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Tang Y, Ma T, Jia S, Zhang Q, Liu S, Qi L, Yang L. The Mechanism of Interleukin-35 in Chronic Hepatitis B. Semin Liver Dis 2021; 41:516-524. [PMID: 34233371 DOI: 10.1055/s-0041-1731708] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Interleukin-35 (IL-35) is a newly identified inhibitory cytokine. It has recently been found to play an extremely important role in chronic hepatitis B disease, which makes it likely to be a target for new therapies for hepatitis B malady. IL-35 modulates a variety of immune mechanisms to cause persistent viral infections, such as affecting the ratio of helper T cells, reducing the activity of cytotoxic T cells, hindering the antigen presentation capacity for dendritic cells, and increasing the transcription level of hepatitis B virus. On the other hand, IL-35 can control the inflammation caused by hepatitis B liver injury. Therefore, to seek a breakthrough in curing hepatitis B disease, the contradictory part of IL-35 in the occurrence and development of this sickness is worthy of further discussion and research. This article will systematically review the biological effects of IL-35 and the specific mechanisms affecting the disease.
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Affiliation(s)
- Ying Tang
- Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Tianyi Ma
- Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Shengnan Jia
- Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Qian Zhang
- Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Siqi Liu
- Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
| | - Ling Qi
- Department of Core Medical Laboratory, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan, China
| | - Lanlan Yang
- Diseases Center, Department of Hepatopancreatobiliary Medicine, The Second Hospital, Jilin University, Changchun, China
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Farag MMS, Suef RA, Al-Toukhy GM, Selim MA, Elbahnasawy MA, El Sharkawy N, Ezzat S, Shebl N, Mansour MTM. HBVsvp-Pulsed Dendritic Cell Immunotherapy Induces Th1 Polarization and Hepatitis B Virus-Specific Cytotoxic T Lymphocytes Production. Infect Drug Resist 2020; 13:2699-2709. [PMID: 32821133 PMCID: PMC7418458 DOI: 10.2147/idr.s265681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 07/16/2020] [Indexed: 12/27/2022] Open
Abstract
Background In chronic hepatitis B virus (CHB) patients, both dendritic cells (DCs) and T cells are functionally impaired and consequently the HBV-specific cellular immune responses are downregulated. The present study aims to investigate whether monocyte-derived DC (MoDCs)-pulsed-HBV subviral particles (HBVsvp) can polarize Th1 cells to induce HBV-specific cytotoxic T-lymphocytes (CTL) responses in CHB patients. Methods and Materials To this end, the human hepatoma HepG2.2.15 cell line was used to produce HBVsvp as a culturing system, and HBVsvp were concentrated for highly virus titer using the polyethylene glycol protocol. Peripheral blood mononuclear cells (PBMCs), collected from CHB patients and healthy donors, were differentiated into MoDCs and T cells. PBMCs-derived MoDCs were first pulsed with HBVsvp and then cultured with PBMCs-derived T cells. MoDCs and/or T subsets cells were identified for phenotypic activation by FACS analysis. The cytokine secretion of IL-4, IL-12, and IFN-γ in the culture supernatants was detected. Results The MoDCs were restored for their activation upon pulsing with HBVsvp in vitro, as identified by significantly overexpression of both CD86 and HLA-DR, and overproduction of IL-4 and IL-12. Furthermore, MoDCs-pulsed-HBVsvp induced Th1 frequencies and activated HBV-specific CTL to produce significantly highest amount of IFN-γ. Enhanced HBV-specific CTL led to strong cytolytic capacity against HepG2.2.15. Conclusion Overall, our data suggest that in vitro activation of MoDCs with HBVsvp overcomes the functionally impaired DCs and T cells in CHB patients offering a promising tool for therapeutic or vaccine-based approaches against HBV.
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Affiliation(s)
- Mohamed M S Farag
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt
| | - Reda A Suef
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt
| | - Ghada M Al-Toukhy
- Virology & Immunology Department, Children's Cancer Hospital, Cairo 57357, Egypt
| | - Mohamed A Selim
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt
| | - Mostafa A Elbahnasawy
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Cairo 11884, Egypt
| | - Nahla El Sharkawy
- Clinical Pathology Department, National Cancer Institute, Cairo University and Children Cancer Hospital, Cairo 57357, Egypt
| | - Sameera Ezzat
- Epidemiology & Preventive Medicine Department, National Liver Institute, Menoufia University, Al Minufya, Egypt
| | - Nashwa Shebl
- Hepatology Department, National Liver Institute, Menoufia University, Al Minufya, Egypt
| | - Mohamed T M Mansour
- Virology & Immunology Department, National Cancer Institute, Cairo University and Children Cancer Hospital, Cairo 57357, Egypt
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Raihan R, Akbar SMF, Al Mahtab M, Khan MSI, Tabassum S, Tee KK, Mohamed RB. Increased Proinflammatory Cytokine Production by Chronic Hepatitis B Patients with Mutant Hepatitis B Virus: Plausible Mechanisms Underlying Severe Liver Diseases in These Patients. Viral Immunol 2020; 33:530-534. [PMID: 32513066 DOI: 10.1089/vim.2019.0198] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatitis B virus (HBV) is a noncytopathic virus and billions of HBV-infected patients live uneventful lives and do not suffer from notable liver damage. However, HBV also causes progressive liver diseases characterized by hepatic inflammation, hepatic fibrosis, and liver cancer in millions of HBV-infected patients. The goal of this study was to evaluate the role of mutant HBV in HBV pathogenesis. In a cohort of 360 chronic HBV-infected patients, mutations at T1762/A1764 of HBV genome were detected in most of the patients with HBV-induced liver cirrhosis and hepatocellular carcinoma. To explore if mutations at T1762/A1764 of HBV genome has any role in progressive liver disease, peripheral blood mononuclear cells (PBMCs) and antigen-presenting dendritic cells (DCs) were isolated from five chronic hepatitis B (CHB) patients with mutations at T1762/A1764 and five comparable patients of CHB without mutations at T1762/A1764. DCs were pulsed with hepatitis B surface antigen (HBsAg). The levels of cytokines produced by PBMCs and DCs as well as nitrite production by DCs were evaluated. Significantly higher levels of interleukin-12, tumor necrosis factor-alpha, interferon-gamma, and transforming growth factor-beta were detected in cultures of PBMCs, DCs, and HBsAg-pulsed DCs from CHB patients with mutations at T1762/A1764 compared with those without mutations (p < 0.05). DCs of all CHB patients with mutations produced significantly higher levels of nitrite compared with those without mutation at T1762/A1764 (p < 0.001). This study discusses the inflammatory potential of mutant HBV that may be responsible for diverse levels of pathogenicity of HBV. Further studies involving larger cohorts would provide more insight into these unresolved issues about HBV pathogenesis and these insights may aid in developing immune therapy for CHB patients.
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Affiliation(s)
- Ruksana Raihan
- Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Sheikh Mohammad Fazle Akbar
- Department of Pathology, Ehime University Proteo-Science Center, Ehime University Graduate School of Medicine, Toon City, Japan.,Miyakawa Memorial Research Foundation, Tokyo, Japan
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Md Sakirul Islam Khan
- Department of Anatomy and Embryology, Ehime University Graduate School of Medicine, Matsuyama, Japan
| | - Shahina Tabassum
- Department of Virology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Kok Keng Tee
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.,School of Healthcare and Medical Sciences, Sunway University, Bandar Sunway, Malaysia
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Li J, Bao M, Ge J, Ren S, Zhou T, Qi F, Pu X, Dou J. Research progress of therapeutic vaccines for treating chronic hepatitis B. Hum Vaccin Immunother 2017; 13:986-997. [PMID: 28118084 DOI: 10.1080/21645515.2016.1276125] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Hepatitis B virus (HBV) is a member of Hepadnavirus family, which leads to chronic infection in around 5% of patients with a high risk of developing liver cirrhosis, liver failure, and hepatocellular carcinoma. 1 Despite the availability of prophylactic vaccines against hepatitis B for over 3 decades, there are still more than 2 billion people have been infected and 240 million of them were chronic. Antiviral therapies currently used in the treatment of CHB (chronic hepatitis B) infection include peg-interferon, standard α-interferon and nucleos/tide analogs (NAs), but none of them can provide sustained control of viral replication. As an alternative strategy, therapeutic vaccines for CHB patients have been widely studied and showed some promising efficacies in dozens of preclinical and clinical trials. In this article, we review current research progress in several types of therapeutic vaccines for CHB treatment, including protein-based vaccines, DNA-based vaccines, live vector-based vaccines, peptide-based vaccines and cell-based therapies. These researches may provide some clues for developing new treatments in CHB infection.
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Affiliation(s)
- Jianqiang Li
- a Jiangsu Theravac Bio-pharmaceutical Co., Ltd. , Nanjing , China
| | - Mengru Bao
- a Jiangsu Theravac Bio-pharmaceutical Co., Ltd. , Nanjing , China
| | - Jun Ge
- a Jiangsu Theravac Bio-pharmaceutical Co., Ltd. , Nanjing , China
| | - Sulin Ren
- a Jiangsu Theravac Bio-pharmaceutical Co., Ltd. , Nanjing , China
| | - Tong Zhou
- a Jiangsu Theravac Bio-pharmaceutical Co., Ltd. , Nanjing , China
| | - Fengchun Qi
- a Jiangsu Theravac Bio-pharmaceutical Co., Ltd. , Nanjing , China
| | - Xiuying Pu
- b School of Life Science and Engineering, Lanzhou University of Technology , Lanzhou , China
| | - Jia Dou
- c Dalian Institute for Drug Control , Dalian , China
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Ghasemi M, Erturk M, Buruk K, Sonmez M. Induction of potent protection against acute and latent herpes simplex virus infection in mice vaccinated with dendritic cells. Cytotherapy 2013; 15:352-61. [PMID: 23579060 DOI: 10.1016/j.jcyt.2012.11.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Revised: 10/07/2012] [Accepted: 11/11/2012] [Indexed: 12/30/2022]
Abstract
BACKGROUND AIMS Dendritic cells (DCs) are the most potent antigen presenting cells of the immune system and have been under intense study with regard to their use in immunotherapy against cancer and infectious disease agents. In the present study, DCs were employed to assess their value in protection against live virus challenge in an experimental model using lethal and latent herpes simplex virus (HSV) infection in Balb/c mice. METHODS DCs obtained ex vivo in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4 were loaded with HSV-1 proteins (DC/HSV-1 vaccine). Groups of mice were vaccinated twice, 7 days apart, via subcutaneous, intraperitoneal or intramuscular routes with DC/HSV-1 and with mock (DC without virus protein) and positive (alum adjuvanted HSV-1 proteins [HSV-1/ALH]) control vaccines. After measuring anti-HSV-1 antibody levels in blood samples, mice were given live HSV-1 intraperitoneally or via ear pinna to assess the protection level of the vaccines with respect to lethal or latent infection challenge. RESULTS Intramuscular, but not subcutaneous or intraperitoneal, administration of DC/HSV-1 vaccine provided complete protection against lethal challenge and establishment of latent infection as assessed by death and virus recovery from the trigeminal ganglia. It was also shown that the immunity was not associated with antibody production because DC/HSV-1 vaccine, as opposed to HSV-1/ALH vaccine, produced very little, if any, HSV-1-specific antibody. CONCLUSIONS Overall, our results may have some impact on the design of vaccines against genital HSV as well as chronic viral infections such as hepatitis B virus, hepatitis C virus and human immunodeficiency virus.
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Affiliation(s)
- Mehdi Ghasemi
- Medical Microbiology Department, Medical School, Karadeniz Technical University, Trabzon, Turkey.
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Therapeutic vaccines and immune-based therapies for the treatment of chronic hepatitis B: perspectives and challenges. J Hepatol 2011; 54:1286-96. [PMID: 21238516 DOI: 10.1016/j.jhep.2010.12.031] [Citation(s) in RCA: 104] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2010] [Revised: 11/23/2010] [Accepted: 12/20/2010] [Indexed: 12/24/2022]
Abstract
The treatment of chronic hepatitis B virus (HBV) infection has greatly improved over the last 10 years, but alternative treatments are still needed. Therapeutic vaccination is a promising new strategy for controlling chronic infection. However, this approach has not been as successful as initially anticipated for chronic hepatitis B. General impairment of the immune responses generated during persistent HBV infection, with exhausted T cells not responding correctly to therapeutic vaccination, is probably responsible for the poor clinical responses observed to date. Intensive research efforts are now focusing on increasing the efficacy of therapeutic vaccination without causing liver disease. Here we describe new approaches to use with therapeutic vaccination, in order to overcome the inhibitory mechanisms impairing immune responses. We also describe innovative strategies for generating functional immune responses and inducing sustained control of this persistent infection.
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Akbar SMF, Furukawa S, Horiike N, Abe M, Hiasa Y, Onji M. Safety and immunogenicity of hepatitis B surface antigen-pulsed dendritic cells in patients with chronic hepatitis B. J Viral Hepat 2011; 18:408-14. [PMID: 20487261 DOI: 10.1111/j.1365-2893.2010.01320.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The immune modulator capacity of antigen-pulsed dendritic cells (DC) has been documented in patients with cancers and in animal models of chronic viral infections. Cancer antigen-pulsed DC are now used for treating patients with cancer. But viral antigen-pulsed DC are not used in chronic viral-infected patients because safety of antigen-pulsed DC has not been evaluated in these patients. DC were isolated from human peripheral blood mononuclear cells by culturing with human-grade granulocyte-macrophage colony stimulating factor and interleukin-4. Human blood DC were cultured with hepatitis B surface antigen (HBsAg) for 8h to prepare HBsAg-pulsed DC. After immunogenicity assessment of HBsAg-pulsed DC in vitro, five million HBsAg-pulsed DC were administered intradermally to five patients with chronic hepatitis B (CHB) 1-3 times. HBsAg-pulsed DC were immunogenic in nature because they produced significantly higher levels of interleukin-12 and interferon-γ compared to unpulsed DC (P<0.05). Also, HBsAg-pulsed DC induced proliferation of HBsAg-specific T lymphocytes in vitro. CHB patients injected with HBsAg-pulsed DC did not exhibit generalized inflammation, exacerbation of liver damage, abnormal kidney function, or features of autoimmunity. Administration of HBsAg-pulsed DC induced anti-HBs in two patients and HBsAg-specific cellular immunity in 1 patient. This is the first study about preparation of antigen-pulsed DC using human consumable materials for treating patients with CHB. Because HBsAg-pulsed DC were safe for all patients with CHB and had immune modulation capacity in some patients, phase I and phase II clinical trials with antigen-pulsed DC in CHB and other chronic infections are warranted.
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Affiliation(s)
- S M F Akbar
- Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan
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8
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Wang XY, Zhang XX, Yao X, Jiang JH, Xie YH, Yuan ZH, Wen YM. Serum HBeAg sero-conversion correlated with decrease of HBsAg and HBV DNA in chronic hepatitis B patients treated with a therapeutic vaccine. Vaccine 2010; 28:8169-74. [PMID: 20937312 DOI: 10.1016/j.vaccine.2010.09.093] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Revised: 09/20/2010] [Accepted: 09/24/2010] [Indexed: 01/27/2023]
Abstract
Currently, there are various approaches for developing therapeutic vaccines for chronic hepatitis B patients. Previously, an antigen-antibody-based therapeutic vaccine (YIC) has been conducted in a double-blind placebo controlled phase IIb clinical trial in 242 chronic hepatitis B patients. At the end of follow-up for 24 weeks, HBeAg sero-conversion rate was 21.6% in the 60 μg immunized group, compared to 9% in the alum immunized control group (p=0.03). To analyze the correlation between HBeAg-seroconversion, and decrease of serum HBsAg and HBV DNA, serum samples were back quantified for serum HBsAg and HBV DNA collected at baseline, end of treatment, and end of follow-up from patients who were treated either with 60 μg of YIC, or with placebo. Patients were dichotomized to HBeAg sero-converted and non-converted groups in comparison with patients in the placebo group. The correlations between HBeAg seroconversion and the decrease of HBsAg, HBV DNA and ALT levels during study period were analyzed using a logistic regression model. Results showed marked and sustained reduction of HBsAg, HBV DNA and ALT level in HBeAg sero-converted patients compared to those in patients of HBeAg non-converted and placebo groups. Reduction of HBV DNA and elevation of ALT was markedly associated with HBeAg seroconversion with an adjusted OR of 0.09 (95%CI: 0.01-0.62) and 0.08 (95%CI: 0.02-0.37) respectively after adjusted by age and sex, while reduction of HBsAg level was close to of significance (p=0.054). Analysis indicated that HBeAg sero-conversion was a reasonable endpoint for therapeutic vaccination.
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Affiliation(s)
- Xuan-Yi Wang
- Institutes of Biomedical Sciences, Fudan University, Shanghai, People's Republic of China
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Abe M, Metes D, Thomson AW. Dendritic cells and regulation of alloimmune responses: relevance to outcome and therapy of organ transplantation. Expert Rev Clin Immunol 2010; 1:419-30. [PMID: 20476992 DOI: 10.1586/1744666x.1.3.419] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Dendritic cells are uniquely well-equipped for antigen capture, processing and presentation. They are highly-efficient antigen-presenting cells that induce and regulate T-cell reactivity. Due to their inherent tolerogenicity, immature dendritic cells offer considerable potential as candidate cellular vaccines for negative regulation of immune reactivity/promotion of tolerance. Both classic myeloid and, more recently, characterized plasmacytoid dendritic cells, exhibit tolerogenic properties. Manipulation of dendritic cells differentiation/ maturation in the laboratory using cytokines, pharmacologic agents or genetic engineering approaches can render stably immature dendritic cells that promote organ transplant tolerance in rodents. There are also indications from human studies of the ability of dendritic cells to promote T-cell tolerance and induce T-regulatory cells, with potential for therapeutic application in organ transplantation. In addition, recent clinical observations suggest that modulation of dendritic cell function (e.g., by immunosuppressive drugs) affects the outcome of transplantation. The challenge confronting applied dendritic cell biology is the identification of optimal strategies and therapeutic regimens to allow the potential of these powerful immune regulatory cells to be realized in the clinic.
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Affiliation(s)
- Masanori Abe
- Thomas E Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA.
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Luo J, Li J, Chen RL, Nie L, Huang J, Liu ZW, Luo L, Yan XJ. Autologus dendritic cell vaccine for chronic hepatitis B carriers: a pilot, open label, clinical trial in human volunteers. Vaccine 2010; 28:2497-2504. [PMID: 20117267 DOI: 10.1016/j.vaccine.2010.01.038] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2009] [Revised: 12/23/2009] [Accepted: 01/17/2010] [Indexed: 01/07/2023]
Abstract
Antigen-presenting autologous dendritic cells (ADCs), primed with antigen, have been used in immunotherapy. We evaluated ADCs for treatment of chronic hepatitis B (CHB). ADCs were administered to 380 CHB patients. Virological, biochemical, and serological responses were evaluated in each patient over the course of 48 weeks. Undetectable levels of HBV DNA were reported in 46.36% of patients negative for the hepatitis B "e" antigen (HBeAg) and 3.13% HBeAg-positive patients. Normalization of alanine aminotransferase levels occurred in both HBeAg-positive (P=0.007) and HBeAg-negative (P=0.003) patients. It appears that ADC vaccination effectively reconstructed the immunity and elicited virological, serological, and biochemical improvements in some patients with chronic HBV. No side effects were observed.
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Affiliation(s)
- Jin Luo
- Institute of Genetic Diagnosis, Department of Pharmacogenomics, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, Shaanxi, China
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Wen YM. Antigen–antibody immunogenic complex: promising novel vaccines for microbial persistent infections. Expert Opin Biol Ther 2009; 9:285-91. [DOI: 10.1517/14712590802715749] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Chen W, Shi M, Shi F, Mao Y, Tang Z, Zhang B, Zhang H, Chen L, Chen L, Xin S, Wang FS. HBcAg-pulsed dendritic cell vaccine induces Th1 polarization and production of hepatitis B virus-specific cytotoxic T lymphocytes. Hepatol Res 2009; 39:355-65. [PMID: 19889049 DOI: 10.1111/j.1872-034x.2008.00468.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIM Dendritic cells (DCs) pulsed with HBsAg efficiently reverse the immune tolerance to hepatitis B virus (HBV) and induce HBV-specific cytotoxic T lymphocyte (CTL) responses in transgenic mice and healthy volunteers. However, it is not clear whether HBV core antigen (HBcAg)-pulsed DCs can effectively induce CD4(+) helper T cells polarization into Th1, which contribute to the induction and maintenance of HBV-specific CD8(+) T cells in chronic hepatitis B (CHB) patients. To address this issue, we conducted this study and investigated whether HBcAg-pulsed DCs could polarize Th1 cells and induce an HBcAg-specific CTL response. METHODS HBcAg-pulsed DCs were generated from 21 CHB patients. The capacity of the HBcAg-pulsed DC vaccine to stimulate CD4(+) and CD8(+) T cells to produce IFN-gamma and IL-4 was estimated by intercellular cytokine staining, and the HBcAg-pulsed DCs derived from 10 humam leucocyte antigen (HLA)-A2(+) CHB patients were tested for the induction of HBV-specific CTLs from autologous T cells by pentamer staining. The cytotoxicity of these CTLs was evaluated in vitro by flow cytometry. RESULTS The HBcAg-pulsed DCs derived from CHB patients exhibited a stronger capacity to stimulate autologous CD4(+) and CD8(+) T cells to release IFN-gamma rather than IL-4, which could induce HBV core 18-27 specific CTLs, suggesting a specific cytotoxicity against T2 cells that had been loaded with the HBV core 18-27 peptide in vitro. CONCLUSION HBcAg-pulsed DC vaccine derived from CHB patients efficiently induced autologous T cell polarization to Th1 and generation of HBV core 18-27 specific CTLs.
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Affiliation(s)
- Weiwei Chen
- Center for Clinical Laboratory, Bijing Institute of Infectious Diseases, Beijing, China
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Chen W, Zhang Z, Shi M, Chen L, Fu J, Shi F, Zhang B, Zhang H, Jin L, Wang FS. Activated plasmacytoid dendritic cells act synergistically with hepatitis B core antigen-pulsed monocyte-derived dendritic cells in the induction of hepatitis B virus-specific CD8 T-cell response. Clin Immunol 2008; 129:295-303. [PMID: 18774748 DOI: 10.1016/j.clim.2008.07.026] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2008] [Revised: 06/20/2008] [Accepted: 07/15/2008] [Indexed: 02/02/2023]
Abstract
It is important to further improve the efficiency of hepatitis B core antigen-pulsed monocyte-derived dendritic cell (core-DC) vaccine in clinical immunotherapy for chronic hepatitis B virus (HBV) infection in humans. Our study shows that CpG-treated plasmacytoid dendritic cells (pDCs) can efficiently promote core-DC terminal maturation and increase interleukin-12 production. These CpG-activated pDCs can act synergistically in vitro with core-DCs in inducing autologous HBV-specific CD8 T-cell proliferation and interferon (IFN)-gamma production. This promotion was mainly dependent on pDC-derived IFN-alpha, because blockade of IFN-alpha nearly completely aborted the effects of pDCs on core-DCs. In addition, the supernatants derived from CpG-treated peripheral blood mononuclear cells can also effectively improve the aforementioned maturation and function of core-DCs. These findings will facilitate a better understanding of how the pDCs regulate myeloid dendritic cell-mediated immune responses, and highlight the notion that manipulating pDCs might have implications in DC vaccine therapy for patients with chronic hepatitis B.
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Affiliation(s)
- Weiwei Chen
- Research Center for Biological Therapy, Beijing 302 Hospital, Beijing 100039, China
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14
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Xu DZ, Zhao K, Guo LM, Chen XY, Wang HF, Zhang JM, Xie Q, Ren H, Wang WX, Li LJ, Xu M, Liu P, Niu JQ, Bai XF, Shen XL, Yuan ZH, Wang XY, Wen YM. A randomized controlled phase IIb trial of antigen-antibody immunogenic complex therapeutic vaccine in chronic hepatitis B patients. PLoS One 2008; 3:e2565. [PMID: 18596958 PMCID: PMC2430617 DOI: 10.1371/journal.pone.0002565] [Citation(s) in RCA: 95] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2007] [Accepted: 05/28/2008] [Indexed: 12/31/2022] Open
Abstract
Background The safety of the immune complexes composed of yeast-derived hepatitis B surface antigen (HBsAg) and antibodies (abbreviated as YIC) among healthy adults and chronic hepatitis B patients has been proved in phase I and phase IIa trial. A larger number of patients for study of dosage and efficacy are therefore needed. Methods and Principal Findings Two hundred forty two HBeAg-positive chronic hepatitis B patients were immunized with six injections of either 30 µg YIC, 60 µg of YIC or alum adjuvant as placebo at four-week intervals under code. HBV markers and HBV DNA were monitored during immunization and 24 weeks after the completion of immunization. The primary endpoint was defined as loss of HBeAg, or presence of anti-HBe antibody or suppression of HBV DNA, while the secondary endpoint was both HBeAg seroconversion and suppression of HBV DNA. Statistical significance was not reached in primary endpoints four weeks after the end of treatment among three groups, however, at the end of follow-up, HBeAg sero-conversion rate was 21.8%(17/78) and 9% (7/78) in the 60 µg YIC and placebo groups respectively (p = 0.03), with 95% confidence intervals at 1.5% to 24.1%. Using generalized estimating equations (GEEs) model, a significant difference of group effects was found between 60 µg YIC and the placebo groups in terms of the primary endpoint. Eleven serious adverse events occurred, which were 5.1%, 3.6%, and 5.0% in the placebo, 30 µg YIC and 60 µg YIC groups respectively (p>0.05). Conclusions Though statistical differences in the preset primary and secondary endpoints among the three groups were not reached, a late and promising HBeAg seroconversion effect was shown in the 60 µg YIC immunized regimen. By increasing the number of patients and injections, the therapeutic efficacy of YIC in chronic hepatitis B patients will be further evaluated. Trial Registration ChiCTR.org ChiCTR-TRC-00000022
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Affiliation(s)
| | - Kai Zhao
- Beijing Institute of Vaccine and Biological Products, Beijing, China
| | | | - Xin-Yue Chen
- You-An Hospital, Capital Medical University, Beijing, China
| | | | - Ji-Ming Zhang
- Hua-Shan Hospital, Fudan University, Shanghai, China
| | - Qin Xie
- Rui-Jin Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Hong Ren
- Second affiliated hospital, Chongqing Medical University, Chongqing, China
| | - Wen-Xiang Wang
- First affiliated hospital, Chongqing Medical University, Chongqing, China
| | - Lan-Juan Li
- First affiliated hospital, Zhejiang University, Hanzhou, Zhejiang Province, China
| | - Min Xu
- Guangzhou Eighth Hospital, Guangzhou, Guangdong Province, China
| | - Pei Liu
- Second Hospital Affiliated to China Medical University, Shenyang, Liaoning Province, China
| | - Jun-Qi Niu
- First affiliated hospital, Jilin University, Changchun, Jilin Province, China
| | - Xue-Fan Bai
- Tangdu Hospital, Fourth Military Medical University, Xi'an, Shanxi Province, China
| | - Xin-Liang Shen
- Beijing Institute of Vaccine and Biological Products, Beijing, China
| | - Zheng-Hong Yuan
- Key Laboratory Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xuan-Yi Wang
- Key Laboratory Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China
- Institute of Biological Sciences, Fudan University, Shanghai, China
| | - Yu-Mei Wen
- Key Laboratory Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China
- * E-mail:
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15
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Abe M, Thomson AW. Antigen Processing and Presentation in the Liver. LIVER IMMUNOLOGY 2008:49-59. [DOI: 10.1007/978-1-59745-518-3_5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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16
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Abstract
Approximately 350-400 million people worldwide are chronically infected with the hepatitis B virus (HBV). These individuals harbor the virus for their whole life and they transmit the virus to uninfected individuals. In addition, considerable numbers of chronic HBV carriers develop progressive liver diseases like chronic hepatitis B, liver cirrhosis and hepatocellular carcinoma. At present, antiviral agents like type-1 interferons, lamivudine, adefovir and entacavir are used to treat a selected population of chronic HBV carriers. These antiviral treatments are not satisfactory in that they are unable to eradicate HBV, only partially efficient in less than 30% subjects, expensive, can have debilitating side-effects and require constant monitoring. In addition, once treatment is stopped, the virus and clinical conditions return in many patients. Recent advancements in cellular and molecular biology indicate that the host's immune responses to HBV play cardinal roles during acquisition, pathogenesis, progression, and complications of chronic HBV infection. Immune responses are also important in the context of antiviraltherapy and clinical recovery. This explains why the efficacy of antiviral drugs is limited even in some selected patients with chronic HBV infection. Various published work now state that HBV-specific immunity may be beneficial for patients with chronic HBV infection and non-HBV-specific immunity may be related to flare up of liver diseases. Accordingly, a new few field of immunological research and clinical application of prophylactic vaccines (vaccine therapy) has been started in chronic HBV carriers. Vaccine therapy has inspired optimism as a new therapeutic approach, but it is unlikely that the present regimen of vaccine therapy will stand the test of time. Based on present understandings about vaccine/host interactions, we provide herein an outline for engineering more potent regimen of HBV-specific immune therapy against HBV.
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Affiliation(s)
- Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan
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17
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Ishikawa T, Kakumu S. Use of hepatitis B vaccine for the treatment of chronic hepatitis B. Hepatol Res 2007; 37 Suppl 3:S347-50. [PMID: 17931185 DOI: 10.1111/j.1872-034x.2007.00231.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Current therapeutic approaches to control chronic hepatitis B (CH-B), such as administrations of interferon or nucleoside analogs, are still unsatisfactory. Vaccination with conventional hepatitis B (HB) vaccine is another therapeutic approach with lower cost and potentially long-lasting beneficial effect. However, a response rate to vaccination therapy is not necessarily high. Therefore, combination therapy of interferon, nucleoside analogs and vaccination, would be the promising therapeutic approach that improves therapeutic effect and solves the problems of individual therapies. Herein, we report the results of the clinical trial, the combination therapy of lamivudine (LAM) and HB vaccine in patientswith B-CH as one of the candidates for the combination therapies. The results indicate that the combination therapy of LAM and HB vaccine was more effective in regulating viral replication than the LAM monotherapy was. In addition, no adverse effect was observed in the patients given HB vaccine. This novel therapy should be further examined for the improvement of its efficacy and achievement of continuous suppression of HB virus replication.
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Affiliation(s)
- Tetsuya Ishikawa
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Aichi, and Tokai Society for the Study of Chronic Hepatitis B, Aichi, Japan
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18
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Wang FS. Clinical immune characterization of hepatitis B virus infection and implications for immune intervention: Progress and challenges. Hepatol Res 2007; 37 Suppl 3:S339-46. [PMID: 17931184 DOI: 10.1111/j.1872-034x.2007.00222.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The host immune response plays an important role in mediating hepatitis B virus (HBV) control and induction of liver damage, which determines the outcome of infection. However, interactions between HBV, the immune system, and the liver microenvironment, remain poorly understood. This review briefly outlines what we know about innate and adaptive immune responses to HBV, as well as the liver immunology in infected patients. It addresses how our knowledge of the anti-HBV immune response might aid the development of adoptive immune therapeutic strategies against HBV. This review also highlights the challenges we are facing in understanding the cellular and molecular mechanisms bywhich the innate, adaptive and liver immune responses exert a synergistic antiviral function and influence disease progression. It concludes by addressing future directions and unanswered questions regarding the use of clinical immunotherapy. We hope this review will help hepatologists and gastroenterologists to understand the anti-HBV immune response, as well as current challenges and potential immunotherapeutic strategies against this disease.
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Affiliation(s)
- Fu-Sheng Wang
- Research Center for Biological Therapy, Beijing 302 Hospital, Beijing Institute of Infectious Diseases, Beijing, China
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19
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Abstract
BACKGROUND AND AIM Lamivudine (LAM) has problems of breakthrough hepatitis (BTH) and post-treatment relapse despite its significant effect for suppressing hepatitis B virus (HBV) replication. In order to find solutions for the problems, the efficacy of combination therapy of LAM plus hepatitis B (HB) vaccine in patients with chronic HBV infection was assessed. PATIENTS AND METHODS Fifty-three patients with chronic hepatitis B, 33 hepatitis B e-antigen positive (HBeAg+), and 20 HBeAg negative (HBeAg-) patients, were enrolled in the study, and randomized to receive either LAM monotherapy or combination therapy of LAM and HB vaccine. In the combination therapy group, 100 mg/day of LAM was administered as a baseline therapy, and 10 mug of HB vaccine was injected subcutaneously every month starting at 2 months after LAM administration, six times in total. RESULTS HBeAg negative patients responded well to LAM therapy, and there were no significant differences in short-term effects between the two therapy groups. With regard to the ratio of developing BTH, there was no difference betweenthe two groups. In HBeAg+ patients, HBV replication was suppressed more efficiently in the combination therapy group than in the monotherapy group. The ratio of developing BTH was significantly lower in the combination therapy group than in the monotherapy group. Regardless of HBeAg serologic status or therapy protocols, post-treatment relapse was seen in most patients when the administrations of LAM were discontinued. No adverse effect with the use of HB vaccine was observed in all the patients treated with the combination therapy. CONCLUSION Combination therapy of LAM and HB vaccine is a safe and effective way to control HBV replication and prevent the development of BTH especially in patients with high viral load. However, further study is required in order to achieve the continuous suppression of HBV replication even after cessation of LAM.
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Affiliation(s)
- Tetsuya Ishikawa
- Division of Gastroenterology, Department of Internal Medicine, Aichi Medical University School of Medicine, Aichi and Tokai Society for the Study of Chronic Hepatitis B, Aichi, Japan
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20
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Shi M, Qian S, Chen WW, Zhang H, Zhang B, Tang ZR, Zhang Z, Wang FS. Hepatitis B virus (HBV) antigen-pulsed monocyte-derived dendritic cells from HBV-associated hepatocellular carcinoma patients significantly enhance specific T cell responses in vitro. Clin Exp Immunol 2007; 147:277-86. [PMID: 17223969 PMCID: PMC1810470 DOI: 10.1111/j.1365-2249.2006.03281.x] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
To investigate whether hepatitis B virus (HBV) antigen-pulsed monocyte-derived dendritic cells (MoDC) could mount a T cell response in hepatocellular carcinoma (HCC) patients associated with chronic HBV infection, peripheral blood mononuclear cells (PBMCs) from 36 HBV-associated HCC patients were induced into MoDC and pulsed with hepatitis B core antigen (HBcAg) and hepatitis B surface antigen (HBsAg), alone and in combination. Co-stimulatory molecules CD80, CD86 and CD40, as well as human leucocyte antigens D-related (HLA-DR) were found to express at the highest level on MoDC pulsed with HBcAg or HBsAg + HBcAg, at a median level on MoDC pulsed with HBcAg or HBsAg alone, and at the lowest level on non-antigen-pulsed MoDC. Interleukin (IL)-10 and IL-12 cytokines were released by antigen-pulsed MoDC at increased levels in the order: no-antigen < HBsAg < HBcAg < HBcAg + HBsAg. MoDC pulsed with HBcAg or HBsAg + HBcAg also had the strongest ability to stimulate autologous T cell proliferation and intracellular interferon (IFN)-gamma production. HBcAg- or HBsAg + HBcAg-pulsed MoDC could also induce HBV core peptide-specific CD8(+) T cell proliferation determined by tetramer staining. In addition, the antigen-pulsed MoDC were found to have a stronger capacity to produce IL-12 and induce T cell response in vitro for patients with higher alanine transaminase (ALT) levels than those with lower ALT levels, indicating that antigen pulse could substantially reverse the impaired function of MoDC in primary HCC patients with active chronic hepatitis B. In conclusion, HBV antigen-pulsed MoDC from HCC patients with chronic hepatitis B could induce HBV-specific T cell response in vitro.
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Affiliation(s)
- M Shi
- Research Center of Biological Therapy, Beijing 302 Hospital, Beijing Institute of Infectious Diseases, Beijing, China
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21
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Rustgi VK, Koff RS. Future therapy for hepatitis B. Future Virol 2007. [DOI: 10.2217/17460794.2.1.79] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Therapy for hepatitis B virus (HBV) infection, the most common worldwide cause of viremia and chronic liver disease, is currently limited to interferon preparations and nucleoside or nucleotide analogs. Although these treatments result in suppression of HBV replication, virologic rebounds are common when treatment is ended or when viral resistance emerges. This review considers novel approaches targeting viral or host factors involved in the HBV lifecycle, as well as immunomodulatory strategies that are likely to be used concomitantly with antiviral drugs in future research.
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Affiliation(s)
- Vinod K Rustgi
- Transplant Institute, Georgetown University, School of Medicine, Washington, DC, USA
| | - Raymond S Koff
- University of Connecticut, School of Medicine, Farmington, Connecticut, USA
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22
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Huang CH, Ou-Yang L, Huang JG, Li GP, Jiang PF, Yao JL. Induction of specific cytotoxic T lymphocyte responses against hepatitis B virus by hepatitis B virus antigen gene-modified dendritic cells. Shijie Huaren Xiaohua Zazhi 2006; 14:1864-1869. [DOI: 10.11569/wcjd.v14.i19.1864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore whether hepatitis B virus (HBV) antigen gene-modified dendritic cells (DCs) are able to induce a specific cytotoxic T lymphocyte (CTL) response.
METHODS: Three recombinant adenoviruses, Ad-HBs, Ad-HBe and Ad-HBc (carrying HBsAg, HBeAg and HBcAg genes respectively), were prepared and transfected into DCs generated from cord blood. The efficacy of transfection was observed through the expression of enhanced green fluorescent protein (EGFP) in DCs and the expression of HBV antigen were detected by enzyme-linked immunosorbent assay (ELISA). HBV antigen gene-modified DCs were co-cultured with T lymphocytes from cord blood and the proliferation of T cells were detected using mixed lymphocyte reaction (MLR). Lactate dehydrogenase (LDH) release assay was carried out to assess the killing ability of CTL cells against HepG222.1.5 cells.
RESULTS: HBV antigen genes were expressed in DCs with a high efficacy by recombinant adenoviral vector. EGFP were observed in 90% transfected DCs and DCs kept their typical forms after transfection. The titers (absorbance) of HBsAg and HBeAg were 0.919 and 0.328, respectively, in the culture supernatant 72 h after transfection. The result of MLR showed that HBV gene-modified DCs effectively stimulated naive T lymphocytes to proliferate. There was no significant difference among Ad-HBs, Ad-HBe, Ad-HBc transfection group and normal group (F = 1.194, P = 0.389). The specific CTL cells generated by HBV antigen gene-modified DCs had obvious cytotoxity against HepG222.1.5 cells, and the cytotoxity in Ad-HBs, Ad-HBe, Ad-HBc transfection group was significantly higher than that in normal group (all P < 0.001). The cytotoxity in Ad-HBc transfected group was the strongest.
CONCLUSION: HBV gene-modified DCs are able to effectively stimulate naive T lymphocytes to proliferate and enhance the specific CTL response at the same time, showing its promising future for developing anti-viral vaccine.
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23
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Akbar SMF, Horiike N, Onji M. Immune therapy including dendritic cell based therapy in chronic hepatitis B virus infection. World J Gastroenterol 2006; 12:2876-83. [PMID: 16718812 PMCID: PMC4087804 DOI: 10.3748/wjg.v12.i18.2876] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health problem. Of the approximately 2 billion people who have been infected worldwide, more than 400 million are chronic carriers of HBV. Considerable numbers of chronic HBV carriers suffer from progressive liver diseases. In addition, all HBV carriers are permanent source of this virus. There is no curative therapy for chronic HBV carriers. Antiviral drugs are recommended for about 10% patients, however, these drugs are costly, have limited efficacy, and possess considerable side effects.
Recent studies have shown that immune responses of the host to the HBV are critically involved at every stage of chronic HBV infection: (1) These influence acquisition of chronic HBV carrier state, (2) They are important in the context of liver damages, (3) Recovery from chronic HBV-related liver diseases is dependent on nature and extent of HBV-specific immune responses. However, induction of adequate levels of HBV-specific immune responses in chronic HBV carriers is difficult. During the last one decade, hepatitis B vaccine has been administered to chronic HBV carriers as a therapeutic approach (vaccine therapy). The present regimen of vaccine therapy is safe and cheap, but not so effective. A dendritic cell-based therapeutic vaccine has recently been developed for treating chronic HBV infection. In this review, we will discuss about the concept, scientific logics, strategies and techniques of development of HBV-specific immune therapies including vaccine therapy and dendritic cell-based vaccine therapy for treating chronic HBV infection.
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Affiliation(s)
- Sk Md Fazle Akbar
- Third Department of Internal Medicine, Ehime University School of Medicine, To on City, Ehime 791-0295, Japan.
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Huang Y, Chen Z, Jia H, Wu W, Zhong S, Zhou C. Induction of Tc1 response and enhanced cytotoxic T lymphocyte activity in mice by dendritic cells transduced with adenovirus expressing HBsAg. Clin Immunol 2006; 119:280-90. [PMID: 16531121 DOI: 10.1016/j.clim.2006.01.015] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2005] [Revised: 12/30/2005] [Accepted: 01/17/2006] [Indexed: 01/12/2023]
Abstract
We evaluated the potential of dendritic cells (DCs) engineered to express antigen of hepatitis B virus (HBV) in priming Th/Tc and HBV-specific CTL responses in mice. Recombinant adenovirus expressing hepatitis B surface antigen (HBsAg) (Ad-S) was constructed, and bone marrow-derived DCs were transduced with Ad-S or pulsed with HBsAg protein. Mice were injected with either Ad-S-transduced DCs or HBsAg-pulsed DCs or plasmid DNA encoding HBsAg twice at 3-week intervals. We showed that adenovirus infection had no further effect on the phenotype, the ability to induce IFN-gamma-producing Th1/Tc1 response or the T cell stimulatory capacity of already mature DCs in vitro. We also showed that immunization with Ad-S-transduced DCs effectively induced Tc1 cells and HBsAg-specific CTLs in vivo and down-regulated the circulating HBsAg and HBV DNA in HBV transgenic mice. Furthermore, these efficacies were stronger than that of HBsAg-pulsed DCs and plasmid DNA. Thus, DCs transduced with recombinant adenovirus may be a promising candidate for an effective CTL-based therapeutic vaccine against HBV.
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Affiliation(s)
- Yin Huang
- Institute of Infectious Diseases, First Affiliated Hospital, Medical College, Zhejiang University, Qingchun Road 79, Hangzhou 310003, China
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25
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Yu YS, Tang ZH, Han JC, Xi M, Feng J, Zang GQ. Expression of ICAM-1, HLA-DR, and CD80 on peripheral circulating CD1 α DCs induced in vivo by IFN-α in patients with chronic hepatitis B. World J Gastroenterol 2006; 12:1447-51. [PMID: 16552819 PMCID: PMC4124328 DOI: 10.3748/wjg.v12.i9.1447] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the effects of interferon-α (IFN-α) application on peripheral circulating CD1α dendritic cells (DCs) in patients with chronic hepatitis B, and the expression of HLA-DR, CD80, and ICAM-1 on CD1α DCs in order to explore the mechanism of immune modulation of IFN-α.
METHODS: By flow cytometry technique, changes of CD1α DCs were monitored in 22 patients with chronic hepatitis B treated with IFN-α and in 16 such patients not treated with IFN-α within three months. Meanwhile, the expression of HLA-DR, CD80, and ICAM-1 on CD1α DCs was detected.
RESULTS: In the group of IFN-α treatment, the percentage of CD1α DCs in peripheral blood mononuclear cells was increased after three months of therapy. In patients who became negative for HBV-DNA after IFN-α treatment, the increase of DCs was more prominent, while in control, these changes were not observed. Increased expression of HLA-DR, CD80, and ICAM-1 on CD1α DCs was also observed.
CONCLUSION: CD1α DCs can be induced by IFN-α in vivo, and the immune related molecules such as HLA-DR, CD80, and ICAM-1 are up-regulated to some degree. This might be an important immune related mechanism of IFN-α treatment for chronic hepatitis B.
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Affiliation(s)
- Yong-Sheng Yu
- Department of Infectious Diseases, Sixth People's Hospital of Shanghai Jiaotong University, Shanghai 200233,China.
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26
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Otsu S, Gotoh K, Yamashiro T, Yamagata J, Shin K, Fujioka T, Nishizono A. Transfer of antigen-pulsed dendritic cells induces specific T-Cell proliferation and a therapeutic effect against long-term Helicobacter pylori infection in mice. Infect Immun 2006; 74:984-93. [PMID: 16428744 PMCID: PMC1360321 DOI: 10.1128/iai.74.2.984-993.2006] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Helicobacter pylori causes persistent infection of the stomach and results in chronic gastritis and peptic ulcers. Jaws II cells, derived from mouse bone marrow, were pulsed with live or formalin-killed or whole-cell sonicates (WCS) of H. pylori. Representative cell surface molecules were expressed at substantial levels on Jaws II cells, indicating that appropriate maturation of the cells was achieved with the three H. pylori antigens without any significant differences. H. pylori WCS-pulsed Jaws II cells secreted a significant amount of tumor necrosis factor alpha into the culture supernatant. The naïve T cells exposed to the WCS-pulsed Jaws II cells showed significant proliferation and gamma interferon (IFN-gamma) and interleukin-10 (IL-10) production in vitro. A 2-log reduction in the number of colonizing bacteria was observed in the mice treated with the WCS-pulsed Jaws II cells; however, no significant reductions were achieved in mice treated with Jaws II cells pulsed with other H. pylori antigens. Up-regulated production of IFN-gamma and IL-10 was observed in the stomachs of the mice treated with the WCS-pulsed Jaws II cells, which is consistent with the result obtained in vitro. There were no differences in gastritis scores or H. pylori-specific antibody titers among the mice treated with Jaws II cells pulsed with the three different H. pylori antigens. The results suggest that Th1 cell-mediated immunity in combination with Th2 cell-mediated immunity plays a role in reducing colonizing bacterial numbers in mice with chronic H. pylori infections.
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Affiliation(s)
- Satoshi Otsu
- Department of Infectious Diseases (Microbiology), Faculty of Medicine, Oita University, Idaigaoka 1-1, Hasama-machi, Oita 879-5593, Japan
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27
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N/A. N/A. Shijie Huaren Xiaohua Zazhi 2005; 13:2778-2782. [DOI: 10.11569/wcjd.v13.i23.2778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/26/2023] Open
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28
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Jackson DC, Deliyannis G, Eriksson E, Dinatale I, Rizkalla M, Gowans EJ. Dendritic Cell Immunotherapy of Hepatitis C Virus Infection: Toxicology of Lipopeptide-Loaded Dendritic Cells. Int J Pept Res Ther 2005. [DOI: 10.1007/s10989-005-9270-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Furukawa S, Akbar SMF, Hasebe A, Horiike N, Onji M. Production of hepatitis B surface antigen-pulsed dendritic cells from immunosuppressed murine hepatitis B virus carrier: evaluation of immunogenicity of antigen-pulsed dendritic cells in vivo. Immunobiology 2005; 209:551-7. [PMID: 15568619 DOI: 10.1016/j.imbio.2004.07.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Vaccines containing hepatitis B surface antigen (HBsAg) induce antibody to HBsAg (anti-HBs) in most normal individuals and protects them from hepatitis B virus (HBV) infection. However, these vaccines are not efficient at inducing anti-HBs in immunosuppressed individuals, especially in immunosuppressed HBV carriers. The aim of this study was to prepare and to assess the efficacy of a dendritic cell (DC)-based vaccine in an immunosuppressed HBV transgenic mouse (HBV-Tg), an animal model of the HBV carrier state. In order to prepare immunosuppressed HBV-Tg, HBV-Tg were injected with FK-506, an immunosuppressive agent, once daily, intraperitoneally for 15 days. Spleen cells of immunosuppressed HBV-Tg expressed very little mRNAs for interleukin-2 and interferon-gamma. DCs were isolated from the spleen of immunosuppressed HBV-Tg and cultured with HBsAg (100 microg) for 48 h to prepare HBsAg-pulsed DCs. Immunosuppressed HBV-Tg expressing HBsAg in the sera were administered with HBsAg-pulsed DCs or unpulsed DCs or HBsAg in adjuvant for different durations. Immunosuppressed HBV-Tg (n = 8) twice administered with HBsAg-pulsed DCs expressed anti-HBs in the sera within 6 weeks of first injection. Seven of eight immunosuppressed HBV-Tg remained positive for anti-HBs in the sera for the next 12 weeks of observation in spite of receiving daily injection of FK-506 for the entire duration. However, immunosuppressed HBV-Tg administered with unpulsed DCs or HBsAg in adjuvant did not express anti-HBs in the sera. The data show that DCs from immunosuppressed HBV-Tg can be loaded with HBsAg to prepare immunogenic HBsAg-pulsed DCs. HBsAg-pulsed DCs induced anti-HBs in immunosuppressed HBV-Tg. This approach may be of use to induce and maintain anti-HBs in immunosuppressed human HBV carriers.
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Affiliation(s)
- Shinya Furukawa
- Third Department of Internal Medicine, Ehime University, School of Medicine, Shigenobu-Cho, Onsen-Gun, Ehime 791-0295, Japan
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Abstract
Dendritic cells (DCs), the most prevalent antigen-presenting cell in vivo, had been widely characterized in the last three decades. DCs are present in almost all tissues of the body and play cardinal roles in recognition of microbial agents, autoantigens, allergens and alloantigen. DCs process the microbial agents or their antigens and migrate to lymphoid tissues to present the antigenic peptide to lymphocytes. This leads to activation of antigen-specific lymphocytes. Initially, it was assumed that DCs are principally involved in the induction and maintenance of adaptive immune responses, but now it is evident that DCs also have important roles in innate immunity. These features make DCs very good candidates for therapy against various pathological conditions including malignancies. Initially, DC-based therapy was used in animal models of cancers. Data from these studies inspired considerable optimism and DC-based therapies was started in human cancers 8 years ago. In general, DC-based therapy has been found to be safe in patients with cancers, although few controlled trials have been conducted in this regard. Because, the fundamentals principles of human cancers and animal models of cancers are different, the therapeutic efficacy of the ongoing regime of DC-based therapy in cancer patients is not satisfactory. In this review, we covered the various aspects that should be considered for developing better regime of DC-based therapy for human cancers.
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