanne, Lausanne, Switzerland
| | - G Coukos
- Department of Oncology, CHUV, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland
| | - K Zaman
- Department of Oncology, CHUV, University of Lausanne, Lausanne, Switzerland
| | - A Sarivalasis
- Department of Oncology, CHUV, University of Lausanne, Lausanne, Switzerland
| | - L E Kandalaft
- Department of Oncology, CHUV, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.
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22
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Mannie MD, DeOca KB, Bastian AG, Moorman CD. Tolerogenic vaccines: Targeting the antigenic and cytokine niches of FOXP3 + regulatory T cells. Cell Immunol 2020; 355:104173. [PMID: 32712270 PMCID: PMC7444458 DOI: 10.1016/j.cellimm.2020.104173] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/06/2020] [Accepted: 07/10/2020] [Indexed: 02/06/2023]
Abstract
FOXP3+ regulatory T cells (Tregs) constitute a critical barrier that enforces tolerance to both the self-peptidome and the extended-self peptidome to ensure tissue-specific resistance to autoimmune, allergic, and other inflammatory disorders. Here, we review intuitive models regarding how T cell antigen receptor (TCR) specificity and antigen recognition efficiency shape the Treg and conventional T cell (Tcon) repertoires to adaptively regulate T cell maintenance, tissue-residency, phenotypic stability, and immune function in peripheral tissues. Three zones of TCR recognition efficiency are considered, including Tcon recognition of specific low-efficiency self MHC-ligands, Treg recognition of intermediate-efficiency agonistic self MHC-ligands, and Tcon recognition of cross-reactive high-efficiency agonistic foreign MHC-ligands. These respective zones of TCR recognition efficiency are key to understanding how tissue-resident immune networks integrate the antigenic complexity of local environments to provide adaptive decisions setting the balance of suppressive and immunogenic responses. Importantly, deficiencies in the Treg repertoire appear to be an important cause of chronic inflammatory disease. Deficiencies may include global deficiencies in Treg numbers or function, subtle 'holes in the Treg repertoire' in tissue-resident Treg populations, or simply Treg insufficiencies that are unable to counter an overwhelming molecular mimicry stimulus. Tolerogenic vaccination and Treg-based immunotherapy are two therapeutic modalities meant to restore dominance of Treg networks to reverse chronic inflammatory disease. Studies of these therapeutic modalities in a preclinical setting have provided insight into the Treg niche, including the concept that intermediate-efficiency TCR signaling, high IFN-β concentrations, and low IL-2 concentrations favor Treg responses and active dominant mechanisms of immune tolerance. Overall, the purpose here is to assimilate new and established concepts regarding how cognate TCR specificity of the Treg repertoire and the contingent cytokine networks provide a foundation for understanding Treg suppressive strategy.
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Affiliation(s)
- Mark D Mannie
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States.
| | - Kayla B DeOca
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Alexander G Bastian
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Cody D Moorman
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
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23
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Yuan C, Liu Y, Wang T, Sun M, Chen X. Nanomaterials as Smart Immunomodulator Delivery System for Enhanced Cancer Therapy. ACS Biomater Sci Eng 2020; 6:4774-4798. [DOI: 10.1021/acsbiomaterials.0c00804] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Congshan Yuan
- College of Marine Life Science, Ocean University of China, Qingdao 266003, P.R. China
| | - Ya Liu
- College of Marine Life Science, Ocean University of China, Qingdao 266003, P.R. China
| | - Ting Wang
- College of Marine Life Science, Ocean University of China, Qingdao 266003, P.R. China
| | - Mengjie Sun
- College of Marine Life Science, Ocean University of China, Qingdao 266003, P.R. China
| | - Xiguang Chen
- College of Marine Life Science, Ocean University of China, Qingdao 266003, P.R. China
- Qingdao National Laboratory for Marine Science and Technology, Qingdao 266000, P.R. China
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Cadmus SI, Akinseye VO, Taiwo BO, Pinelli EO, van Soolingen D, Rhodes SG. Interactions between helminths and tuberculosis infections: Implications for tuberculosis diagnosis and vaccination in Africa. PLoS Negl Trop Dis 2020; 14:e0008069. [PMID: 32498074 PMCID: PMC7272205 DOI: 10.1371/journal.pntd.0008069] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Africa is the second most populous continent and has perennial health challenges. Of the estimated 181 million school aged children in sub-Saharan Africa (SSA), nearly half suffer from ascariasis, trichuriasis, or a combination of these infections. Coupled with these is the problem of tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection, which is a leading cause of death in the region. Compared to the effect of the human immunodeficiency virus on the development of TB, the effect of chronic helminth infections is a neglected area of research, yet helminth infections are as ubiquitous as they are varied and may potentially have profound effects upon host immunity, particularly as it relates to TB infection, diagnosis, and vaccination. Protection against active TB is known to require a clearly delineated T-helper type 1 (Th1) response, while helminths induce a strong opposing Th2 and immune-regulatory host response. This Review highlights the potential challenges of helminth-TB co-infection in Africa and the need for further research.
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Affiliation(s)
- Simeon I. Cadmus
- Depeartment of Veterinary Public Health & Preventive Medicine, University of Ibadan, Ibadan, Nigeria
- Centre for Control and Prevention of Zoonoses, University of Ibadan, Ibadan, Nigeria
| | - Victor O. Akinseye
- Depeartment of Veterinary Public Health & Preventive Medicine, University of Ibadan, Ibadan, Nigeria
| | - Babafemi O. Taiwo
- Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - Elena O. Pinelli
- Center for Infectious Disease Control Netherlands (CIb), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
| | - Dick van Soolingen
- Center for Infectious Disease Control Netherlands (CIb), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands
- Department of Medical Microbiology, Radboud University Medical Center Nijmegen, the Netherlands
| | - Shelley G. Rhodes
- TB Research Group, Animal and Plant Health Agency, Surrey, United Kingdom
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Fatehi F, Kyrychko YN, Blyuss KB. Stochastic dynamics in a time-delayed model for autoimmunity. Math Biosci 2020; 322:108323. [PMID: 32092469 DOI: 10.1016/j.mbs.2020.108323] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 01/21/2020] [Accepted: 02/10/2020] [Indexed: 12/18/2022]
Abstract
In this paper we study interactions between stochasticity and time delays in the dynamics of immune response to viral infections, with particular interest in the onset and development of autoimmune response. Starting with a deterministic time-delayed model of immune response to infection, which includes cytokines and T cells with different activation thresholds, we derive an exact delayed chemical master equation for the probability density. We use system size expansion and linear noise approximation to explore how variance and coherence of stochastic oscillations depend on parameters, and to show that stochastic oscillations become more regular when regulatory T cells become more effective at clearing autoreactive T cells. Reformulating the model as an Itô stochastic delay differential equation, we perform numerical simulations to illustrate the dynamics of the model and associated probability distributions in different parameter regimes. The results suggest that even in cases where the deterministic model has stable steady states, in individual stochastic realisations, the model can exhibit sustained stochastic oscillations, whose variance increases as one gets closer to the deterministic stability boundary. Furthermore, in the regime of bi-stability, whereas deterministically the system would approach one of the steady states (or periodic solutions) depending on the initial conditions, due to the presence of stochasticity, it is now possible for the system to reach both of those dynamical states with certain probability. Biological significance of this result lies in highlighting the fact that since normally in a laboratory or clinical setting one would observe a single individual realisation of the course of the disease, even for all parameters characterising the immune system and the strength of infection being the same, there is a proportion of cases where a spontaneous recovery can be observed, and similarly, where a disease can develop in a situation that otherwise would result in a normal disease clearance.
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Affiliation(s)
- Farzad Fatehi
- Department of Mathematics, University of York, York YO10 5DD, UK.
| | - Yuliya N Kyrychko
- Department of Mathematics, University of Sussex, Falmer, Brighton BN1 9QH, UK.
| | - Konstantin B Blyuss
- Department of Mathematics, University of Sussex, Falmer, Brighton BN1 9QH, UK.
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Chen WT, Wei JF, Wang L, Zhang DW, Tang W, Wang J, Yong Y, Wang J, Zhou YL, Yuan L, Fu GQ, Wang S, Song JG. Effects of perioperative transcutaneous electrical acupoint stimulation on monocytic HLA-DR expression in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass: study protocol for a double-blind randomized controlled trial. Trials 2019; 20:789. [PMID: 31888744 PMCID: PMC6937832 DOI: 10.1186/s13063-019-3889-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 11/06/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Cardiac surgery involving cardiopulmonary bypass (CPB) is known to be associated with a transient postoperative immunosuppression. When severe and persistent, this immune dysfunction predisposes patients to infectious complications, which contributes to a prolonged stay in the intensive care unit (ICU), and even mortality. Effective prevention and treatment methods are still lacking. Recent studies revealed that acupuncture-related techniques, such as electroacupuncture and transcutaneous electrical acupoint stimulation (TEAS), are able to produce effective cardioprotection and immunomodulation in adult and pediatric patients undergoing cardiac surgery with CPB, which leads to enhanced recovery. However, whether perioperative application of TEAS, a non-invasive technique, is able to improve immunosuppression of the patients with post-cardiosurgical conditions is unknown. Thus, as a preliminary study, the main objective is to evaluate the effects of TEAS on the postoperative expression of monocytic human leukocyte antigen (-D related) (mHLA-DR), a standardized "global" biomarker of injury or sepsis-associated immunosuppression, in patients receiving on-pump coronary artery bypass grafting (CABG). METHODS This study is a single-center clinical trial. The 88 patients scheduled to receive CABG under CPB will be randomized into two groups: the group receiving TEAS, and the group receiving transcutaneous acupoint pseudo-electric stimulation (Sham TEAS). Expression of mHLA-DR serves as a primary endpoint, and other laboratory parameters (e.g., interleukin [IL]-6, IL-10) and clinical outcomes (e.g., postoperative infectious complications, ICU stay time, and mortality) as the secondary endpoints. In addition, immune indicators, such as high mobility group box 1 protein and regulatory T cells will also be measured. DISCUSSION The current study is a preliminary monocentric clinical trial with a non-clinical primary endpoint, expression of mHLA-DR, aiming at determining whether perioperative application of TEAS has a potential to reverse CABG-associated immunosuppression. Although the immediate clinical impact of this study is limited, its results would inform further large-sample clinical trials using relevant patient-centered clinical outcomes as primary endpoints. TRIAL REGISTRATION ClinicalTrials.gov, NCT02933996. Registered on 13 October 2016.
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Affiliation(s)
- Wen-ting Chen
- Anesthesiology Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jin-feng Wei
- Guangdong Cardiovascular Institute & Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province China
- Shantou University Medical College, Shantou, Guangdong Province China
| | - Lan Wang
- Anesthesiology Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Deng-wen Zhang
- Guangdong Cardiovascular Institute & Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province China
| | - Wei Tang
- Anesthesiology Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jian Wang
- Anesthesiology Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yue Yong
- Anesthesiology Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Wang
- Anesthesiology Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ya-lan Zhou
- Anesthesiology Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lan Yuan
- Anesthesiology Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guo-qiang Fu
- Anesthesiology Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Sheng Wang
- Guangdong Cardiovascular Institute & Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province China
| | - Jian-gang Song
- Anesthesiology Department, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Acupuncture and Anesthesia Research Institute, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Whiteside TL. Human regulatory T cells (Treg) and their response to cancer. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2019; 4:215-228. [PMID: 32953989 PMCID: PMC7500484 DOI: 10.1080/23808993.2019.1634471] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 06/18/2019] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Regulatory T cells (Treg) and their role in health and disease is being intensively investigated. Today, human Treg emerge as a highly heterogeneous subset of CD4+ T cells which mediate immune suppression but also regulate responses of non-immune cells. In cancer, Treg occupy a critical although not yet entirely understood role. AREAS COVERED Newly acquired insights into Treg indicate a much greater plasticity and functional heterogeneity of this T cell subset than was previously known. Functional redundancy of Treg and their interactions with a variety of immune and non-immune cellular targets emphasize the central role Treg play in cancer. Treg not only regulate the host responses to cancer; they may also regulate responses to immune therapies. The impact of immune checkpoint blockade on Treg survival, stability and suppressive activity remains to be elucidated. T cell reprogramming by tumor-derived factors, including tumor-derived exosomes (TEX), plays a key role in shaping the Treg repertoire in the tumor microenvironment (TME). The reprogrammed or induced iTreg acquire capabilities to strongly down-regulate anti-tumor immune responses by mechanisms that are specific for each TME. Therapeutic silencing of such Treg calls for the discrimination of "bad" from "good" Treg subsets, an approach that remains elusive in the absence of a definitive "Treg signature." EXPERT OPINION Context-related plasticity and heterogeneity of Treg in the TME are significant barriers to selective therapeutic depletion of those Treg subsets that are reprogramed by the tumor to suppress anti-tumor immunity.
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Affiliation(s)
- Theresa L. Whiteside
- Departments of Pathology, Immunology and Otolaryngology, University of Pittsburgh School of Medicine and UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA
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Abstract
Daclizumab is a humanized monoclonal antibody that prevents formation of high-affinity interleukin (IL)-2 receptor (IL-2R). Because activated T cells up-regulate high-affinity IL-2R and IL-2 is used to grow activated T cells in vitro, daclizumab was envisioned to selectively inhibit activated T cells. However, the mechanism of action (MOA) of daclizumab is surprisingly broad and it includes many unanticipated effects on innate immunity. Specifically, daclizumab modulates the development of innate lymphoid cells, leading to expansion of immunoregulatory CD56bright natural killer (NK) cells. Activated CD56bright NK cells migrate to the intrathecal compartment in multiple sclerosis (MS) and regulate autoreactive T cells via cytotoxicity. Finally, daclizumab also restricts initial steps of T-cell activation by blocking trans-presentation of IL-2 by dendritic cells to antigen-specific T cells. In conclusion, daclizumab has complex immunomodulatory effects with resultant inhibition of central nervous system inflammation in MS.
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Affiliation(s)
- Bibiana Bielekova
- Neuroimmunological Diseases Unit (NDU), Neuroimmunology Branch (NIB), National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), Bethesda, Maryland 20892
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Xiao J, Zhang L, Dong Y, Liu X, Peng L, Yang Y, Wang Y. PD-1 Upregulation Is Associated with Exhaustion of Regulatory T Cells and Reflects Immune Activation in HIV-1-Infected Individuals. AIDS Res Hum Retroviruses 2019; 35:444-452. [PMID: 30618263 DOI: 10.1089/aid.2018.0218] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
We hypothesized that PD-1expressed by regulatory T cells (Tregs) would be functional and their expression levels may associate with activation status of CD4+ T and CD8+ T cells and the disease progression of HIV-1-infected patients. To prove it, we dynamically examined PD-1 expression levels by Tregs in peripheral blood of HIV-1-infected individuals not receiving antiretroviral therapy. Eighty-one HIV-1-infected individuals not undergoing antiretroviral therapy and 22 HIV-1-seronegative donors were enrolled in our study. Tregs were defined as CD4+CD25+CD127lo/- by flow cytometry. Expression of PD-1 and the activation markers CD38, HLA-DR, and Ki67 by Tregs and CD4+ T and CD8+ T cells was also determined by flow cytometry. TGF-β and IL-10 were measured to evaluate the suppressive function of Tregs. In all Tregs, the proportion of PD-1+ Tregs observed in HIV-1-infected persons was significantly greater than that seen in HIV-1-seronegative donors, and correlated with the activation of Tregs and CD4+ T and CD8+ T cells. This increased proportion of Tregs was also statistically associated with the disease progression. Blockade of PD-1/PD-L1 pathway with anti-PD-L1 mAb profoundly increased the level of intracellular TGF-β and IL-10 in CD4+CD25+CD127lo/- Tregs. Our data not only support that PD-1 plays a critical role to predict the activation status of cellular immunity and disease progression during HIV-1 infection but also indicate that blockade of PD-1/PD-L1 pathway represents a novel therapeutic approach to AIDS.
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Affiliation(s)
- Jian Xiao
- Department of Immunology, GuangXi University of Chinese Medicine, Nanning, China
- GuangXi Medical Transformational Key Laboratory of Combine Traditional Chinese and Western Medicine and High Incidence of Infectious Diseases, Nanning, China
- Department of AIDS/STD, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
| | - Lifeng Zhang
- Department of Immunology, GuangXi University of Chinese Medicine, Nanning, China
- GuangXi Medical Transformational Key Laboratory of Combine Traditional Chinese and Western Medicine and High Incidence of Infectious Diseases, Nanning, China
| | - Yuan Dong
- Department of AIDS/STD, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
| | - Xian Liu
- Department of Immunology, GuangXi University of Chinese Medicine, Nanning, China
- GuangXi Medical Transformational Key Laboratory of Combine Traditional Chinese and Western Medicine and High Incidence of Infectious Diseases, Nanning, China
| | - Lishan Peng
- Department of Immunology, GuangXi University of Chinese Medicine, Nanning, China
- GuangXi Medical Transformational Key Laboratory of Combine Traditional Chinese and Western Medicine and High Incidence of Infectious Diseases, Nanning, China
| | - Yang Yang
- Department of Immunology, GuangXi University of Chinese Medicine, Nanning, China
- GuangXi Medical Transformational Key Laboratory of Combine Traditional Chinese and Western Medicine and High Incidence of Infectious Diseases, Nanning, China
| | - Ying Wang
- Department of AIDS/STD, Shanghai Municipal Center for Disease Control and Prevention, Shanghai, China
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Saito M, Otsuka K, Ushio A, Yamada A, Arakaki R, Kudo Y, Ishimaru N. Unique Phenotypes and Functions of Follicular Helper T Cells and Regulatory T Cells in Sjögren's Syndrome. Curr Rheumatol Rev 2019; 14:239-245. [PMID: 28124612 PMCID: PMC6225342 DOI: 10.2174/1573397113666170125122858] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 01/13/2017] [Accepted: 01/23/2017] [Indexed: 02/07/2023]
Abstract
Sjogren’s syndrome (SS) is a T cell-mediated autoimmune disease of the systemic exocrine glands, such as salivary and lacrimal glands. A variety of T-cell subpopulations maintain immune tolerance in the thymus and periphery through complex immune responses including cellular and humoral immunity. The T-cell subpopulations exhibiting abnormal or unique phenotypes and impaired functionality have been reported to play important roles in the cellular mechanisms of autoimmunity in SS patients and animal models of SS. In this review, we focused on follicular helper T cells related to antibody production and regulatory T cells to control immune tolerance in the pathogenesis of SS. The unique roles of these T-cell subpopulations in the process of the onset or development of SS have been demonstrated in this review of recent publications. The clinical application of these T-cell subpopulations will be helpful for the development of new techniques for diagnosis or treatment of SS in the future.
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Affiliation(s)
- Masako Saito
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Kunihiro Otsuka
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Aya Ushio
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Akiko Yamada
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Rieko Arakaki
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Yasusei Kudo
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
| | - Naozumi Ishimaru
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan
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Hu Y, Zhou H, Gao B, Wang G, Wang Y. Role of regulatory T cells in CD47/donor-specific transfusion-induced immune tolerance in skin-heart transplantation mice. Transpl Infect Dis 2018; 21:e13012. [PMID: 30320937 DOI: 10.1111/tid.13012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 08/10/2018] [Accepted: 08/21/2018] [Indexed: 11/30/2022]
Abstract
OBJECTIVES To explore the role of regulatory T (Treg ) cells in the establishment of immune tolerance induced by donor-specific transfusion (DST) in mice with skin-heart transplantation. METHODS C57BL/6 mice received DST of splenocytes from CD47+/+ or CD47-/- H-2bm1 mice or no DST 7 days before skin-heart transplantation from major histocompatibility complex class I-mismatched H-2bm1 donors. The number and proportion of Treg cells in graft and lymphoid organs were measured by flow cytometry (FACS) and immunohistochemistry (IHC). The inhibitory function of Treg cells and anti-donor T-cell responses were assessed by mixed lymphocyte reaction. RESULTS We observed that mean survival time (MST) of skin or heart graft was significantly longer in C57BL/6 mice which received DST from CD47+/+ H-2bm1 mice than from CD47-/- H-2bm1 mice. By FACS, we found that the number of Treg cells in spleen was increased significantly in mice which received CD47-/- DST compared to mice which received CD47+/+ DST. However, the percentages of Treg cells in total splenocytes and lymph node cells were significantly higher in mice that received CD47+/+ DST than mice which received CD47-/- DST. Immunohistochemistry showed an increased heart grafts infiltration of Treg cells in the recipients with CD47-/- DST, but not CD47+/+ DST. Supporting this, we found that donor T-cell proliferation was significantly suppressed in mice which received CD47+/+ DST compared to mice which received CD47-/- DST. There was no difference of inhibitory function of Treg cells between these two groups. CONCLUSION Our results indicated that CD47 expression on DST cells plays an important role in the induction of immune tolerance in mice with skin-heart transplantation. Increased percentage of Treg cells may contribute to immune tolerance induced by CD47+/+ DST.
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Affiliation(s)
- Yu Hu
- Department of Pathology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Honglan Zhou
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Baoshan Gao
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Gang Wang
- Department of Urology, The First Hospital of Jilin University, Changchun, China
| | - Yuantao Wang
- Department of Urology, The First Hospital of Jilin University, Changchun, China
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Relationship of Transforming Growth Factor-βl and Arginase-1 Levels with Long-term Survival after Kidney Transplantation. Curr Med Sci 2018; 38:455-460. [PMID: 30074212 DOI: 10.1007/s11596-018-1900-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Revised: 03/27/2018] [Indexed: 10/28/2022]
Abstract
In this study, we compared the serum levels of transforming growth factor-pi (TGF-β1), interleukin-10 (IL-10), and arginase-1 in long-term survival kidney transplant recipients (LTSKTRs) with those in short-term survival kidney transplant recipients (STSKTRs). We then evaluated the relationship between these levels and graft function. Blood samples were collected from 50 adult LTSKTRs and 20 STSKTRs (graft survival approximately 1-3 years post-transplantation). All patients had stable kidney function. The samples were collected at our institution during the patients' follow-up examinations between March 2017 and September 2017. The plasma levels of TGF-β1, IL-10, and arginase-1 were analyzed using enzyme-linked immunosorbent assays (ELIS A). The levels of TGF-β1 and arginase-1 were significantly higher in the LTSKTRs than in the STSKTRs. The time elapsed since transplantation was positively correlated with the levels of TGF-β1 and arginase-1 in the LTSKTRs. The estimated glomerular filtration rate was positively correlated with the TGF-β1 level, and the serum creatinine level was negatively correlated with the TGF-β1 level. Higher serum levels of TGF-pi and arginase-1 were found in LTSKTRs than in STSKTRs, and we found that TGF-β1 was positively correlated with long-term graft survival and function. Additionally, TGF-β1 and arginase-1 levels were positively correlated with the time elapsed since transplantation. On the basis of these findings, TGF-β1 and arginase-1 may play important roles in determining long-term graft survival. Thus, we propose that TGF-pi and arginase-1 may potentially be used as predictive markers for evaluating long-term graft survival.
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Shevach EM. Foxp3 + T Regulatory Cells: Still Many Unanswered Questions-A Perspective After 20 Years of Study. Front Immunol 2018; 9:1048. [PMID: 29868011 PMCID: PMC5962663 DOI: 10.3389/fimmu.2018.01048] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 04/27/2018] [Indexed: 01/03/2023] Open
Abstract
T regulatory (Treg) cells were discovered more than 20 years ago and have remained a topic of intense investigation by immunologists. The initial doubts about their existence were dissipated by the discovery in 2003 of the lineage specific transcription factor Foxp3. In this article, I will discuss some of the questions that I believe still need to be answered before we will be able to fully apply Treg therapy to the clinic. The major issue that remains to be resolved is how they mediate their suppressive functions. In order to correct defective suppression in autoimmune disease (assuming it is a causative factor) or to augment suppression in graft versus host disease or during organ transplantation, we still need to fully understand the biochemical nature of suppressor mechanisms. Similarly, in cancer, it is now widely accepted that reversal of Treg suppression would be highly desirable, yet which of the many purported pathways of suppression are operative in different tumors in different anatomic sites. Many of the concepts we have developed are based on in vitro studies, and it remains unclear if these concepts can readily be applied to Treg function in vivo. Our lack of a specific cell surface marker that readily allows us to identify and target Treg in vivo, particularly in man, remains a major stumbling block. Finally, I will review in some detail controversies regarding the origin of Treg, thymus versus periphery, and attempts to reverse Treg suppression by targeting antigens on their cell surface, particularly members of the TNF receptor superfamily. Hopefully, these areas of controversy will be resolved by in depth studies over the next few years and manipulation of Treg function will be placed on a more solid experimental footing.
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Affiliation(s)
- Ethan M Shevach
- Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States
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Autoimmune Hepatitis and Autoimmune Hepatitis Overlap With Sclerosing Cholangitis: Immunophenotype Markers in Children and Adolescents. J Pediatr Gastroenterol Nutr 2018; 66:204-211. [PMID: 29045346 DOI: 10.1097/mpg.0000000000001783] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
OBJECTIVE The pathophysiology of autoimmune hepatitis (AIH) may involve the activation of immune cells and changes in the expression of cellular markers. The aim of the present study was to characterize the immunophenotype markers of lymphocytes and monocytes in the peripheral blood of children and adolescents with type 1 AIH and AIH overlap with sclerosing cholangitis (overlap syndrome [OS]). METHODS This is a cross-sectional study of 20 children and adolescents diagnosed with type 1 AIH and 19 with OS. Fifteen healthy subjects were included as controls. Flow cytometric analysis was used to identify markers of inflammation and autoimmunity. RESULTS The total number of CD4 T cells was higher in the AIH patients compared with the controls. The number of CD4 T cells expressing CCR3 and CD28 was higher in the AIH group than in the control group. CD45RO was more highly expressed in the AIH group, whereas CD45RA was more highly expressed in the OS group. In regard to CD8 T lymphocytes, the CCR3 expression was higher in both groups of patients. Patients with OS had the highest expression of CD45RA and CD25. In monocytes, human leukocyte antigen DR (HLA-DR) was less expressed in both groups of patients. CONCLUSIONS Complex phenotype features may be involved in the pathophysiology of AIH, accounting for changes in immune system regulation mechanisms. In conclusion, even after good response to treatment, patients still have immune activity signals at the cellular level.
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36
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Li G, Quan Y, Che F, Wang L. B7-H3 in tumors: friend or foe for tumor immunity? Cancer Chemother Pharmacol 2018; 81:245-253. [PMID: 29299639 DOI: 10.1007/s00280-017-3508-1] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 12/21/2017] [Indexed: 12/11/2022]
Abstract
B7-H3 is a type I transmembrane co-stimulatory molecule of the B7 family. B7-H3 mRNA is widely distributed in most tissues; however, B7-H3 protein is not constitutively expressed. Few molecules have been shown to mediate the regulation of B7-H3 expression, and their regulatory mechanisms remain unexplored. Recently, TREM-like transcript 2 (TLT-2) has been identified as a potential receptor of B7-H3. However, TLT-2 may not be the only receptor of B7-H3, as B7-H3 has many contradictory roles. As a co-stimulatory molecule, B7-H3 increases the proliferation of both CD4+ and CD8+ T-cells and enhances cytotoxic T-cell activity. However, greatly increased T-cell proliferation and IL-2 levels have been observed in the absence of B7-H3. Thus far, it has been shown that various tumors test positive for B7-H3 expression and that B7-H3 levels correlate with tumor growth, invasion, metastasis, malignant stage, and recurrence rate. Furthermore, transfection of cells with a B7-H3 plasmid and treatment with monoclonal antibodies to block B7-H3 are the main immunotherapeutic strategies for cancer treatment. Several groups have generated anti-B7-H3 antibodies and observed tumor growth suppression in vitro and in vivo. Therefore, it is likely that B7-H3 plays an important role in cancer diagnosis and treatment, aside from its role as a co-stimulatory molecule.
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Affiliation(s)
- Gen Li
- Department of Neurology, Clinical Medicine College, Weifang Medical University, No. 7166, Baotong West Street, Weifang city, Shandong Province, 261053, China.,Central Laboratory, Linyi People's Hospital, Shandong University, NB27, Eastern Part of Jiefang Road, Lanshan District, Linyi city, Shandong Province, 276000, China
| | - Yanchun Quan
- Central Laboratory, Linyi People's Hospital, Shandong University, NB27, Eastern Part of Jiefang Road, Lanshan District, Linyi city, Shandong Province, 276000, China
| | - Fengyuan Che
- Central Laboratory, Linyi People's Hospital, Shandong University, NB27, Eastern Part of Jiefang Road, Lanshan District, Linyi city, Shandong Province, 276000, China. .,Department of Neurology, Linyi People's Hospital, Shandong University, NB27, Eastern Part of Jiefang Road, Lanshan District, Linyi city, Shandong Province, 276000, China.
| | - Lijuan Wang
- Central Laboratory, Linyi People's Hospital, Shandong University, NB27, Eastern Part of Jiefang Road, Lanshan District, Linyi city, Shandong Province, 276000, China. .,Department of Hematology, Linyi People's Hospital, Shandong University, NB27, Eastern Part of Jiefang Road, Lanshan District, Linyi city, Shandong Province, 276000, China.
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Schlöder J, Berges C, Tuettenberg A, Jonuleit H. Novel Concept of CD4-Mediated Activation of Regulatory T Cells for the Treatment of Graft-Versus-Host Disease. Front Immunol 2017; 8:1495. [PMID: 29167672 PMCID: PMC5682297 DOI: 10.3389/fimmu.2017.01495] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 10/24/2017] [Indexed: 01/28/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation is the only curative treatment option for several hematological malignancies and immune deficiency syndromes. Nevertheless, the development of a graft-versus-host disease (GvHD) after transplantation is a high risk and a severe complication with high morbidity and mortality causing therapeutic challenges. Current pharmacological therapies of GvHD lead to generalized immunosuppression followed by severe adverse side effects including infections and relapse of leukemia. Several novel cell-based immunomodulatory strategies for treatment or prevention of GvHD have been developed. Herein, thymus-derived regulatory T cells (tTreg), essential for the maintenance of peripheral immunologic tolerance, are in the focus of investigation. However, due to the limited number of tTreg in the peripheral blood, a complex, time- and cost-intensive in vitro expansion protocol is necessary for the production of an efficient cellular therapeutic. We demonstrated that activation of tTreg using the CD4-binding human immunodeficiency virus-1 protein gp120 leads to a substantially increased suppressor activity of tTreg without the need for additional expansion. Gp120-activated tTreg prevent GvHD development in a preclinical humanized mouse model. In addition, gp120 is not only effective in prevention but also in therapy of GvHD by suppressing all clinical symptoms and improving survival of treated mice. These data indicate that tTreg activation by gp120 is a feasible and potent strategy for significant functional improvement of tTreg as cellular therapeutic for GvHD treatment without the need of complicated, time-intensive, and expensive in vitro expansion of isolated tTreg.
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Affiliation(s)
- Janine Schlöder
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Carsten Berges
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Andrea Tuettenberg
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
| | - Helmut Jonuleit
- Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany
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Abstract
Foxp3+ regulatory T cells (Tregs) play an indispensable role in controlling tolerance and immunity against self- and foreign antigens. The failure of Tregs to properly function is the direct cause of systemic and chronic inflammation as well as immune suppression. It is now evident that Tregs are highly heterogeneous populations depending on the surface phenotypes, cytokine profiles, and anatomical locations. Yet, our understanding of the cellular and molecular pathways underlying such heterogeneity is very limited. Furthermore, some Tregs lose the phenotype (and suppressive functions) and instead acquire pathogenicity. Since utilizing Tregs as a tool for immunotherapy is being implemented in many clinical settings, it is of utmost importance to understand the precise mechanisms by which the loss of Treg phenotype (and function) is prevented. In this review, both cellular and molecular factors involved in Treg heterogeneity and stability are discussed.
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Affiliation(s)
- Booki Min
- Department of Immunology/NB30, Lerner Research Institute , Cleveland Clinic Foundation, Cleveland, Ohio
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Almon E, Khoury T, Drori A, Gingis-Velitski S, Alon S, Chertkoff R, Mushkat M, Shaaltiel Y, Ilan Y. An oral administration of a recombinant anti-TNF fusion protein is biologically active in the gut promoting regulatory T cells: Results of a phase I clinical trial using a novel oral anti-TNF alpha-based therapy. J Immunol Methods 2017; 446:21-29. [PMID: 28392436 DOI: 10.1016/j.jim.2017.03.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Revised: 03/30/2017] [Accepted: 03/30/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND An orally administered BY-2 plant cell-expressed recombinant anti-TNF fusion protein (PRX-106) consists of the soluble form of the human TNF receptor (TNFR) fused to the Fc component of a human IgG1 domain. Aim This study aim at determining the safety and the immune modulatory effect of an oral administration of PRX-106 in humans. METHODS Three different doses (2, 8 or 16mg/day) of PRX-106 were orally administered for five consecutive days in 14 healthy volunteered participants. Subjects were followed for safety parameters and for an effect on T lymphocytes subsets and cytokine levels. RESULTS An oral administration of PRX-106 was safe and well tolerated. The PK study showed that PRX106 is not absorbed. No effect on white blood cells and lymphocytes counts were noted. A dose dependent effect was noted on systemic lymphocytes. The oral administration of all three dosages was associated with an increase in CD4+CD25+ and CD8+CD25+ subset of suppressor lymphocytes. A marked increase in CD4+CD25+FoxP3 regulatory T cells was noted in the 8mg treated group. In addition, NKT regulatory cells, CD3+CD69+ and CD4+CD62 lymphocyte subsets increased with treatment. No changes in serum TNF alpha were observed. CONCLUSION An oral administration of the non-absorbable recombinant anti-TNF fusion protein, PRX-106, is safe, not associated with immune suppression, while inducing a favorable anti-inflammatory immune modulation. The PRX-106 may provide a safe orally administered effective anti-TNF alpha-based immune therapy for inflammatory bowel diseases and non-alcoholic steatohepatitis, as well as other autoimmune, TNF-mediated diseases.
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Affiliation(s)
| | - Tawfik Khoury
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Ariel Drori
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | | | | | | | - Mordechai Mushkat
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | | | - Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
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Mishra R, Panda SK, Sahoo PK, Bal MS, Satapathy AK. Increased Fas ligand expression of peripheral B-1 cells correlated with CD4+T-cell apoptosis in filarial-infected patients. Parasite Immunol 2017; 39. [DOI: 10.1111/pim.12421] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 02/09/2017] [Indexed: 01/09/2023]
Affiliation(s)
- R. Mishra
- Regional Medical Research Centre (ICMR); Bhubaneswar Odisha India
| | - S. K. Panda
- Institutes of Life Sciences (DBT); Bhubaneswar Odisha India
| | - P. K. Sahoo
- Regional Medical Research Centre (ICMR); Bhubaneswar Odisha India
| | - M. S. Bal
- Regional Medical Research Centre (ICMR); Bhubaneswar Odisha India
| | - A. K. Satapathy
- Regional Medical Research Centre (ICMR); Bhubaneswar Odisha India
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Ding L, Zhu H, Yang Y, Yan HM, Zhang HH, Han DM, Wang ZD, Zheng XL, Liu J, Zhu L, Mei-Xue, Guo ZK, Wang HX. The absolute number of regulatory T cells in unmanipulated peripheral blood grafts predicts the occurrence of acute graft-versus-host disease post haplo-identical hematopoietic stem cell transplantation. Leuk Res 2017; 56:13-20. [PMID: 28161606 DOI: 10.1016/j.leukres.2017.01.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Revised: 12/22/2016] [Accepted: 01/05/2017] [Indexed: 01/06/2023]
Abstract
CD4+CD25+Foxp3+ regulatory T cells (Tregs) have been reported to play a central role in suppressing acute graft-versus-host disease (aGVHD), but whether the Treg contents of grafts correlates with the occurrence of aGVHD post haplo-identical hematopoietic stem cell transplantation (haplo-HSCT) remains unclear. In the present study, changes in Tregs in peripheral blood (PB) were followed before and after granulocyte colony-stimulating factor (G-CSF) mobilization. In addition, functional analyses of Tregs in PB grafts and bone marrow (BM) grafts were performed. To probe the prognostic value of Tregs for aGVHD, an analysis of Tregs in haplo-identical grafts was conducted in 61 patients. Moreover, univariate and multivariate analyses of both clinical variables and cellular subsets were performed. The results showed that both the percentage Tregs of CD4+ T cells and absolute numbers of Tregs per 106 total nucleated cells significantly increased after G-CSF administration. Additionally, Tregs in PB grafts exhibited a stronger inhibitory effect on antigen-specific T cell proliferation than did Tregs in BM grafts. Strikingly, patients receiving more Tregs in PB grafts had a lower cumulative incidence of aGVHD II-IV (36% versus 58%, P=0.046). Further, in a multivariate analysis, the number of Tregs in PB grafts was significantly associated with a lower occurrence of aGVHD II-IV (P=0.02). In contrast, the number of Tregs in BM grafts was not associated with the occurrence of aGVHD in the current study. Further analysis showed that the Treg content in grafts did not affect Treg reconstitution, infection rate, or incidence of chronic GVHD after haplo-HSCT. Moreover, no significant correlations between cell types in grafts and the survival end points or relapse rates were found in the present study. In conclusion, our results suggest that a high number of Tregs in PB grafts is associated with reduced risk of aGVHD in haplo-HSCT in our transplant setting.
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Affiliation(s)
- Li Ding
- Department of Hematology, General Hospital of Air Forces, PLA, Beijing, China
| | - Heng Zhu
- Department of Cell Biology, Institute of Basic Medical Sciences, Beijing, China.
| | - Yang Yang
- Department of Hematology, General Hospital of Air Forces, PLA, Beijing, China
| | - Hong-Min Yan
- Department of Hematology, General Hospital of Air Forces, PLA, Beijing, China
| | - Hai-Hong Zhang
- Department of General Surgery, General Hospital of Air Forces, PLA, Beijing, China
| | - Dong-Mei Han
- Department of Hematology, General Hospital of Air Forces, PLA, Beijing, China
| | - Zhi-Dong Wang
- Department of Hematology, General Hospital of Air Forces, PLA, Beijing, China
| | - Xiao-Li Zheng
- Department of Hematology, General Hospital of Air Forces, PLA, Beijing, China
| | - Jing Liu
- Department of Hematology, General Hospital of Air Forces, PLA, Beijing, China
| | - Ling Zhu
- Department of Hematology, General Hospital of Air Forces, PLA, Beijing, China
| | - Mei-Xue
- Department of Hematology, General Hospital of Air Forces, PLA, Beijing, China
| | - Zi-Kuan Guo
- Department of Experimental Hematology, Institute of Radiation Medicine, Beijing, China.
| | - Heng-Xiang Wang
- Department of Hematology, General Hospital of Air Forces, PLA, Beijing, China.
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Marino J, Paster J, Benichou G. Allorecognition by T Lymphocytes and Allograft Rejection. Front Immunol 2016; 7:582. [PMID: 28018349 PMCID: PMC5155009 DOI: 10.3389/fimmu.2016.00582] [Citation(s) in RCA: 157] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 11/24/2016] [Indexed: 11/13/2022] Open
Abstract
Recognition of donor antigens by recipient T cells in secondary lymphoid organs initiates the adaptive inflammatory immune response leading to the rejection of allogeneic transplants. Allospecific T cells become activated through interaction of their T cell receptors with intact allogeneic major histocompatibility complex (MHC) molecules on donor cells (direct pathway) and/or donor peptides presented by self-MHC molecules on recipient antigen-presenting cells (APCs) (indirect pathway). In addition, recent studies show that alloreactive T cells can also be stimulated through recognition of allogeneic MHC molecules displayed on recipient APCs (MHC cross-dressing) after their transfer via cell-cell contact or through extracellular vesicles (semi-direct pathway). The specific allorecognition pathway used by T cells is dictated by intrinsic and extrinsic factors to the allograft and can influence the nature and magnitude of the alloresponse and rejection process. Consequently, various organs and tissues such as skin, cornea, and solid organ transplants are recognized differently by pro-inflammatory T cells through these distinct pathways, which may explain why these grafts are rejected in a different fashion. On the other hand, the mechanisms by which anti-inflammatory regulatory T cells (Tregs) recognize alloantigen and promote transplantation tolerance are still unclear. It is likely that thymic Tregs are activated through indirect allorecognition, while peripheral Tregs recognize alloantigens in a direct fashion. As we gain insights into the mechanisms underlying allorecognition by pro-inflammatory and Treg cells, novel strategies are being designed to prevent allograft rejection in the absence of ongoing immunosuppressive drug treatment in patients.
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Affiliation(s)
- Jose Marino
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Joshua Paster
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Gilles Benichou
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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Li CX, Ling CC, Shao Y, Xu A, Li XC, Ng KTP, Liu XB, Ma YY, Qi X, Liu H, Liu J, Yeung OWH, Yang XX, Liu QS, Lam YF, Zhai Y, Lo CM, Man K. CXCL10/CXCR3 signaling mobilized-regulatory T cells promote liver tumor recurrence after transplantation. J Hepatol 2016; 65:944-952. [PMID: 27245433 DOI: 10.1016/j.jhep.2016.05.032] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Revised: 05/02/2016] [Accepted: 05/20/2016] [Indexed: 01/19/2023]
Abstract
BACKGROUND & AIMS Liver graft injury and tumor recurrence are the major challenges of liver transplantation for the patients with hepatocellular carcinoma (HCC). Here, we aimed to explore the role and mechanism of liver graft injury mobilizing regulatory T cells (Tregs), which lead to late phase tumor recurrence after liver transplantation. METHODS The correlation among tumor recurrence, liver graft injury and Tregs mobilization were studied in 257 liver transplant recipients with HCC and orthotopic rat liver transplantation models. The direct roles of CXCL10/CXCR3 signaling on Tregs mobilization and tumor recurrence were investigated in CXCL10-/- and CXCR3-/- mice models with hepatic IR injury. RESULTS Clinically, patients received the graft with graft weight ratio (GWR) <60% had higher HCC recurrence after liver transplantation than the recipients with GWR ⩾60% graft. More circulating Tregs and higher intragraft TLR4/CXCL10/CXCR3 levels were detected in recipients with GWR <60% graft. These results were further validated in rat transplantation model. Foxp3+ cells and expressions of TLR4, CXCL10, TGFβ, CTLA-4 and CD274 were increased in rat liver tumor tissues from small-for-size graft group. In mouse model, the mobilization and recruitment of Tregs were decreased in TLR4-/-, CXCL10-/- and CXCR3-/- mice compared to wild-type mice. Moreover, less CXCR3+ Tregs were recruited into liver in CXCL10-/- mice after hepatic IR injury. The knockout of CXCL10 and depletion of Tregs inhibited tumor recurrence after hepatic IR injury. CONCLUSION CXCL10/CXCR3 signaling upregulated at liver graft injury directly induced the mobilization and intragraft recruitment of Tregs, which further promoted HCC recurrence after transplantation. LAY SUMMARY There were positive correlation among tumor recurrence, circulating Tregs and liver graft injury after human transplantation for HCC patients. The knockout of CXCL10 decreased hepatic recruitment of CXCR3+ Tregs and late phase tumor recurrence after hepatic IR injury.
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Affiliation(s)
- Chang Xian Li
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Chang Chun Ling
- Department of Surgery, The University of Hong Kong, Hong Kong, China; Department of General Surgery, Affiliated Hospital of Nantong University, Nantong city, 226001, China
| | - Yan Shao
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Aimin Xu
- Department of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xiang Cheng Li
- Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Kevin Tak-Pan Ng
- Department of Surgery, The University of Hong Kong, Hong Kong, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, China
| | - Xiao Bing Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Yuen Yuen Ma
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Xiang Qi
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Hui Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Jiang Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | | | - Xin Xiang Yang
- Department of Surgery, The University of Hong Kong, Hong Kong, China; Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qing Sheng Liu
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Yin Fan Lam
- Department of Surgery, The University of Hong Kong, Hong Kong, China
| | - Yuan Zhai
- Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, USA
| | - Chung Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, China
| | - Kwan Man
- Department of Surgery, The University of Hong Kong, Hong Kong, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The University of Hong Kong, Hong Kong, China; Shenzhen Institute of Research and Innovation, The University of Hong Kong, China.
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Huang H, Luo Y, Liang Y, Long X, Peng Y, Liu Z, Wen X, Jia M, Tian R, Bai C, Li C, He F, Lin Q, Wang X, Dong X. CD4(+)CD25(+) T Cells in primary malignant hypertension related kidney injury. Sci Rep 2016; 6:27659. [PMID: 27278520 PMCID: PMC4899787 DOI: 10.1038/srep27659] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 05/18/2016] [Indexed: 01/10/2023] Open
Abstract
CD4(+)CD25(+) T cells are critical for maintenance of immunologic self-tolerance. We measured the number of CD4(+)CD25(+) cells in the patients with primary malignant hypertension related kidney injury, to explore the molecular pathogenesis of this disease. We selected 30 patients with primary malignant hypertension related kidney injury and 30 healthy volunteers. Information on clinical characteristics and laboratory tests was obtained from each subject. The number of CD4(+)CD25(+) cells and glomerular injury were assessed by flow cytometry and histopathology, respectively. Both serum IL-2, IL-4, and IL-6 and endothelial cell markers were analyzed by ELISA. ADAMTS13 antibody was detected by Western blotting. CD4(+)CD25(+) cells were significantly reduced in patients with primary malignant hypertension related kidney injury compared to controls (P < 0.05). The number of CD4(+)CD25(+) cells was negatively related to blood urea nitrogen, serum uric acid, proteinuria, and supernatant IL-4; whereas positively associated with estimated glomerular filtration rate in patients. Gradually decreasing CD4(+)CD25(+) cells were also found as increasing renal injury. Additionally, patients exhibited increasing supernatant IL-4, serum IL-2 and IL-6, endothelial cell markers, and anti-ADAMTS13 antibody compared with controls (all P < 0.05). CD4(+)CD25(+) cells may play a key role in the pathogenesis of primary malignant hypertension related kidney injury.
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Affiliation(s)
- Hongdong Huang
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, The 9th Affiliated Hospital of Peking University, Beijing, P.R. China
- Division of Nephrology, Hunan Normal University, Hunan Provincial People’s Hospital of China, Changsha, Hunan Province, P.R. China
| | - Yang Luo
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, The 9th Affiliated Hospital of Peking University, Beijing, P.R. China
| | - Yumei Liang
- Division of Nephrology, Hunan Normal University, Hunan Provincial People’s Hospital of China, Changsha, Hunan Province, P.R. China
| | - Xidai Long
- Department of Liver Surgery, the Affiliated Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Youming Peng
- Hunan Key Laboratory of Nephrology and Hemoperfusion, Division of Nephrology, Second Xiangya Hospital of Central South University, Changsha, Hunan Province, P.R. China
| | - Zhihua Liu
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, The 9th Affiliated Hospital of Peking University, Beijing, P.R. China
| | - Xiaojun Wen
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, The 9th Affiliated Hospital of Peking University, Beijing, P.R. China
| | - Meng Jia
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, The 9th Affiliated Hospital of Peking University, Beijing, P.R. China
| | - Ru Tian
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, The 9th Affiliated Hospital of Peking University, Beijing, P.R. China
| | - Chengli Bai
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, The 9th Affiliated Hospital of Peking University, Beijing, P.R. China
| | - Cui Li
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, The 9th Affiliated Hospital of Peking University, Beijing, P.R. China
| | - Fuliang He
- Department of Interventional Therapy, Beijing Shijitan Hospital, Capital Medical University, The 9th Affiliated Hospital of Peking University, Beijing, P.R. China
- Section of Hematology/Oncology, Section of Gastroenterology, Stephenson Cancer Center, Department of Internal Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, USA
| | - Qiushi Lin
- Section of Hematology/Oncology, Section of Gastroenterology, Stephenson Cancer Center, Department of Internal Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, USA
| | - Xueyan Wang
- Center of Allergy, Beijing Shijitan Hospital, Capital Medical University, Beijing, P.R. China
| | - Xiaoqun Dong
- Department of Interventional Therapy, Beijing Shijitan Hospital, Capital Medical University, The 9th Affiliated Hospital of Peking University, Beijing, P.R. China
- Section of Hematology/Oncology, Section of Gastroenterology, Stephenson Cancer Center, Department of Internal Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, USA
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Kheirouri S, Hadi V, Alizadeh M. Immunomodulatory Effect of Nigella sativa Oil on T Lymphocytes in Patients with Rheumatoid Arthritis. Immunol Invest 2016; 45:271-83. [PMID: 27100726 DOI: 10.3109/08820139.2016.1153649] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND AND OBJECTIVES Abundant evidence indicates the involvement of CD4(+), CD8(+), and CD4(+)CD25(+) T lymphocytes in the induction and/or protection of rheumatoid arthritis (RA). We aimed to investigate the modulatory effect of Nigella sativa (NS) oil on the selected T cell subset percentage in females with RA. METHODS A randomized, double-blinded placebo-controlled, 2 months, parallel-group clinical trial was conducted. Forty-three female patients (20-50 years) with mild to moderate RA were recruited and assigned into NS (n = 23) and placebo (n = 20) groups to receive one gram of NS oil, or starch, capsule in two divided doses, respectively. The disease activity scores of 28 joints (DAS28) were calculated and percentages of CD4(+), CD8(+), and CD4(+)CD25(+) T cells were examined using flow cytometry. RESULTS Treatment with NS led to significant reduction of the serum high-sensitivity C-reactive protein (hs-CRP) level and DAS-28 score and an improved number of swollen joints compared with baseline and placebo groups. A relatively comparable CD4(+) T cell percentage was observed in the NS and placebo groups either in baseline or the end of study. The treatment also resulted in reduced CD8(+), and increased CD4(+)CD25(+) T cell percentage and the CD4(+)/CD8(+) ratio as compared to placebo and baseline. A negative significant correlation between changes in CD8(+) and changes in CD4(+)CD25(+) T cells and a positive significant correlation between changes in CD4(+)CD25(+) T cells and changes in the CD4(+)/CD8(+) ratio was observed in the NS group. CONCLUSION This study gives strength to the potential relevance of NS in clinical management of RA through modulation of T lymphocytes.
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Affiliation(s)
- Sorayya Kheirouri
- a Department of Nutrition , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Vahid Hadi
- a Department of Nutrition , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Mohammad Alizadeh
- a Department of Nutrition , Tabriz University of Medical Sciences , Tabriz , Iran
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Huang H, Luo Y, Liang Y, Long XD, Peng Y, Liu Z, Wen X, Jia M, Tian R, Bai C, Li C, Dong X. CD4+CD25+ cells in multiple myeloma related renal impairment. Sci Rep 2015; 5:16565. [PMID: 26564056 PMCID: PMC4643310 DOI: 10.1038/srep16565] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Accepted: 10/15/2015] [Indexed: 11/19/2022] Open
Abstract
CD4(+)CD25(+) cells are critical regulators in almost all of the animal models of human organ-specific autoimmune diseases, transplant rejection and allergic diseases. We aimed to explore the role of CD4(+)CD25(+) cells in the pathogenesis of multiple myeloma (MM) related renal impairment (RI). Thirty patients with MM related RI and 30 healthy volunteers were studied. The number of CD4(+)CD25(+) cells was examined by flow cytometry. Clinical and laboratory data were collected from each subject. Glomerular injury was assessed by histopathology. Serum IL-2, IL-4 and IL-6 were analyzed by ELISA. CD4(+)CD25(+) cells significantly decreased in MM related RI patients compared to the controls (P<0.05). CD4(+)CD25(+) cell number was negatively associated with blood urea nitrogen (BUN), supernatant IL-4, serum IL-6, monoclonal immunoglobulin and β2-microglobulin, as well as bone marrow plasma cell percentage and proteinuria; whereas positively associated with estimated glomerular filtration rate (eGFR) (all P < 0.05). CD4(+)CD25(+) cells gradually decreased as the Clinic Stage increased. The number of CD4(+)CD25(+) cells reduced in MM related RI patients, and was correlated with disease severity. CD4(+)CD25(+) cells may play an important role in the pathogenesis of MM related RI.
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Affiliation(s)
- Hongdong Huang
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, P.R. China
- Division of Nephrology, Hunan Normal University, Hunan Provincial People’s Hospital of China, Changsha, P.R. China
| | - Yang Luo
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, P.R. China
| | - Yumei Liang
- Division of Nephrology, Hunan Normal University, Hunan Provincial People’s Hospital of China, Changsha, P.R. China
| | - Xi-Dai Long
- Department of Liver Surgery, the Affiliated Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China
| | - Youming Peng
- Hunan Key Laboratory of Nephrology and Hemoperfusion, Division of Nephrology, Second Xiangya Hospital of Central South University, Changsha, Hunan Province, P.R. China
| | - Zhihua Liu
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, P.R. China
| | - Xiaojun Wen
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, P.R. China
| | - Meng Jia
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, P.R. China
| | - Ru Tian
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, P.R. China
| | - Chengli Bai
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, P.R. China
| | - Cui Li
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, P.R. China
| | - Xiaoqun Dong
- Section of Hematology/Oncology, Section of Gastroenterology, Stephenson Cancer Center, Department of Internal Medicine, College of Medicine, The University of Oklahoma Health Sciences Center, USA
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Hasanain AFA, Zayed AAAH, Mahdy RE, Nafee AMA, Attia RAMH, Mohamed AO. Hookworm infection among patients with pulmonary tuberculosis: Impact of co-infection on the therapeutic failure of pulmonary tuberculosis. Int J Mycobacteriol 2015; 4:318-22. [PMID: 26964815 DOI: 10.1016/j.ijmyco.2015.09.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 09/02/2015] [Indexed: 10/23/2022] Open
Abstract
OBJECTIVE/BACKGROUND The aim of this study is to determine the rate of hookworm infection among patients with pulmonary tuberculosis (TB) and to find out if there is a relation between hookworm infection and the therapeutic failure of pulmonary TB. METHODS We carried out a prospective, hospital-based study. The study included 231 naïve patients with pulmonary TB, consecutively. Patients were evaluated at the 4th month of therapy for persistence of Mycobacterium tuberculosis infection. All patients had clinical evaluation, laboratory investigations (including sputum culture and stool microscopic examination), and imaging studies (abdominal ultrasonography and chest radiography). RESULTS The study population mean age was 42.7±13.9 years old with 26.8% of them 40 years old or more. Out of 231 patients, 133 (57.6%) were men. Therapeutic failure rate of pulmonary TB was 29.4%. Hookworm infection was diagnosed among 16.5% of patients and 27.7% had diabetes mellitus (DM). Using multivariate analysis, it was found that age of 40 years or more (odds ratio [OR] 8.4; 95% confidence interval [CI] 1.7-41.3; p=.009), hookworm infection (OR 7.6; 95% CI 1.2-49.9; p=.034), and DM (OR 5.9; 1.2-28; p=.027) were independently associated with therapeutic failure of pulmonary TB among the study population with pulmonary TB. CONCLUSION In conclusion, the rate of therapeutic failure of pulmonary TB is high. Besides older age and DM, hookworm infection can reduce the therapeutic response of pulmonary TB. Screening for and control of DM and hookworm infection among patients with pulmonary TB may improve their therapeutic response.
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Affiliation(s)
| | | | - Reem Ezzat Mahdy
- Department of Internal Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | | | | | - Asmaa Omar Mohamed
- Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt.
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Guerreiro MLDS, Morais IRB, Andrade SG. Immunological response to re-infections with clones of the Colombian strain of Trypanosoma cruzi with different degrees of virulence: influence on pathological features during chronic infection in mice. Mem Inst Oswaldo Cruz 2015; 110:500-6. [PMID: 25946153 PMCID: PMC4501413 DOI: 10.1590/0074-02760140286] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 02/12/2015] [Indexed: 11/04/2022] Open
Abstract
Re-infections with Trypanosoma cruzi are an aggravating factor for
Chagas disease morbidity. The Colombian strain of T. cruzi
represents multiclonal populations formed by clonally propagating organisms with
different tropisms and degrees of virulence. In the present study, the influence of
successive inoculations with clones of the Colombian strain, exhibiting different
degrees of virulence, on chronic myocarditis and the humoral and cellular immune
responses (Col-C1 high virulence, Col-C8 medium virulence and Col-C5 low virulence)
were demonstrated. Mice from three groups with a single infection were evaluated
during the acute (14th-30th day) and chronic phases for 175 days. An
immunofluorescence assay, ELISA and delayed type hypersensitivity (DTH) cutaneous
test were also performed. Mice with a triple infection were studied on the
115th-175th days following first inoculation. The levels of IgM and IgG2a were higher
in the animals with a triple infection. DTH showed a higher intensity in the
inflammatory infiltrate based on the morphometric analysis during a 48 h period of
the triple infection and at 24 h with a single infection. The histopathology of the
heart demonstrated significant exacerbation of cardiac inflammatory lesions confirmed
by the morphometric test. The humoral responses indicate a reaction to the triple
infection, even with clones of the same strain.
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Affiliation(s)
- Marcos Lazaro da Silva Guerreiro
- Laboratório de Chagas Experimental, Autoimunidade e Imunologia Celular, Centro de Pesquisas Gonçalo Moniz, Fiocruz, Salvador, BA, Brasil
| | - Isa Rita Brito Morais
- Laboratório de Chagas Experimental, Autoimunidade e Imunologia Celular, Centro de Pesquisas Gonçalo Moniz, Fiocruz, Salvador, BA, Brasil
| | - Sonia Gumes Andrade
- Laboratório de Chagas Experimental, Autoimunidade e Imunologia Celular, Centro de Pesquisas Gonçalo Moniz, Fiocruz, Salvador, BA, Brasil
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Huang H, Sun W, Liang Y, Peng Y, Long XD, Liu Z, Wen X, Jia M, Tian R, Bai C, Li C. CD4 (+)CD 25 (+)Treg cells and IgA nephropathy patients with tonsillectomy: a clinical and pathological study. Int Urol Nephrol 2014; 46:2361-2369. [PMID: 25281312 DOI: 10.1007/s11255-014-0851-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 09/22/2014] [Indexed: 12/23/2022]
Abstract
BACKGROUND The relationship between tonsillar autoimmune response and the pathogenesis of IgA nephropathy (IgAN) has been previously demonstrated. However, the role of CD4 (+)CD25 (+)Treg cells, which play critical roles in maintaining peripheral tolerance and preventing autoimmunity, has not yet been defined in IgAN. METHODS Thirty-five patients with IgAN and 35 patients without renal disease were studied. The CD4 (+)CD25 (+)Treg cells were examined by flow cytometry. Clinical and laboratory data, such as serum creatinine and urinary samples, were obtained from each patient. Glomerular injury was assessed by histopathology. Serum IgA, C3, IL-2, IL-4 and IL-6 were analyzed by ELISA. RESULTS CD4 (+)CD25 (+)Treg cells significantly decreased in IgAN patients compared with the controls before tonsillectomy (p < 0.05). CD4 (+)CD25 (+)Treg cells were negatively correlated with blood urea nitrogen, supernatant IL-4 and proteinuria in IgAN patients, and positively with estimated glomerular filtration rate. CD4 (+)CD25 (+)Treg cells gradually decreased as the severity of renal histology increased. In addition, serum IgA, IL-2, IL-6 and supernatant IL-4 elevated while CD4 (+)CD25 (+)Treg cells decreased in IgAN patients. CD4 (+)CD25 (+)Treg cells were significantly increased when serum IgA, IL-2, IL-6 and supernatant IL-4, urine protein and urine erythrocytes were decreased after tonsillectomy in patients with IgAN, but were still lower than those of the controls (p < 0.05). CONCLUSIONS CD4 (+)CD25 (+)Treg cells were associated with IgAN, and tonsillectomy may increase CD4 (+)CD25 (+)Treg cells in IgAN patients, leading to clinical improvement.
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Affiliation(s)
- Hongdong Huang
- Division of Nephrology, Beijing Shijitan Hospital, Capital Medical University, 10 Yangfangdian Tieyi Road, Haidian District, Beijing, 100038, People's Republic of China,
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