|
1
|
Shakiba Y, Vorobyev PO, Mahmoud M, Hamad A, Kochetkov DV, Yusubalieva GM, Baklaushev VP, Chumakov PM, Lipatova AV. Recombinant Strains of Oncolytic Vaccinia Virus for Cancer Immunotherapy. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:823-841. [PMID: 37748878 DOI: 10.1134/s000629792306010x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 04/06/2023] [Accepted: 04/24/2023] [Indexed: 09/27/2023]
Abstract
Cancer virotherapy is an alternative therapeutic approach based on the viruses that selectively infect and kill tumor cells. Vaccinia virus (VV) is a member of the Poxviridae, a family of enveloped viruses with a large linear double-stranded DNA genome. The proven safety of the VV strains as well as considerable transgene capacity of the viral genome, make VV an excellent platform for creating recombinant oncolytic viruses for cancer therapy. Furthermore, various genetic modifications can increase tumor selectivity and therapeutic efficacy of VV by arming it with the immune-modulatory genes or proapoptotic molecules, boosting the host immune system, and increasing cross-priming recognition of the tumor cells by T-cells or NK cells. In this review, we summarized the data on bioengineering approaches to develop recombinant VV strains for enhanced cancer immunotherapy.
Collapse
Affiliation(s)
- Yasmin Shakiba
- Moscow Institute of Physics and Technology, Dolgoprudny, Moscow Region, 141701, Russia.
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia
| | - Pavel O Vorobyev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
| | - Marah Mahmoud
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
| | - Azzam Hamad
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
| | - Dmitriy V Kochetkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
| | - Gaukhar M Yusubalieva
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
- Federal Research Clinical Center for Specialized Medical Care and Medical Technologies, Federal Medical-Biological Agency (FMBA), Moscow, 115682, Russia
- Federal Center of Brain Research and Neurotechnologies of the FMBA of Russia, Moscow, 117513, Russia
| | - Vladimir P Baklaushev
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
- Federal Research Clinical Center for Specialized Medical Care and Medical Technologies, Federal Medical-Biological Agency (FMBA), Moscow, 115682, Russia
- Federal Center of Brain Research and Neurotechnologies of the FMBA of Russia, Moscow, 117513, Russia
| | - Peter M Chumakov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
| | - Anastasia V Lipatova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia.
| |
Collapse
|
|
2
|
Huy TXN, Nguyen TT, Reyes AWB, Vu SH, Min W, Lee HJ, Lee JH, Kim S. Immunization With a Combination of Four Recombinant Brucella abortus Proteins Omp16, Omp19, Omp28, and L7/L12 Induces T Helper 1 Immune Response Against Virulent B. abortus 544 Infection in BALB/c Mice. Front Vet Sci 2021; 7:577026. [PMID: 33553273 PMCID: PMC7854899 DOI: 10.3389/fvets.2020.577026] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 12/21/2020] [Indexed: 01/11/2023] Open
Abstract
Protective efficiency of a combination of four recombinant Brucella abortus (B. abortus) proteins, namely outer membrane protein (Omp) 16, Omp19, Omp28, and 50S ribosomal protein L7/L12 was evaluated as a combined subunit vaccine (CSV) against B. abortus infection in RAW 264.7 cell line and murine model. The immunoreactivity of these four recombinant proteins as well as pCold-TF vector reacted with Brucella-positive serum individually, but not with Brucella-negative serum by immunoblotting assay. CSV-treated RAW 264.7 cells significantly induced production of IFN-γ and IL-12 while decreased IL-10 production at the late stage of infection compared to PBS-treated control cells. In addition, the enhancement of nitric oxide production together with cytokines secretion profile in CSV-treated cells proved that CSV notably activated bactericidal mechanisms in macrophages. Consistently, mice immunized with CSV strongly elicited production of pro-inflammatory cytokines TNF-α, IL-6 and MCP-1 compared to PBS control group. Moreover, the concentration of IFN-γ was >IL-10 and titers of IgG2a were also heightened compared to IgG1 in CSV-immunized mice which suggest that CSV induced predominantly T helper 1 T cell. These results suggest that the CSV used in the present study is a potential candidate as a preventive therapy against brucellosis.
Collapse
Affiliation(s)
- Tran Xuan Ngoc Huy
- Institute of Applied Sciences, Ho Chi Minh City University of Technology - HUTECH, Ho Chi Minh City, Vietnam.,Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, South Korea
| | - Trang Thi Nguyen
- Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, South Korea
| | | | - Son Hai Vu
- Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, South Korea
| | - WonGi Min
- Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, South Korea
| | - Hu Jang Lee
- Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, South Korea
| | - John Hwa Lee
- College of Veterinary Medicine, Chonbuk National University, Iksan, South Korea
| | - Suk Kim
- Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju, South Korea
| |
Collapse
|
|
3
|
Mejía-Terrazas GE, Ruíz-Suárez M, Vadillo-Ortega F, Franco Y Bourland RE, López-Muñoz E. Effect of interscalene nerve block on the inflammatory response in shoulder surgery: a randomized trial. J Shoulder Elbow Surg 2019; 28:e291-e303. [PMID: 31227466 DOI: 10.1016/j.jse.2019.02.030] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 02/18/2019] [Accepted: 02/27/2019] [Indexed: 02/01/2023]
Abstract
BACKGROUND Comparing techniques of general anesthesia and regional anesthesia in arthroscopic shoulder surgery, some studies have shown differences in the intensity of immediate postoperative pain and neuroendocrine response, but the inflammatory response when using balanced general anesthesia (BGA) vs. an ultrasound-guided (USG) single-dose interscalene block (SDIB) has not been compared. MATERIALS AND METHODS In a single-center, prospective, randomized clinical trial, the inflammatory response of 2 groups of 10 patients scheduled to undergo arthroscopic shoulder surgery was evaluated through measurement of a panel of cytokines that act on cells of the adaptive immune response to promote or inhibit inflammation, chemokines involved in chemotaxis, the erythrocyte sedimentation rate (ESR), the high-sensitivity C-reactive protein (CRP) level, and the white blood cell (WBC) count in 3 blood samples (before anesthesia, immediately postoperatively, and 24 hours postoperatively) with 2 types of anesthesia (BGA vs. USG SDIB). Postoperative pain intensity (immediately, at 12 hours, and at 24 hours) was also assessed. RESULTS The ESR and CRP level increased significantly at 24 hours after surgery; however, the increase in ESR (P < .0001) and CRP level (P < .0001) was lower in the USG SDIB group. Significant increases in the levels of soluble interleukin 2 receptor α (P = .022) and interleukin 12p40 (P = .016) occurred in the immediate postoperative period in the USG SDIB group. Immediate postoperative pain showed a significant increase (P < .001) in the BGA group. CONCLUSIONS In arthroscopic shoulder surgery, the use of a USG SDIB compared with the use of BGA is possibly associated with improved pain control in the immediate postoperative period and lower immunosuppression, even at 24 hours after surgery.
Collapse
Affiliation(s)
| | - Michell Ruíz-Suárez
- Traumatology Service, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra," Mexico City, Mexico
| | - Felipe Vadillo-Ortega
- Unit of Vinculation, Faculty of Medicine, Universidad Nacional Autónoma de México and Laboratory of Metabolism and Nutrition in Experimental Medicine, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | | | - Eunice López-Muñoz
- Medical Research Unit in Reproductive Medicine, Unidad Médica de Alta Especialidad, Hospital de Gineco Obstetricia No. 4, "Luis Castelazo Ayala," Instituto Mexicano del Seguro Social, Mexico City, Mexico
| |
Collapse
|
|
4
|
Li F, Zhu Y, Xie X, Ke R, Li S, Liu L, Lu J, Li M. Interleukin-12B gene polymorphisms and bronchial asthma risk: A meta-analysis. J Asthma 2017; 54:777-783. [PMID: 28287286 DOI: 10.1080/02770903.2016.1277536] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 12/13/2016] [Accepted: 12/26/2016] [Indexed: 01/09/2023]
Abstract
OBJECTIVE This meta-analysis aims to investigate whether interleukin-12B (IL-12B) -1188A/C or the promoter polymorphisms may be a risk factor for asthma. DATA SOURCES Web of Science, PubMed, China National Knowledge Infrastructure (CNKI) and Wanfang databases were searched (updated August 20, 2015). STUDY SELECTIONS Articles evaluating the association between IL-12B genetic polymorphisms and asthma risk were selected. RESULTS 13 eligible studies with a total of 5092 subjects were finally included in this meta-analysis. For IL-12B -1188A/C, analysis by ethnicity indicated that there was a markedly reduced risk for asthma in East Asian (CC + AC vs. AA: OR = 0.64, 95% CI = 0.50-0.81, P < 0.001). For IL-12B promoter, analysis by ethnicity indicated there was a markedly increased risk in East Asian (MM vs. WM + WW: OR = 1.57, 95% CI = 1.18-2.10, P = 0.002). Analysis by allergic state revealed the similar results in atopic subgroup. CONCLUSIONS IL-12B -1188 C allele may be a protective factor against asthma in East Asian. In addition, promoter MM genotype may be a risk factor for asthma in East Asian and allergic people.
Collapse
Affiliation(s)
- Fangwei Li
- a Department of Respiratory Medicine , the First Affiliated Hospital of Xi'an Jiaotong University , Xi'an , China
| | - Yanting Zhu
- a Department of Respiratory Medicine , the First Affiliated Hospital of Xi'an Jiaotong University , Xi'an , China
| | - Xinming Xie
- a Department of Respiratory Medicine , the First Affiliated Hospital of Xi'an Jiaotong University , Xi'an , China
| | - Rui Ke
- a Department of Respiratory Medicine , the First Affiliated Hospital of Xi'an Jiaotong University , Xi'an , China
| | - Shaojun Li
- a Department of Respiratory Medicine , the First Affiliated Hospital of Xi'an Jiaotong University , Xi'an , China
| | - Lu Liu
- a Department of Respiratory Medicine , the First Affiliated Hospital of Xi'an Jiaotong University , Xi'an , China
| | - Jun Lu
- b Department of Clinical Research Center , the First Affiliated Hospital of Xi'an Jiaotong University , Xi'an , China
| | - Manxiang Li
- a Department of Respiratory Medicine , the First Affiliated Hospital of Xi'an Jiaotong University , Xi'an , China
| |
Collapse
|
|
5
|
Chen G, Kang K, Kang S, Rook AH, Kubin M, Voorhees JJ, Cooper KD. Differential Induction of IL-12 p40 and IL-10 mRNA in Human Langerhans' Cells and Keratinocytes by in Vivo Occlusion, Vehicle, and All-TRANS Retinoic Acid. J Cutan Med Surg 2016. [DOI: 10.1177/120347549600100203] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Background: Hydration and pharmacologic manipulation of the skin may have immunomodulatory effects. For instance, retinoic acid (RA) in vivo upregulates antigen-presenting cell (APC) activity of Langerhans' cells (LC). Objective: Our study was to determine whether RA increases LC APC activity via alteration of the potent immunoregulatory and reciprocally acting cytokines, IL-12 and IL-10. Methods: 0.1% RA and vehicle solvent only (V) as a control were applied under occlusion on the skin of normal volunteers. Freshly selected CD1a+ LC and keratinocytes from keratome were subject to semiquantitative determination of IL-12 p40 and IL-10 mRNA levels. IL-12 p40 protein was measured by radioimmunoassay. Results: Occlusion alone and open vehicle alone did not induce LC immunoregulatory cytokines; LCs demonstrated significant induction of IL-12 p40 mRNA, when the vehicle was occluded for 48 hours and, to a lesser extent, IL-10 as well. IL-12 p40 mRNA could be further induced by RA-LC at the 20-hour time point; however, IL-10 mRNA was induced at the 48-hour time point. Neither occlusion nor RA significantly induced IL-12 p40 or IL-10 mRNA in CD1a keratinocytes at any time points. Conclusion: A tight reciprocal regulation of IL-10 and IL-12 is present in LCs and is consistent with the initial, but self-limited, inflammatory effect of occlusion and topical retinoids.
Collapse
Affiliation(s)
- Guofen Chen
- Department of Dermatology, Case Western Reserve University, and University Hospitals of Cleveland. Cleveland, Ohio, the University of Michigan, Ann Arbor, Michigan
| | - Kefei Kang
- Department of Dermatology, Case Western Reserve University, and University Hospitals of Cleveland. Cleveland, Ohio, the University of Michigan, Ann Arbor, Michigan
| | - Sewon Kang
- Department of Dermatology, University of Pennsylvania, Seattle, Washington
| | - Alain H. Rook
- Department of Dermatology, Philadelphia, Pennsylvania; Seattle, Washington
| | - Marek Kubin
- Department of Dermatology, Immunex Corp., Seattle, Washington
| | - John J. Voorhees
- Department of Dermatology, University of Pennsylvania, Seattle, Washington
| | - Kevin D. Cooper
- Department of Dermatology, Case Western Reserve University, and University Hospitals of Cleveland. Cleveland, Ohio, the University of Michigan, Ann Arbor, Michigan
| |
Collapse
|
|
6
|
Herrera JJ, Bockhorst K, Kondraganti S, Stertz L, Quevedo J, Narayana PA. Acute White Matter Tract Damage after Frontal Mild Traumatic Brain Injury. J Neurotrauma 2016; 34:291-299. [PMID: 27138134 DOI: 10.1089/neu.2016.4407] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Our understanding of mild traumatic brain injury (mTBI) is still in its infancy and to gain a greater understanding, relevant animal models should replicate many of the features seen in human mTBI. These include changes to diffusion tensor imaging (DTI) parameters, absence of anatomical lesions on conventional neuroimaging, and neurobehavioral deficits. The Maryland closed head TBI model causes anterior-posterior plus sagittal rotational acceleration of the brain, frequently observed with motor vehicle and sports-related TBI injuries. The injury reflects a concussive injury model without skull fracture. The goal of our study was to characterize the acute (72 h) pathophysiological changes occurring following a single mTBI using magnetic resonance imaging (MRI), behavioral assays, and histology. We assessed changes in fractional anisotropy (FA), mean (MD), longitudinal (LD), and radial (RD) diffusivities relative to pre-injury baseline measures. Significant differences were observed in both the longitudinal and radial diffusivities in the fimbria compared with baseline. A significant difference in radial diffusivity was also observed in the splenium of the corpus callosum compared with baseline. The exploratory activity of the mTBI animals was also assessed using computerized activity monitoring. A significant decrease was observed in ambulatory distance, average velocity, stereotypic counts, and vertical counts compared with baseline. Histological examination of the mTBI brain sections indicated a significant decrease in the expression of myelin basic protein in the fimbria, splenium, and internal capsule. Our findings demonstrate the vulnerability of the white matter tracts, specifically the fimbria and splenium, and the ability of DTI to identify changes to the integrity of the white matter tracts following mTBI.
Collapse
Affiliation(s)
- Juan J Herrera
- 1 Department of Diagnostic and Interventional Imaging, The University of Texas Health Science Center at Houston (UTHealth) , McGovern Medical School, Houston, Texas
| | - Kurt Bockhorst
- 1 Department of Diagnostic and Interventional Imaging, The University of Texas Health Science Center at Houston (UTHealth) , McGovern Medical School, Houston, Texas
| | - Shakuntala Kondraganti
- 1 Department of Diagnostic and Interventional Imaging, The University of Texas Health Science Center at Houston (UTHealth) , McGovern Medical School, Houston, Texas
| | - Laura Stertz
- 2 Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth) , McGovern Medical School, Houston, Texas
| | - João Quevedo
- 2 Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth) , McGovern Medical School, Houston, Texas.,3 Center of Excellence on Mood Disorders, Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center at Houston (UTHealth) , McGovern Medical School, Houston, Texas
| | - Ponnada A Narayana
- 1 Department of Diagnostic and Interventional Imaging, The University of Texas Health Science Center at Houston (UTHealth) , McGovern Medical School, Houston, Texas
| |
Collapse
|
|
7
|
Interleukin 12B gene polymorphisms and susceptibility to rheumatoid arthritis: a data synthesis. Clin Rheumatol 2016; 36:299-307. [PMID: 27312970 DOI: 10.1007/s10067-016-3327-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 05/02/2016] [Accepted: 06/08/2016] [Indexed: 10/21/2022]
Abstract
The aim of this study was to investigate the association of two common interleukin 12B (IL-12B) polymorphisms (rs3212227 and rs6887695) with rheumatoid arthritis (RA) susceptibility through meta-analyses. A systematic literature search of PubMed, Web of Science, Cochrane Library, and Embase databases was conducted on articles published before 28 February 2016. Then odds ratio (OR) with 95 % confidence interval (CI) was used to quantify the strength of association for homozygote, heterozygote, dominant, and recessive genetic models. Nine articles with a total of 17 case-control studies (12 for IL-12B rs3212227 polymorphism and 5 for IL-12B rs6887695 polymorphism) met our inclusion criteria. The pooled results demonstrated that IL-12B rs3212227 (homozygote model: OR = 0.96, 95 % CI = 0.81-1.15; heterozygote model: OR = 1.07, 95 % CI = 0.93-1.23; dominant model: OR = 1.05, 95 % CI = 0.91-1.20; recessive model: OR = 0.93, 95 % CI = 0.79-1.10) and rs6887695 (homozygote model: OR = 1.01, 95 % CI = 0.84-1.21; heterozygote model: OR = 1.14, 95 % CI = 0.86-1.51; dominant model: OR = 1.14, 95 % CI = 0.87-1.48; recessive model: OR = 1.01, 95 % CI = 0.85-1.21) polymorphisms may not be associated with RA risk. Our meta-analyses demonstrated that IL-12B rs3212227 and rs6887695 polymorphisms do not confer susceptibility to RA.
Collapse
|
|
8
|
Kim HS, Jeong HY, Lee YK, Kim KS, Park YS. Synergistic antitumoral effect of IL-12 gene cotransfected with antiangiogenic genes for angiostatin, endostatin, and saxatilin. Oncol Res 2014; 21:209-16. [PMID: 24762227 DOI: 10.3727/096504014x13907540404798] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Previously, it was reported that the cotransfection of angiostatin K1-3, endostatin, and saxatilin genes using cationic liposomes significantly inhibited tumor progression. IL-12 is a well-known immune modulator that promotes Th1-type antitumor immune responses and also induces antiangiogenic effects. In this study, we have examined the antitumoral function of the IL-12 gene cotransfected with antiangiogenic genes for angiostatin K1-3, endostatin, and saxatilin by O,O'-dimyristyl-N-lysyl glutamate (DMKE) cationic liposomes in a mouse tumor model. According to our results, the administration of the IL-12 gene or the genes for angiostatin K1-3, endostatin, and saxatilin exhibited effective inhibition of B16BL6 melanoma growth in mice. In particular, intravenous administration of the IL-12 gene along with intratumoral administration of the three antiangiogenic genes synergistically inhibited the B16BL6 tumor growth. These results suggest that systemically expressed IL-12 enhances antitumoral efficacy of locally expressed antiangiogenic proteins.
Collapse
Affiliation(s)
- Hong Sung Kim
- Department of Biomedical Laboratory Science, Korea Nazarene University, Cheonan, Korea
| | | | | | | | | |
Collapse
|
|
9
|
|
|
10
|
Han J, Dakhama A, Jia Y, Wang M, Zeng W, Takeda K, Shiraishi Y, Okamoto M, Ziegler SF, Gelfand EW. Responsiveness to respiratory syncytial virus in neonates is mediated through thymic stromal lymphopoietin and OX40 ligand. J Allergy Clin Immunol 2012; 130:1175-1186.e9. [PMID: 23036746 DOI: 10.1016/j.jaci.2012.08.033] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2011] [Revised: 08/03/2012] [Accepted: 08/10/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND Recent studies revealed a critical role for thymic stromal lymphopoietin (TSLP) released from epithelial cells and OX40 ligand (OX40L) expressed on dendritic cells (DCs) in T(H)2 priming and polarization. OBJECTIVES We sought to determine the importance of the TSLP-OX40L axis in neonatal respiratory syncytial virus (RSV) infection. METHODS Mice were initially infected with RSV as neonates or adults and reinfected 5 weeks later. Anti-OX40L or anti-TSLP were administered during primary or secondary infection. Outcomes included assessment of airway function and inflammation and expression of OX40L, TSLP, and IL-12. RESULTS OX40L was expressed mainly on CD11c(+)MHC class II (MHCII)(+)CD11b(+) DCs but not CD103(+) DCs. Treatment of neonates with OX40L antibody during primary RSV infection prevented the subsequent enhancement of airway hyperresponsiveness and the development of airway eosinophilia and mucus hyperproduction on reinfection. Administration of anti-TSLP before neonatal RSV infection reduced the accumulation of lung DCs, decreased OX40L expression on lung DCs, and attenuated the enhancement of airway responses after reinfection. CONCLUSIONS In mice initially infected as neonates, TSLP expression induced by RSV infection is an important upstream event that controls OX40L expression, lung DC migration, and T(H)2 polarization, accounting for the enhanced response on reinfection.
Collapse
Affiliation(s)
- Junyan Han
- Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, USA
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
11
|
In vivo suppression of plasma IL-12 levels by acute and chronic stress paradigms: potential mediating mechanisms and sex differences. Brain Behav Immun 2012; 26:996-1005. [PMID: 22659252 PMCID: PMC3398208 DOI: 10.1016/j.bbi.2012.05.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 05/17/2012] [Accepted: 05/19/2012] [Indexed: 01/08/2023] Open
Abstract
Interleukin-12 (IL-12) is a major pro-inflammatory cytokine, which promotes cell-mediated immunity and T(H)1 differentiation. In vitro studies indicated suppression of IL-12 production by several stress-related factors, but no effects of behavioral stress were shown on plasma IL-12 levels. Therefore, in the current study we (i) examined the in vivo effects of various behavioral and pharmacological stress paradigms on baseline plasma IL-12 levels; (ii) compared these in vivo findings to those obtained following in vitro stimulation of leukocytes from the same rats; and (iii) assessed potential sexual dimorphism in these outcomes. The findings indicated that plasma IL-12 levels were significantly reduced by social confrontation, wet-cage exposure, surgery, and the administration of corticosterone, epinephrine, or prostaglandin-E(2). Notably, most in vivo impacts on plasma levels were not evident when assessed in vitro. The IL-12-reducing effects of wet-cage exposure, and of corticosterone and epinephrine administration, were significantly greater in males than in females, although females exhibited greater total corticosterone levels following stress. The duration of acute stressors predicted the degree of IL-12 reduction, but more prolonged stressors did not. Furthermore, seven days of alternating behavioral stressors reduced plasma IL-12 levels more than 14 days. These findings suggest animals' behavioral habituation to stress conditions, or a specific immune mechanism restricting the duration of IL-12 reduction. Overall, our findings indicate a generic and robust stress-induced reduction in plasma IL-12 levels, and suggest epinephrine, corticosterone, and prostaglandin-E(2), as potential mediators that should be scrutinized in vivo in the context of natural physiological stress responses.
Collapse
|
|
12
|
Kim KS, Pham TNN, Jin CJ, Umeyama A, Shoji N, Hashimoto T, Lee JJ, Takei M. Uncarinic Acid C Isolated from Uncaria rhynchophylla Induces Differentiation of Th1-Promoting Dendritic Cells Through TLR4 Signaling. Biomark Insights 2011; 6:27-38. [PMID: 21499439 PMCID: PMC3076018 DOI: 10.4137/bmi.s6441] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Uncarinic acid C (URC) is triterpene isolated from Uncaria rhynchophylla and is a pharmacologically active substance. The induction of dendritic cells (DC) is critical for the induction of Ag-specific T lymphocyte responses and may be essential for the development of human vaccines relying on T cell immunity. DC might be a potential target for URC. We demonstrate that URC activates human DC as documented by phenotypic and functional maturation, and altered cytokine production. The expression of CD1a, CD38, CD40, CD54, CD80, CD83, CD86, HLA-DR and CCR7 on URC-primed DC was enhanced. The production of IL-12p70 by URC-primed DC was higher than that of lipopolysaccharide (LPS)-primed DC. The production of IL-12p70 by URC-primed DC was inhibited by the anti-Toll-like receptor 4 (TLR4) monoclonal antibody (mAb), but partially abolished by anti-TLR2 mAb. mRNA coding for TLR2 and TLR4 was expressed in URC-primed DC. URC-primed DC induced the NF-κB transcription factor. Naïve T cells co-cultured with URC-primed DC turned into typical Th1 cells that produced large quantities of IFN-γ depending on IL-12 secretion. URC enhanced the T cell stimulatory capacity in an allo MLR. In the cytotoxic T-lymphocyte assay (CTL) assay, DNA fragmentation assay and (51)Cr release on URC-primed DC were more augmented than that of TNF-α-primed DC. DC matured with URC had an intermediate migratory capacity towards CCL19 and CCL21. These results suggest that URC modulates DC function in a fashion that favors Th1 polarization via the activation of IL-12p70 dependent on TLR4 signaling, and may be used on DC-based vaccine for cancer immunotherapy.
Collapse
Affiliation(s)
- Kyu Sik Kim
- Department of Pulmonary Medicine, Chonnam National University Medical School, Gwangiu
| | - Thanh Nhan Nguyen Pham
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, 160 IIsim-ri, Hwasun-eup, Hwasun-gun, Jeollanam-do 519-809, South Korea
| | - Chun-Ji Jin
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, 160 IIsim-ri, Hwasun-eup, Hwasun-gun, Jeollanam-do 519-809, South Korea
- Department of Surgery, Chonnam National University Medical School, Gwangju
| | - Akemi Umeyama
- Faculty of Pharmaceutical Sciences, Tokushima University, Yamashiro-cho, Tokushima, 770-8514, Japan
| | - Noboru Shoji
- Faculty of Pharmaceutical Sciences, Tokushima University, Yamashiro-cho, Tokushima, 770-8514, Japan
| | - Toshihiro Hashimoto
- Faculty of Pharmaceutical Sciences, Tokushima University, Yamashiro-cho, Tokushima, 770-8514, Japan
| | - Je-Jung Lee
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, 160 IIsim-ri, Hwasun-eup, Hwasun-gun, Jeollanam-do 519-809, South Korea
- Department of Hematology-Oncology, Chonnam National University Medical School, Gwangiu
| | - Masao Takei
- Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, 160 IIsim-ri, Hwasun-eup, Hwasun-gun, Jeollanam-do 519-809, South Korea
| |
Collapse
|
|
13
|
Cao S, Li Y, Ye J, Yang X, Chen L, Liu X, Chen H. Japanese encephalitis Virus wild strain infection suppresses dendritic cells maturation and function, and causes the expansion of regulatory T cells. Virol J 2011; 8:39. [PMID: 21269456 PMCID: PMC3038949 DOI: 10.1186/1743-422x-8-39] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Accepted: 01/26/2011] [Indexed: 11/25/2022] Open
Abstract
Background Japanese encephalitis (JE) caused by Japanese encephalitis virus (JEV) accounts for acute illness and death. However, few studies have been conducted to unveil the potential pathogenesis mechanism of JEV. Dendritic cells (DCs) are the most prominent antigen-presenting cells (APCs) which induce dual humoral and cellular responses. Thus, the investigation of the interaction between JEV and DCs may be helpful for resolving the mechanism of viral escape from immune surveillance and JE pathogenesis. Results We examined the alterations of phenotype and function of DCs including bone marrow-derived DCs (bmDCs) in vitro and spleen-derived DCs (spDCs) in vivo due to JEV P3 wild strain infection. Our results showed that JEV P3 infected DCs in vitro and in vivo. The viral infection inhibited the expression of cell maturation surface markers (CD40, CD80 and CD83) and MHCⅠ, and impaired the ability of P3-infected DCs for activating allogeneic naïve T cells. In addition, P3 infection suppressed the expression of interferon (IFN)-α and tumor necrosis factor (TNF)-α but enhanced the production of chemokine (C-C motif) ligand 2 (CCL2) and interleukin (IL)-10 of DCs. The infected DCs expanded the population of CD4+ Foxp3+ regulatory T cell (Treg). Conclusion JEV P3 infection of DCs impaired cell maturation and T cell activation, modulated cytokine productions and expanded regulatory T cells, suggesting a possible mechanism of JE development.
Collapse
Affiliation(s)
- Shengbo Cao
- State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan, Hubei 430070, PR China
| | | | | | | | | | | | | |
Collapse
|
|
14
|
Jung TY, Pham TNN, Umeyama A, Shoji N, Hashimoto T, Lee JJ, Takei M. Ursolic acid isolated from Uncaria rhynchophylla activates human dendritic cells via TLR2 and/or TLR4 and induces the production of IFN-gamma by CD4+ naïve T cells. Eur J Pharmacol 2010; 643:297-303. [PMID: 20599915 DOI: 10.1016/j.ejphar.2010.06.030] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2009] [Revised: 06/09/2010] [Accepted: 06/16/2010] [Indexed: 11/16/2022]
Abstract
Ursolic acid is triterpene isolated from Uncaria rhynchophylla and is a pharmacologically active substance. The induction of dendritic cell maturation is critical for the induction of Ag-specific T-lymphocyte response and may be essential for the development of human vaccine relying on T cell immunity. In this study, we investigated that the effect of Ursolic acid on the phenotypic and functional maturation of human monocyte-derived dendritic cells in vitro. Dendritic cells harvested on day 8 were examined using functional assay. The expression levels of CD1a, CD80, CD83, CD86, HLA-DR and CCR7 on Ursolic acid-primed dendritic cells was slightly enhanced. Ursolic acid dose-dependently enhanced the T cell stimulatory capacity in an allogeneic mixed lymphocyte reaction, as measured by T cell proliferation. The production of IL-12p70 induced by Ursolic acid-primed dendritic cells was inhibited by the anti-Toll-like receptor-2 (TLR2) mAb and anti-TLR4 mAb. Moreover, Ursolic acid-primed dendritic cells expressed levels of mRNA coding for both TLR2 and TLR4. The majority of cells produced considerable interferon-gamma (IFN-gamma), but also small amounts of interleukin (IL-4)-4. Ursolic acid-primed dendritic cells have an intermediate migratory capacity towards CCL19 and CCL21. These results suggest that Ursolic acid modulates human dendritic cells function in a fashion that favors Th1 polarization via the activation of IL-12p70 dependent on TLR2 and/or TLR4, and may be used on dendritic cells-based vaccines for cancer immunotherapy.
Collapse
Affiliation(s)
- Tae-Young Jung
- Department of Neurosurgery, Chonnam National University Medical School, Gwangiu, South Korea
| | | | | | | | | | | | | |
Collapse
|
|
15
|
Laurent S, Carrega P, Saverino D, Piccioli P, Camoriano M, Morabito A, Dozin B, Fontana V, Simone R, Mortara L, Mingari MC, Ferlazzo G, Pistillo MP. CTLA-4 is expressed by human monocyte-derived dendritic cells and regulates their functions. Hum Immunol 2010; 71:934-41. [PMID: 20650297 DOI: 10.1016/j.humimm.2010.07.007] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2010] [Revised: 06/22/2010] [Accepted: 07/12/2010] [Indexed: 12/26/2022]
Abstract
Cytotoxic T lymphocyte antigen-4 (CTLA-4) is the major negative regulator of T-cell responses, although growing evidence supports its wider role as an immune attenuator that may also act in other cell lineages. Here, we have analyzed the expression of CTLA-4 in human monocytes and monocyte-derived dendritic cells (DCs), and the effect of its engagement on cytokine production and T-cell stimulatory activity by mature DCs. CTLA-4 was highly expressed on freshly isolated monocytes, then down-modulated upon differentiation toward immature DCs (iDCs) and it was markedly upregulated on mature DCs obtained with different stimulations (lipopolysaccharides [LPS], Poly:IC, cytokines). In line with the functional role of CTLA-4 in T cells, treatment of mDCs with an agonistic anti-CTLA-4 mAb significantly enhanced secretion of regulatory interleukin (IL)-10 but reduced secretion of IL-8/IL-12 pro-inflammatory cytokines, as well as autologous CD4+ T-cell proliferation in response to stimulation with recall antigen purified protein derivative (PPD) loaded-DCs. Neutralization of IL-10 with an anti-IL-10 antibody during the mDCs-CD4+ T-cell co-culture partially restored the ability of anti-CTLA-4-treated mDCs to stimulate T-cell proliferation in response to PPD. Taken together, our data provide the first evidence that CTLA-4 receptor is expressed by human monocyte-derived mDCs upon their full activation and that it exerts immune modulatory effects.
Collapse
Affiliation(s)
- Stefania Laurent
- Department of Hematology and Oncology, University of Genoa, Genoa, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Takei M, Umeyama A, Shoji N, Hashimoto T. Polyacetylenediols regulate the function of human monocyte-derived dendritic cells. Int Immunopharmacol 2010; 10:913-21. [PMID: 20493278 DOI: 10.1016/j.intimp.2010.05.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2009] [Revised: 03/13/2010] [Accepted: 05/10/2010] [Indexed: 11/29/2022]
Abstract
Callyspongidiol and 14,15-dihydrosiphonodiol are Polyacetylenediols isolated from marine sponges and are pharmacologically active substances. Dendritic cells (DC) play an important role in the initiation and regulation of immune response. DC have a key influence in the differentiation of naïve T cells into Th1, Th2 or Th17 effector cells. We demonstrated that callyspongidiol and 14,15-dihydrosiphonodiol activate human DC as documented by phenotypic and functional maturation, and altered cytokine production. Up regulation of cell surface expression of CD1a, CD80, CD83, CD86, HLA-DR and CCR7 was observed following DC treatment with callyspongidiol and 14,15-dihydrosiphonodiol. The production of IL-10 by callyspongidiol-primed DC after stimulation with CD40-L was higher than that of LPS- or 14,15-dihydrosiphonodiol-primed DC. Naïve T cells co-cultured with allogeneic 14,15-dihydrosiphonodiol-primed DC at 1:5 DC/T cell ratio turned into typical Th1 cells depending on IL-12 secretion and independent on TLR2 or TLR4. In contrast, callyspongidiol-primed DC co-cultured with naïve T cells secreted IL-4 and IL-10, but had little effect on IFN-gamma. Callyspongidiol-primed DC induced the development of Th2 cells via the inhibition of IL-12p70 and the enhancement of IL-10. Polyacetylenediols-primed DC expressed the chemokine receptor CCR7 and had a high migration to CCL19. These results suggested that some Polyacetylenediols modulate human DC function in a fashion that favors Th1/Th2 cell polarization or IL-10 producing T cells, and might have implication in tumor or in autoimmune diseases.
Collapse
Affiliation(s)
- Masao Takei
- Division of Cellular Allergology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany.
| | | | | | | |
Collapse
|
|
17
|
Sorensen EW, Gerber SA, Frelinger JG, Lord EM. IL-12 suppresses vascular endothelial growth factor receptor 3 expression on tumor vessels by two distinct IFN-gamma-dependent mechanisms. THE JOURNAL OF IMMUNOLOGY 2010; 184:1858-66. [PMID: 20061409 DOI: 10.4049/jimmunol.0903210] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
IL-12 has been shown to be effective in enhancing antitumor responses. However, how IL-12 exerts its antiangiogenic effect is largely unknown. In this study, we elucidate this mechanism using B16 transfected to express IL-12 (B16/IL-12), a system that provides constant, local production of IL-12 within the tumor microenvironment. Intratumoral IL-12 resulted in a significant delay in tumor growth and phenotypic changes in the vasculature. Vessels found within B16 tumors are chaotic and poorly formed and express vascular endothelial growth factor receptor 3 (VEGFR3), a growth factor receptor not expressed on normal adult vessels. However, the vessels within B16/IL-12 tumors have a more normal morphology and do not express VEGFR3. We have shown that IFN-gamma is required for IL-12 to suppress the aberrant expression of VEGFR3. Indeed, the presence of intratumoral IL-12 stimulates the immune system resulting in more IFN-gamma-producing tumor-infiltrating lymphocytes per tumor when compared with parental B16 tumors, which may have a marked effect on control of tumor growth. Interestingly, within B16/IL-12 tumors, T cells are necessary to suppress VEGFR3 expression on tumor vessels. Finally, using IFN-gamma receptor knockout mice in a bone marrow chimera system, we show that the IFN-gamma produced within the tumor suppresses VEGFR3 expression in two ways: 1) acting directly on tumor vessel endothelial cells, and 2) acting on the tumor-infiltrating lymphocytes to indirectly alter endothelial cells' VEGFR3 expression. Our data indicate a mechanism in which tumor-infiltrating immune cells regulate tumor vessel phenotype.
Collapse
Affiliation(s)
- Elizabeth W Sorensen
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA
| | | | | | | |
Collapse
|
|
18
|
Generation of human dendritic cells that simultaneously secrete IL-12 and have migratory capacity by adenoviral gene transfer of hCD40L in combination with IFN-gamma. J Immunother 2009; 32:524-38. [PMID: 19609245 DOI: 10.1097/cji.0b013e3181a28422] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Dendritic cells (DCs) are professional antigen presenting cells and have key functions in the initiation of immune responses. Hence, antigen-loaded DCs have become important tools for active-specific immunotherapy. In addition to defining strategies for antigen loading, effective T-cell activation by DCs will depend on vaccination protocols that facilitate DC migration to secondary lymphoid tissues and expression of costimulatory molecules and cytokines. Adenoviral gene transfer has been successfully implemented for genetic antigen loading of DCs. In this study, we exploit an adenoviral vector encoding human CD40 ligand (CD40L), Ad5hCD40L, to establish DCs that feature both migration potential and prolonged secretion of the key T-helper 1 cytokine interleukin-12p70 (IL-12p70). Transduction of human monocyte-derived DCs with Ad5hCD40L resulted in efficient CD40L expression, which was detected only intracellularly, and in secretion of IL-12p70. Addition of recombinant interferon (IFN)-gamma shortly after DC transduction substantially increased IL-12p70 secretion. Maturation of DCs was achieved with a standard cytokine maturation cocktail (MC) containing prostaglandin E2 which, however, abolished IL-12p70 secretion by Ad5hCD40L-transduced cells in the absence of IFN-gamma. Only DCs treated with Ad5hCD40L, MC, and IFN-gamma migrated efficiently towards CCL19 and continued to secrete IL-12p70. Finally, DCs transduced with both Ad5hCD40L and an adenoviral vector encoding the melanoma antigen MelanA/MART-1 and treated with MC and IFN-gamma efficiently primed naive autologous CD8+ T cells into antigen-specific cytotoxic T lymphocyte. This strategy to generate DCs that exert both migration capacity and prolonged IL-12p70 secretion after intracellular CD40L expression and IFN-gamma treatment has the potential to further improve current DC vaccination protocols.
Collapse
|
|
19
|
Molnár I. The balance shift in Th1/Th2 related IL-12/IL-5 cytokines in Graves' disease during methimazole therapy. Autoimmunity 2009; 40:31-7. [PMID: 17364495 DOI: 10.1080/08916930601165388] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Th1 and Th2-like cytokines are involved in the pathogenesis of Graves' disease. The shift in balance in IL-12/IL-5 cytokines was applied in judging the immunological events in 74 patients with Graves' disease (50 had ophthalmopathy) during methimazole therapy and in 15 controls. The serum levels of IL-12 and IL-5 were measured with enzyme-linked immunosorbent assay in all Graves' patients. Twelve cases for IL-5 and 20 cases for IL-12 were positive. In Graves' patients only those without ophthalmopathy had higher levels of IL-12 when compared to controls (192.66 +/- 29.19 vs. 85.09 +/- 8.95 pg/ml, P < 0.04). After 2 months of methimazole therapy in Graves' patients without ophthalmopathy an increase in the ratio of IL-12 to IL-5 was also observed as compared to those with eye symptoms (91.78 +/- 34.14 vs. 20.72 +/- 6.36, P < 0.015). Age-related difference in the serum level of IL-5 could be demonstrated between Graves' patients without and those with ophthalmopathy aged < or = 35 years (4.89 +/- 0.57 vs. 50.14 +/- 20.2 pg/ml, P < 0.002). No association was found among the serum levels of IL-5 or IL-12, thyroid hormones and TSH receptor antibodies. The results demonstrated a difference in the balance shift of IL-12/IL-5 between Graves' patients with and without ophthalmopathy. The increased ratio of IL-12 to IL-5 after methimazole therapy could be explained by the elevation of serum IL-12 due to methimazole therapy and the age-related decrease of serum IL-5.
Collapse
Affiliation(s)
- Ildikó Molnár
- 3rd Department of Internal Medicine, Kenézy County and Teaching Hospital, Bartók Bu2-26, Debrecen, Hungary.
| |
Collapse
|
|
20
|
Li B, Jiang B, Boyce BM, Lindsey BA. Multilayer polypeptide nanoscale coatings incorporating IL-12 for the prevention of biomedical device-associated infections. Biomaterials 2009; 30:2552-8. [PMID: 19215980 DOI: 10.1016/j.biomaterials.2009.01.042] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2008] [Accepted: 01/16/2009] [Indexed: 10/21/2022]
Abstract
Biomedical device-associated infection is one of the most common and problematic complications faced by millions of patients worldwide. The current antibiotic therapy strategies face challenges, the most serious of which is antibiotic resistance. Studies have shown that the systemic level of interleukin 12 (IL-12) decreases following major injuries resulting in decreased cell-mediated immune response. Here we report the development of IL-12 nanoscale coatings using electrostatic layer-by-layer self-assembly nanotechnology. We found that IL-12 nanoscale coatings at the implant/tissue interface substantially decrease infections in vivo, and IL-12 nanoscale coatings are advantageous over traditional treatments. This approach could be a revolutionary step toward preventing device-associated infections using a non-antibiotic approach.
Collapse
Affiliation(s)
- Bingyun Li
- Biomaterials, Bioengineering & Nanotechnology Laboratory, Department of Orthopaedics, School of Medicine, West Virginia University, Morgantown, WV 26506-9196, USA.
| | | | | | | |
Collapse
|
|
21
|
Wang Q, Sun B, Wang D, Ji Y, Kong Q, Wang G, Wang J, Zhao W, Jin L, Li H. Murine bone marrow mesenchymal stem cells cause mature dendritic cells to promote T-cell tolerance. Scand J Immunol 2008; 68:607-15. [PMID: 18959624 DOI: 10.1111/j.1365-3083.2008.02180.x] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Bone mesenchymal stem cells (BMSC) are attractive not only in regenerative medicine, but also for the treatment of autoimmune diseases and graft-versus-host disease. BMSC also play a role in enabling alloantigen tolerance. An in-depth mechanistic understanding of this phenomenon of tolerance could lead to novel cell-based therapies for autoimmune disease. We demonstrate here that co-culture of mature dendritic cells (DC) with BMSC in a transwell system (BMSC-DC) downregulated expression of the maturation marker, CD83 and CD80/86 co-stimulatory molecules on DC, while increasing their endocytic activity. This resulted in defective antigen presentation and co-stimulatory capacity of mature DC. Functionally, BMSC-DC have impaired T-cell stimulatory activity in a mixed lymphocyte reaction and orchestrate a shift from predominantly pro-inflammatory T-helper (Th)-1 to anti-inflammatory Th2 cells. While the expression of MHC II, CD80 and CD86 were upregulated on BMSC co-cultured with DC, these BMSC lacked the ability to stimulate T-cell proliferation. Taken together, these data suggest that the interaction between BMSC and DC modulates the immunoregulatory function of these cells in a coordinated manner, effectively skewing the immune response towards T-cell tolerance.
Collapse
Affiliation(s)
- Q Wang
- Department of Neurobiology, Harbin Medical University Provincial Key Lad of Neurobiology, Harbin, Heilongjiang, China
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Takei M, Umeyama A, Shoji N, Hashimoto T. Diterpenes drive Th1 polarization depending on IL-12. Int Immunopharmacol 2008; 8:1602-8. [PMID: 18674641 DOI: 10.1016/j.intimp.2008.07.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2008] [Revised: 07/01/2008] [Accepted: 07/01/2008] [Indexed: 11/24/2022]
Abstract
Sandaracopimaric acid and Sandaracopimaradiene-3beta-ol are diterpenes isolated from the heatwood of Cryptomeria japonica and are pharmacologically active substances. Dendritic cells (DC) are key antigen presenting cells (APC), which link innate and adaptive immunity, ultimately activating antigen-specific T cells. We demonstrate that Sandaracopimaric acid and Sandaracopimaradiene-3beta-ol activate humans DC as documented by phenotypic and functional maturation and altered cytokine production. The expression of the co-stimulatory molecules such as CD83, CD86 and HLA-DR on Sandaracopimaric acid- and Sandaracopimaradiene-3beta-ol-primed DC was enhanced. Sandaracopimaric acid- and Sandaracopimaradiene-3beta-ol-primed DC also enhanced the T cell stimulatory capacity in an allo MLR. Naive T cells co-cultured with Sandaracopimaric acid- or Sandaracopimaradiene-3beta-ol-primed DC turned into typical Th1 cells, which produced large quantities of IFN-gamma and released small amounts of IL-4 depending on IL-12 secretion. Sandaracopimaric acid- or Sandaracopimaradiene-3beta-ol-primed DC had a high migration to macrophage inflammatory protein (MIP)-3beta. These results suggest that some diterpenes modulate human DC function in a fashion that favors Th1 cell polarization and may be used on DC-based vaccines for cancer immunotherapy.
Collapse
Affiliation(s)
- Masao Takei
- Division of Cellular Allergology, Research Center Borstel, Parkallee 22, D-23845, Germany.
| | | | | | | |
Collapse
|
|
23
|
Takei M, Umeyama A, Shoji N, Hashimoto T. Differential Regulation of DC Function by Siphonodiol. Immunopharmacol Immunotoxicol 2008; 30:425-35. [DOI: 10.1080/08923970801949257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
|
|
24
|
Interleukin-12 p40 gene (IL12B) polymorphisms and the risk of cervical caner in Korean women. Eur J Obstet Gynecol Reprod Biol 2008; 140:71-5. [DOI: 10.1016/j.ejogrb.2008.02.007] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2007] [Revised: 12/17/2007] [Accepted: 02/19/2008] [Indexed: 12/19/2022]
|
|
25
|
Okudaira H, Shuto H, Shuto C, Chiba T, Akiyama H, Ohta I, Matsuzaki G. A shadow of Epstein-Barr virus in the pathogenesis of atopic diseases. Clin Exp Allergy 2008. [DOI: 10.1111/j.1365-2222.2001.00996.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
26
|
Takei M, Umeyama A, Shoji N, Hashimoto T. Diterpene, 16-phyllocladanol enhances Th1 polarization induced by LPS-primed DC, but not TNF-alpha-primed DC. Biochem Biophys Res Commun 2008; 370:6-10. [PMID: 18334227 DOI: 10.1016/j.bbrc.2008.02.157] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2008] [Accepted: 02/28/2008] [Indexed: 11/19/2022]
Abstract
16-Phyllocladanol is diterpene isolated form the heartwood of Cryptomeria japonica. We demonstrate that the effect of 16-phyllocladanol on the phenotypic and functional maturation of human monocytes-derived DC in vitro. Human monocytes were exposed to 16-phyllocladanol alone, or in combination with LPS and thereafter co-cultured with naïve T cells. The expression levels of CD83 and HLA-DR on LPS-primed DC were enhanced by 16-phyllocladanol. 16-Phyllocladanol dose-dependently augmented the T cell stimulatory capacity in an allo MLR to LPS-primed DC and the production of IL-12p70 by LPS-primed DC. The cytokine production by 16-phyllocladanol-primed DC was not inhibited by anti-TLR2 and 4 mAbs. IFN-gamma secretion from naïve T cells co-cultured with DC differentiated with LPS was also augmented by 16-phyllocladanol. These results suggest that the enhancement of Th1 cells polarization to LPS-primed DC induced by 16-phyllocladanol via the activation of IL-12p70 and independent on TLR2 or TLR4.
Collapse
Affiliation(s)
- Masao Takei
- Division of Cellular Allergology, Research Center Borstel, Parkallee 22, Borstel D-23845, Germany.
| | | | | | | |
Collapse
|
|
27
|
Takei M, Tachikawa E, Umeyama A. Dendritic Cells Promoted by Ginseng Saponins Drive a Potent Th1 Polarization. Biomark Insights 2008; 3:269-286. [PMID: 19578511 PMCID: PMC2688358 DOI: 10.4137/bmi.s585] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Dendritic cells (DC) play a pivotal role in the initiation of T-cell-mediated immune responses, making them an attractive cellular adjuvant for use in cancer vaccines. The interaction of T cells with DC is crucial for directing T cell differentiation towards the Th1, Th2 or Th17 type, and several factors determining the direction of the T cell polarization. IL-12 plays a central role in the immune system, not only by augmenting the cytotoxic activity of T cells and NK cells and regulating IFN-gamma production, but also by the capacity of IL-12 to promote the development of Th1 cells. Therefore, it is important to identify factors that might affect the differentiation, maturation and function of DC. Ginseng is a medicinal herb widely used in Asian countries, and many of its pharmacological actions are attributed to the ginsenosides. Moreover, T-cadinol and calamenene are sesquterpenes isolated from the heartwood of Cryptomeria japonica being pharmacologically active substances. We investigated whether M1 and M4, end products of steroidal ginseng saponins metabolized in digestive tracts, as well as T-cadinol and calamenene can drive DC maturation from human monocytes in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days under standard conditions, followed by another 2 days in the presence of M1, M4, T-cadinol or calamenene. The expression levels of CD1a, CD80, CD83, CD86 and HLA-DR on M1-primed DC, M4-primed DC, T-cadinol-primed DC and calamenene-primed DC were enhanced with a concomitant decrease in endocytic activity. M1-primed DC, M4-primed DC, T-cadinol-primed DC or calamenene-primed DC enhanced the T cell stimulatory capacity in an allo MLR (allogeneic mixed lymphocyte reaction). Naïve T cells co-cultured with allogeneic M1-primed DC, M4-primed DC, T-cadinol-primed DC or calamenene-primed DC turned into typical Th1 cells, which produced large quantities of IFN-gamma and released small amounts of IL-4 depending on IL-12 secretion. In the CTL assay (cytotoxic T-lymphocyte assay), the production of IFN-gamma and (51)Cr release on M4-primed DC was more augmented than of immature DC or TNF-alpha-primed DC. These results suggest that M1, M4, T-cadinol and calamenene appear to be a good factor to induce DC maturation, or even better in some respect, for the use in clinical DC therapy to induce strong Th1 type immune responses.
Collapse
Affiliation(s)
- Masao Takei
- Division of Cellular Allergology, Research Center Borstel, Parkallee 22, D-23845, Germany
| | - Eiichi Tachikawa
- Department of Pharmacology, Iwate medical University, Uchimaru 19-1, Morioka 020-8505, Japan
| | - Akemi Umeyama
- Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770–8514, Japan
| |
Collapse
|
|
28
|
Johansen P, Senti G, Maria Martínez Gómez J, Kündig TM. Medication with antihistamines impairs allergen-specific immunotherapy in mice. Clin Exp Allergy 2008; 38:512-9. [DOI: 10.1111/j.1365-2222.2007.02904.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
|
|
29
|
Martino A, Volpe E, Auricchio G, Izzi V, Poccia F, Mariani F, Colizzi V, Baldini PM. Sphingosine 1-Phosphate Interferes on the Differentiation of Human Monocytes into Competent Dendritic Cells. Scand J Immunol 2007; 65:84-91. [PMID: 17212771 DOI: 10.1111/j.1365-3083.2006.01860.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Sphingosine 1-phosphate (S1P) is a lipidic messenger known to exert several physiological functions within the cell. We tested here whether the stimulation of human monocytes with different doses of S1P might interfere with their differentiation into competent dendritic cells (DC). Monocytes cultured with granulocyte macrophage colony stimulating factor, interleukin-4 (IL-4) and S1P differentiated into a DC population lacking CD1a molecules on the surface and acquired some aspects of mature DC (mDC), though in the absence of maturation stimuli. When stimulated with lipopolisaccharide (LPS), CD1a(-) DC produce high amounts of tumour necrosis factor-alpha and IL-10, but not IL-12. Accordingly, these CD1a(-) DC were not capable of stimulating allogenic T lymphocytes so well as CD1a(+) DC generated from untreated monocytes and maturated with LPS. S1P monocyte-derived DC lost their polarizing capacity abrogating the production of gamma-interferon/IL-4 by co-cultured naïve CD4(+)CD45RA(+) T cells. Our findings suggest a mechanism through which S1P can favour the development of immune-related pathological states.
Collapse
Affiliation(s)
- A Martino
- National Institute for Infectious Diseases Lazzaro Spallanzani, IRCCS, Rome, Italy.
| | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Brummer E, Vinoda V, Stevens DA. IL-12 induction of resistance to pulmonary blastomycosis. Cytokine 2006; 35:221-8. [PMID: 17067810 DOI: 10.1016/j.cyto.2006.08.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2006] [Accepted: 08/21/2006] [Indexed: 11/22/2022]
Abstract
BACKGROUND Why severity varies in blastomycosis outbreaks remains unresolved. In experimental pulmonary blastomycosis, susceptibility varied in mouse strains. In susceptible BALB/c the response is Th-2, in immunized, resistance is associated with Th-1. Can susceptibility be redirected by IL-12? Methods, results: BALB/c bronchoalveolar and peritoneal macrophages (PM) were shown deficient in IL-12 production in response to IFN-gamma+LPS. High dose IL-12 (1 microg, subcutaneously) treatment of BALB/c infected intranasally with Blastomyces resulted in enhanced survival (P<0.008). Since IL-12 was poorly tolerated, a new protocol for infected mice, IL-12 0.1 or 0.3 microg, every other day, resulted in minimal toxicity; almost all treated mice survived (P<0.002 vs. controls). When lungs of surviving mice were cultured, the 0.1 microg regimen resulted in fewer (P<0.02) cfu. For weeks after treatment, in vitro IFN-gamma treatment enabled PM Blastomyces killing. After infection spleen cells from IL-12 treated mice produced 4-fold more IFN-gamma and 3-fold less IL-10 in response to Blastomyces. IL-10 abrogated activation of macrophages by IFN-gamma for enhanced Blastomyces killing. CONCLUSIONS A proper IL-12 treatment protocol induces resistance (survival and decreased growth in lungs), low toxicity, macrophage responsiveness to IFN-gamma for killing Blastomyces, up-regulation of IFN-gamma and down-regulation of IL-10 production.
Collapse
Affiliation(s)
- Elmer Brummer
- Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA 95128-2699, USA
| | | | | |
Collapse
|
|
31
|
Saegusa K, Yotsumoto S, Kato S, Aramaki Y. Phosphatidylinositol 3-kinase-mediated regulation of IL-10 and IL-12 production in macrophages stimulated with CpG oligodeoxynucleotide. Mol Immunol 2006; 44:1323-30. [PMID: 16824602 DOI: 10.1016/j.molimm.2006.05.008] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2006] [Revised: 05/23/2006] [Accepted: 05/24/2006] [Indexed: 01/22/2023]
Abstract
The aim of this study was to clarify the role of phosphatidylinositol 3-kinase (PI3K) on the production of interleukine-10 (IL-10) and IL-12 in mouse peritoneal macrophages stimulated with CpG-ODN. CpG-ODN-induced IL-10 mRNA expression and protein production decreased following the treatment of macrophages with wortmannin and LY294002, specific inhibitors for PI3K. In contrast, IL-12 p40 mRNA expression and p70 protein production increased. Neutralizing anti-IL-10 monoclonal antibody (anti-IL-10 mAb) exactly mimicked the effects of PI3K inhibitors to enhance IL-12 p70 production. The enhancement effect of PI3K inhibitors on IL-12 p70 production almost completely disappeared by the treatment with anti-IL-10 mAb. PI3K inhibitors suppressed the activation of extracellular-regulated kinase (ERK), a member of the mitogen-activated protein kinases, by CpG-ODN. A specific ERK inhibitor, U0126, as well as PI3K inhibitors, differentially regulated IL-10 and IL-12 p70 productions. These results suggest that PI3K positively and negatively regulates the production of CpG-ODN-induced IL-10 and IL-12 p70, respectively, and negatively regulates IL-12 p70 production in macrophages through ERK-mediated IL-10 induction.
Collapse
Affiliation(s)
- Kazuharu Saegusa
- School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
| | | | | | | |
Collapse
|
|
32
|
Takei M, Nakagawa H. A sea urchin lectin, SUL-1, from the Toxopneustid sea urchin induces DC maturation from human monocyte and drives Th1 polarization in vitro. Toxicol Appl Pharmacol 2006; 213:27-36. [PMID: 16197973 DOI: 10.1016/j.taap.2005.08.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2005] [Revised: 08/11/2005] [Accepted: 08/15/2005] [Indexed: 11/25/2022]
Abstract
The sea urchin Toxopneustes pileolus belonging to the family Toxopneustidae, they have well-developed globiferous pedicellariae with pharmacologically active substances. We have purified a novel sea urchin lectin-1 (SUL-1) from the large globiferous pedicellariae of T. pileolus. Dendritic cells (DC) are professional APC and play a pivotal role in controlling immune responses. This study investigated whether SUL-1 can drive DC maturation from human immature monocyte-derived DC in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days followed by another 1 day in the presence of SUL-1 or LPS. DC harvested on day 7 were examined using functional assays. The expression levels of CD1a, CD80, CD83, CD86 and HLA-DR as expressed by mean fluorescence intensity (MFI) on DC differentiated from immature DC after culture with 1.0 microg/ml of SUL-1 for 1 day were enhanced and decreased endocytic activity. SUL-1-treated DC also displayed enhanced T cell stimulatory capacity in an MLR, as measured by T cell proliferation. Cell surface expression of CD80, CD83 and CD86 on SUL-1-treated DC was inhibited by anti-DC-SIGN mAb, while anti-DC-SIGN mAb had no influence on allogeneic T cell proliferation by SUL-1-treated DC. DC differentiated with SUL-1 induced the differentiation of naïve T cell towards a helper T cell type 1 (Th1) response at DC/T (1:5) cells ratio depending on IL-12 secretion. In CTL assay, the production of IFN-gamma and 51Cr release on SUL-1-treated DC were more augmented than of immature DC or LPS-treated DC. SUL-1-treated DC expressed CCR7 and had a high migration to MIP-3beta. Intracellular Ca2+ mobilization in SUL-1-treated DC was also induced by MIP-3beta. These results suggest that SUL-1 bindings to DC-SIGN on surface of immature DC may lead to differentiate DC from immature DC. Moreover, it suggests that SUL-1 may be used on DC-based vaccines for cancer immunotherapy.
Collapse
Affiliation(s)
- Masao Takei
- Division of Cellular Allergology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany.
| | | |
Collapse
|
|
33
|
Takei M, Umeyama A, Arihara S. T-cadinol and calamenene induce dendritic cells from human monocytes and drive Th1 polarization. Eur J Pharmacol 2006; 537:190-9. [PMID: 16631732 DOI: 10.1016/j.ejphar.2006.02.047] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2005] [Revised: 02/15/2006] [Accepted: 02/21/2006] [Indexed: 10/24/2022]
Abstract
T-cadinol and calamenene are sesquiterpenes isolated from the heartwood of Cryptomeria japonica and are pharmacologically active substances. Dendritic cells are pivotal in the initiation of adaptive immune responses and are recognized as key to the induction of immune responses to cancer. This study investigated the effects of T-cadinol and calamenene on the phenotypic and functional maturation of human monocyte-derived dendritic cells in vitro. Human monocytes were cultured with recombinant human granulocyte-macrophage colony-stimulation factor (GM-CSF) and recombinant human interleukin-4 (IL-4) for 6 days under standard conditions, followed by another 2 days in the presence of T-cadinol, calamenene, lipopolysaccharide (LPS), CT or nifedipine. Dendritic cells harvested on day 8 were examined using functional assays. The expression levels of CD1a, CD80, CD83, CD86 and HLA-DR on T-cadinol-primed dendritic cells or calamenene-primed dendritic cells were enhanced with a concomitant decrease in endocytic activity. T-cadinol-primed dendritic cells or calamenene-primed dendritic cells also enhanced the T cell stimulatory capacity in an allogeneic mixed lymphocyte reaction, as measured by T cell proliferation. Naïve T cells co-cultured with allogeneic T-cadinol-primed dendritic cells or calamenene-primed dendritic cells at 1:5 dendritic cells/T cell ratio turned into typical Th1 cells which produced large quantities of interferon-gamma (IFN-gamma) and released small amounts of IL-4 depending on IL-12 secretion. In contrast, naïve T cells co-cultured with CT-primed dendritic cells turned into Th2 cells. T-cadinol-primed dendritic cells and calamenene-primed dendritic cells expressed the chemokine receptor CCR7 and had a high migration to macrophage inflammatory protein (MIP-3beta). Intracellular Ca(2+) mobilization in T-cadinol-primed dendritic cells and calamenene-primed dendritic cells was induced by MIP-3beta. The differentiation and functional maturation of human monocyte-derived dendritic cells were not affected by nifedipine. These results suggest that T-cadinol and calamenene may be used in dendritic cells-based immunotherapy for cancer.
Collapse
Affiliation(s)
- Masao Takei
- Division of Cellular Allergology, Research Center Borstel, Parkallee 22, D-23845, Germany.
| | | | | |
Collapse
|
|
34
|
Bozkurt N, Yuce K, Basaran M, Gariboglu S, Kose F, Ayhan A. Correlation of serum and ascitic IL-12 levels with second-look laparotomy results and disease progression in advanced epithelial ovarian cancer patients. Int J Gynecol Cancer 2006; 16:83-6. [PMID: 16445615 DOI: 10.1111/j.1525-1438.2006.00464.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Forty-two consecutive patients with advanced epithelial ovarian cancer who underwent primary surgical treatment were evaluated. The control group comprised 21 patients who had undergone surgery associated with benign pathologies. Forty-one patients had stage III disease except one who had stage IV. Optimal debulking (<1 cm) was performed in all the patients who subsequently received chemotherapy. Based on the results of the second-look laparotomy and follow-up, the patients were divided into three groups: the first group had negative second-look laparotomy or no evidence of disease during follow-up (n= 21), the second group had positive second-look laparotomy or progressive disease (n= 21), and the third was the control group (n= 21). Interleukin-12 (IL-12) levels were measured in preoperative serum and intraoperative ascites samples for all the patients. The mean serum IL-12 levels (+/-SD) in serum (S) and ascites (A) were as follows: in the first group, S: 108.44 +/- 76.40 pg/mL and A: 330.93 +/- 125.25 pg/mL; in the second group, S: 51.80 +/- 40.95 pg/mL and A: 206.89 +/- 113.47 pg/mL; and in the control group, S: 36.55 +/- 33.16 pg/mL and A: 93.62 +/- 73.07 pg/mL (P= 0.01). In the patients with advanced ovarian cancer, IL-12 levels in serum and ascites were higher compared to the levels of the controls. Also, there was an inverse relationship between initial serum and ascitic IL-12 levels and disease progression.
Collapse
Affiliation(s)
- N Bozkurt
- Department of Obstetrics and Gynecology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
| | | | | | | | | | | |
Collapse
|
|
35
|
Takei M, Umeyama A, Arihara S, Matsumoto H. Effect of Piceatannol in Human Monocyte-Derived Dendritic Cells In Vitro. J Pharm Sci 2005; 94:974-82. [PMID: 15793803 DOI: 10.1002/jps.20279] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Piceatannol is an anti-inflammatory, immunomodulatory, and antiproliferative stilbene that has been shown to interfere with the cytokine signaling pathway. Dendritic cells (DCs) play a pivotal in the initiation of T-cell-mediated immune responses, making them an attractive cellular adjuvant for use in cancer vaccines. This study investigated the effect of piceatannol on the phenotypic and functional maturation of human monocyte-derived DCs in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days, followed by another 2 days in the presence of piceatannol or LPS. DCs harvested on day 8 were examined using functional assays. The expression levels of CD1a, CD80, CD83, and CD86 as expressed by mean fluorescence intensity (MFI) on DCs differentiated from immature DCs after culture with 1 muM of piceatannol for 2 days were enhanced and decreased endocytic activity. Piceatannol-treated DCs also displayed enhanced T-cell stimulatory capacity in a MLR, as measured by T-cell proliferation. Similar results were obtained with DCs differentiated with LPS from immature DCs. However, piceatannol did not inhibit phenotypic and functional maturation induced by LPS from immature DCs. Piceatannol-treated DCs induced the differentiation of naive T cells towards a helper T-cell type 1 (Th1) response at DCs/T (1:5) cells ratio depending on IL-12 secretion. These results demonstrate that piceatannol may be used on DC-based vaccine for cancer immunotherapy.
Collapse
Affiliation(s)
- Masao Takei
- Division of Cellular Allergology, Research Center Borstel, Parkallee 22, D-23845, Borstel, Germany.
| | | | | | | |
Collapse
|
|
36
|
Li W, Yajima T, Saito K, Nishimura H, Fushimi T, Ohshima Y, Tsukamoto Y, Yoshikai Y. Immunostimulating properties of intragastrically administered Acetobacter-derived soluble branched (1,4)-beta-D-glucans decrease murine susceptibility to Listeria monocytogenes. Infect Immun 2004; 72:7005-11. [PMID: 15557623 PMCID: PMC529118 DOI: 10.1128/iai.72.12.7005-7011.2004] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
We previously found that AC-1, an extracellular polysaccharide, produced by Acetobacter xylinum and composed of (1,4)-beta-D-glucan with branches of glucosyl residues, showed a strong activity to induce production of interleukin-12 (IL-12) p40 and tumor necrosis factor alpha by macrophages in vitro via Toll-like receptor 4 (TLR-4) signaling. In the present study, we examined the effect of oral administration of AC-1 on protective immunity against Listeria monocytogenes. Mice were given AC-1 or phosphate-buffered saline (PBS) intragastrically 2 days before, on the day of, and 2 days after an intraperitoneal inoculation of L. monocytogenes. The survival rate of AC-1-treated mice was significantly improved and bacterial growth in AC-1-treated mice was severely retarded compared to those of PBS-treated mice after infection with L. monocytogenes. IL-12 p40 levels in serum and magnitudes of CD4+ Th1 and CD8+ Tc1 responses against Listeria antigen were significantly higher in AC-1-treated mice than in PBS-treated mice. The effect of AC-1 on antilisterial activity was diminished in C3H/HeJ mice carrying mutated TLR-4. Thus, AC-1, a potent IL-12 inducer through TLR-4, enhanced protective immunity against L. monocytogenes via augmentation of Th1 responses. These results suggest that infectious processes driven by intracellular microorganisms could be prevented to develop by the (1,4)-beta-D-glucan.
Collapse
Affiliation(s)
- Wei Li
- Division of Host Defense, Research Center for Prevention of Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Tavakoli S, Schwerin W, Rohwer A, Hoffmann S, Weyer S, Weth R, Meisel H, Diepolder H, Geissler M, Galle PR, Löhr HF, Böcher WO. Phenotype and function of monocyte derived dendritic cells in chronic hepatitis B virus infection. J Gen Virol 2004; 85:2829-2836. [PMID: 15448344 DOI: 10.1099/vir.0.80143-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The antiviral T cell failure of patients with chronic hepatitis B virus (HBV) infection was suggested to be caused by a T cell stimulation defect of dendritic cells (DC). To address this hypothesis, monocyte derived DC (MDDC) of patients with chronic or resolved acute HBV infection and healthy controls were studied phenotypically by FACS analyses and functionally by mixed lymphocyte reaction, ELISA, ELISpot and proliferation assays of MDDC cultures or co-cultures with an allogeneic HBc-specific Th cell clone. HBV infection of MDDC was studied by quantitative PCR. MDDC from HBV patients seemed to be infected by the HBV, showed a reduced surface expression of HLA DR and CD40 and exhibited a reduced secretion of IL12p70 in response to HBcAg but not to LPS, as compared to control MDDC. However, after cytokine induced maturation, MDDC from HBV patients revealed an unimpaired phenotype. Moreover, the T cell stimulatory capacity of HBV-DC was intact, since (i) the induction of allospecific proliferative and IFN-gamma responses was not affected in HBV-MDDC, and (ii) HLA DR7 restricted stimulation of an allogeneic HBc-specific Th cell clone was not impaired by HBV-MDDC compared to control MDDC. It is hypothesized that HBV infection of DC might lead to minor phenotypic and functional alterations without significantly affecting their antiviral Th cell stimulatory capacity.
Collapse
Affiliation(s)
- Soheila Tavakoli
- Department of Internal Medicine I, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Wibke Schwerin
- Department of Internal Medicine I, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Andreas Rohwer
- Department of Internal Medicine I, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Sina Hoffmann
- Department of Internal Medicine I, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Sandra Weyer
- Department of Internal Medicine I, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Robert Weth
- Department of Internal Medicine II, University of Freiburg, Germany
| | - Helga Meisel
- Department of Virology, Humboldt University, Berlin, Germany
| | - Helmut Diepolder
- Department of Internal Medicine II, Klinikum Grosshadern, University of Munich, Germany
| | - Michael Geissler
- Department of Internal Medicine II, University of Freiburg, Germany
| | - Peter R Galle
- Department of Internal Medicine I, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Hanns F Löhr
- Department of Internal Medicine I, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Wulf O Böcher
- Department of Internal Medicine I, Johannes Gutenberg University, Langenbeckstrasse 1, 55131 Mainz, Germany
| |
Collapse
|
|
38
|
Randolph AG, Lange C, Silverman EK, Lazarus R, Silverman ES, Raby B, Brown A, Ozonoff A, Richter B, Weiss ST. The IL12B gene is associated with asthma. Am J Hum Genet 2004; 75:709-15. [PMID: 15322986 PMCID: PMC1182059 DOI: 10.1086/424886] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2004] [Accepted: 08/04/2004] [Indexed: 11/03/2022] Open
Abstract
The IL12B gene on chromosome 5q31-33 encodes the p40 subunit of interleukin 12, an immunomodulatory cytokine. To test the hypothesis that the IL12B gene contains polymorphisms associated with asthma, we genotyped six haplotype-tagging polymorphisms in the IL12B gene, both in 708 children enrolled in the Childhood Asthma Management Program (CAMP) and in their parents. Using the family-based association test (FBAT) program and its haplotype (HBAT) and phenotype (PBAT) options, we tested each polymorphism and haplotype for association with asthma and asthma-related phenotypes. We tested positive associations for replication in a case-control study comparing 177 adult moderate-to-severe asthmatics with 177 nonasthmatic controls. In whites in the CAMP cohort, the A allele of the IL12B G4237A polymorphism was undertransmitted to asthmatic children (P=.0008, recessive model), the global test for haplotypes for affection status was positive (P=.009, multiallelic chi (2)), and two polymorphisms were associated with different atopy phenotypes. In addition, we found a strong association between the IL12B_4237 and IL12B_6402 polymorphisms and an asthma-severity phenotype in whites, which we also found in the independent population of white adult asthmatics. IL12B may be an important asthma gene.
Collapse
Affiliation(s)
- Adrienne G Randolph
- Channing Laboratory, Brigham and Women's Hospital, Department of Anesthesia, Children's Hospital, and Harvard Medical School, Boston, MA, USA.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Takei M, Tachikawa E, Hasegawa H, Lee JJ. Dendritic cells maturation promoted by M1 and M4, end products of steroidal ginseng saponins metabolized in digestive tracts, drive a potent Th1 polarization. Biochem Pharmacol 2004; 68:441-52. [PMID: 15242811 DOI: 10.1016/j.bcp.2004.04.015] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2003] [Accepted: 04/22/2004] [Indexed: 12/01/2022]
Abstract
Ginseng is a medicinal herb widely used in Asian countries, and many of its pharmacological actions are attributed to the ginsenosides. Dendritic cells (DCs) play a pivotal in the initiation of T-cell-mediated immune responses, making them an attractive cellular adjuvant for use in cancer vaccines. In this study, we investigated whether M1 and M4, end products of steroidal ginseng saponins metabolized in digestive tracts, can drive DCs maturation from human monocytes in vitro. Human monocytes were cultured with GM-CSF and IL-4 for 6 days, followed by another 2 days in the presence of M1, M4 or TNF-alpha as a maturation stimulus. Stimulation with 20 microM of M1 or M4 increased expression level of CD80, CD83 and CD86 as expressed by mean fluorescence intensity (MFI) and decreased endocytic activity. M4-primed mature DCs also displayed enhanced T cells stimulatory capacity in a MLR, as measured by T cell proliferation. Mature DCs differentiated with M1 or M4 induced the differentiation of naïve T cells towards a helper T cell type 1 (Th1) response at DC/T (1:5) cells ratio depending on IL-12 secretion. In CTL assay, the production of IFN-gamma and 51Cr release on M4-primed mature DCs was more augmented than of immature DCs or TNF-alpha-primed mature DCs. These results suggest that M4 may be used on DC-based vaccines for cancer immunotherapy.
Collapse
Affiliation(s)
- Masao Takei
- Division of Cellular Allergology, Research Center Borstel, Parkallee 22 D-23845, Germany.
| | | | | | | |
Collapse
|
|
40
|
Balu S, Kaiser P. Avian interleukin-12beta (p40): cloning and characterization of the cDNA and gene. J Interferon Cytokine Res 2004; 23:699-707. [PMID: 14769146 DOI: 10.1089/107999003772084815] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We isolated the chicken interleukin-12 (ChIL-12) p40 cDNA from a concanavalin A (ConA)-stimulated spleen cDNA library using the PCR with primers based on a partial 3' EST sequence in a chicken EST library. The cDNA encodes a polypeptide of 315 amino acids (aa), with a predicted mature peptide of 300 aa. ChIL-12 p40 has 46% and 41% amino acid identity with human (HuIL-12) and murine IL-12 (MuIL-12) p40, respectively. We also isolated a partial turkey IL-12 (TuIL-12) p40 cDNA sequence with 95% predicted aa identity with ChIL-12 p40. The structures of the ChIL-12 p40 gene and its promoter were determined by direct sequencing of a chicken BAC identified by hybridization with the cDNA. The gene structures of HuIL-12, MuIL-12, and ChIL-12 p40 all differ. The promoter of the ChIL-12 p40 gene shares some (an ETS consensus sequence, a C/EBP binding site, and a TATA box) but not all (an NF-kappaB binding site and a GA12 site are absent) of the transcription factor binding sites identified in the human and murine promoters. IL-12 p40 mRNA expression was identified in a wide variety of tissues and in B, T, and macrophage cell lines by RT-PCR.
Collapse
Affiliation(s)
- Sucharitha Balu
- Institute for Animal Health, Compton, Berkshire RG20 7NN, U.K.
| | | |
Collapse
|
|
41
|
Degen WGJ, van Daal N, van Zuilekom HI, Burnside J, Schijns VEJC. Identification and molecular cloning of functional chicken IL-12. THE JOURNAL OF IMMUNOLOGY 2004; 172:4371-80. [PMID: 15034052 DOI: 10.4049/jimmunol.172.7.4371] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
By a combination of large-scale sequencing, bioinformatics, and traditional molecular biology, we identified the long-searched-for cDNA sequences encoding the homologues of the chicken IL-12p35 and IL-12p40 chains. These molecules are the first discovered nonmammalian IL-12 subunits. The homologies of the chicken IL-12p35 and IL-12p40 proteins to the corresponding known subunits of various species, i.e., humans, sheep, horse, cat, bovine, mouse, and woodchuck, ranged between 21 and 42%, respectively. The expression of IL-12 subunits was observed in lymphoid cells and proved to be dependent on the cell type and stimulus, while expression was not detected in stimulated primary chicken embryo fibroblast cells. Following transient expression of both molecules in COS-7 cells, we confirmed the necessity of heterodimerization into IL-12p70 to yield bioactivity as was also shown for its mammalian counterparts. The chicken IL-12p70 molecule, generated either by transient coexpression of monomeric IL-12p35 and monomeric IL-12p40 or as a fusion protein (as in a fusion linker construct), induced IFN-gamma synthesis and proliferative activity of freshly exposed chicken splenocytes. The high degree of functional similarity between chicken IL-12 and IL-12 of higher mammalian vertebrates, despite their poor sequence homology, illustrates the conservation and vital importance of the IL-12 molecule since the evolutionary dichotomy of birds and mammals >300 million years ago. In this article, we describe the first nonmammalian IL-12 molecule and show that this chicken IL-12 molecule is bioactive.
Collapse
Affiliation(s)
- Winfried G J Degen
- Department of Vaccine Technology and Immunology, Intervet International BV, Boxmeer, The Netherlands.
| | | | | | | | | |
Collapse
|
|
42
|
Gentile DA, Schreiber R, Howe-Adams J, Trecki J, Patel A, Angelini B, Skoner DP. Diminished dendritic cell interleukin 10 production in atopic children. Ann Allergy Asthma Immunol 2004; 92:538-44. [PMID: 15191022 DOI: 10.1016/s1081-1206(10)61761-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Diminished interleukin 10 (IL-10) and/or IL-12 production may contribute to the pathogenesis of asthma and atopy. Dendritic cells (DCs) produce these cytokines and have been implicated in the pathogenesis of these disorders. OBJECTIVE To determine whether DC IL-10 and/or IL-12 production is diminished in children aged 6 to 12 years with allergic rhinitis (AR) and with or without asthma. METHODS Monocyte-derived DCs were isolated from 20 subjects without AR or asthma (group 1), 20 subjects with AR without asthma (group 2), and 20 subjects with AR and asthma (group 3). Asthma was defined as a history of physician-diagnosed disease, and AR was defined as a positive history and positive puncture skin test responses (wheal > or = 5 mm) to relevant inhalant allergens. DCs were stimulated with either lipopolysaccharide (LPS) or diluent and cultured for 24 hours. Supernatants were assayed for IL-10 and IL-12 levels by enzyme-linked immunosorbent assay. RESULTS DC IL-10 production was diminished in groups 2 and 3 compared with group 1. Median LPS-induced IL-10 levels were 11.0 pg/mL in group 1, 6.1 pg/mL in group 2, and 1.5 pg/mL in group 3. The frequencies of subjects with detectable IL-10 levels were 85%, 20%, and 20% in groups 1, 2 and 3, respectively. Median LPS-induced IL-12 levels were similar in all groups. CONCLUSIONS These data support the hypothesis that atopic subjects have an intrinsic inability to up-regulate DC IL-10 production. Future studies in this area could lead to a better understanding of the pathogenesis of atopy.
Collapse
Affiliation(s)
- Deborah A Gentile
- Division of Allergy, Asthma and Immunology, Department of Pediatrics, Allegheny General Hospital, Pittsburgh, Pennsylvania 15212, USA.
| | | | | | | | | | | | | |
Collapse
|
|
43
|
Kubo S, Takahashi HK, Takei M, Iwagaki H, Yoshino T, Tanaka N, Mori S, Nishibori M. E-prostanoid (EP)2/EP4 receptor-dependent maturation of human monocyte-derived dendritic cells and induction of helper T2 polarization. J Pharmacol Exp Ther 2004; 309:1213-20. [PMID: 14872092 DOI: 10.1124/jpet.103.062646] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Prostaglandin (PG) E(2) induces dendritic cell maturation in cooperation with proinflammatory cytokines [such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta]. To clarify the involvement of E-prostanoid (EP) receptors in the effect of prostaglandin E(2) on human monocyte-derived dendritic cell (MoDC) maturation, we examined the effect of four types of EP receptor-selective agonists on MoDC maturation. PGE(2) as well as 11,15-O-dimethyl prostaglandin (E(2)ONO-AE1-259-01) (EP2 receptor agonist) and ONO-AE1-329 (EP4 receptor agonist) concentration dependently enhanced the expression of CD80, CD86, CD83, and HLA-DR on MoDCs during maturation, especially in the presence of TNF-alpha, whereas 17S-2,5-ethano-6-oxo-17,20-dimethyl prostaglandin E(1) (EP1 receptor agonist) and 16S-9-deoxy-9beta-chloro-15-deoxy-16-hyfroxy-17,17-trimethylene-19,20-didehydro prostaglandin F(2) (EP3 receptor agonist) showed no effect. The maximal effect of ONO-AE1-259-01 was higher than that of ONO-AE1-329; however, the stimulation with ONO-AE1-259-01 was less effective than that with PGE(2). Simultaneous stimulation with both EP receptor agonists produced additive effects and 11-deoxy-PGE(1) (EP2/EP4 receptor mixed agonist) mimicked the effects of PGE(2). Dibutyryl cAMP mimicked the effects of PGE(2), indicating the mediation of PGE(2) action by cAMP. Matured MoDCs induced by PGE(2) or EP2 and/or EP4 receptor agonists showed a decrease in lipopolysaccharide (LPS)-stimulated IL-12p70, IL-6, and IL-10 production. The coculture of naive T cells with matured MoDCs induced under different conditions showed that EP2/EP4-stimulated MoDCs preferentially induced alloresponsive helper T (Th)2 cells. Together, it was concluded that the cooperative stimulation of EP2 and EP4 receptor subtypes by PGE(2) promoted MoDC maturation and inhibited LPS-induced cytokine production in MoDCs. The matured MoDCs under such conditions preferably induced Th2 polarization, indicating the importance of EP2 and EP4 receptors in the determination of Th1/Th2 development of naive T cells.
Collapse
Affiliation(s)
- Shinichiro Kubo
- Department of Pharmacology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan.
| | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Dines I, Rumjanek VM, Persechini PM. What Is Going on with Natural Killer Cells in HIV Infection? Int Arch Allergy Immunol 2004; 133:330-9. [PMID: 15031606 DOI: 10.1159/000077352] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2002] [Accepted: 10/30/2003] [Indexed: 11/19/2022] Open
Abstract
Natural killer (NK) cells represent 10-15% of circulating lymphocytes and are important mediators of both natural and adaptive immunity. They participate in immune surveillance against malignancies and virus infection and are involved in the complex immune responses of transplantation, autoimmune diseases and immunosuppression. They can also mediate physiological regulation of hematopoiesis, homeostasis of reproduction and placentation. In recent years new advances have been achieved in understanding the mechanisms whereby NK cells exert their cytotoxic and regulatory roles. Here, we review the physiology of NK cells with special attention to its role in HIV infection.
Collapse
Affiliation(s)
- Ilana Dines
- Laboratório Multidisciplinar de Pesquisa, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brasil.
| | | | | |
Collapse
|
|
45
|
Batchelder JM, Burns JM, Cigel FK, Lieberg H, Manning DD, Pepper BJ, Yañez DM, van der Heyde H, Weidanz WP. Plasmodium chabaudi adami: interferon-gamma but not IL-2 is essential for the expression of cell-mediated immunity against blood-stage parasites in mice. Exp Parasitol 2004; 105:159-66. [PMID: 14969693 DOI: 10.1016/j.exppara.2003.12.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2003] [Revised: 11/03/2003] [Accepted: 12/01/2003] [Indexed: 11/16/2022]
Abstract
Cell-mediated immunity (CMI) may be important in immunity against blood-stage malaria. Accordingly, we examined the role of type 1 cytokines in the resolution of Plasmodium chabaudi adami malaria in mice genetically modified to have type 1 cytokine gene defects. Parasitemia was prolonged in double knockout (IL-2(-/-), IFNgamma(-/-)) mice compared to control mice. Despite deficiencies in gammadelta T cell and B cell subsets, these mice produced anti-malarial antibodies and eventually cured their infections, possibly by antibody-mediated immunity. However, because acute P. c. adami parasitemia may also be suppressed by CMI, the requirements for IL-2 and IFNgamma were evaluated in mice lacking B cells and functional IL-2 or IFNgamma genes. Acute malaria in J(H)(-/-), IL-2(-/-) mice was prolonged, but eventually cured. In contrast, J(H)(-/-), IFNgamma(-/-) mice developed unremitting parasitemia. These data strongly suggest that IFNgamma, but not IL-2, plays an essential role in the expression of CMI against P. c. adami infections. This finding may prove useful in developing malarial vaccines aimed at inducing CMI.
Collapse
Affiliation(s)
- Joan M Batchelder
- Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, Madison, WI, USA
| | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Kawakami K. Promising immunotherapies with Th1-related cytokines against infectious diseases. J Infect Chemother 2003; 9:201-9. [PMID: 14513386 DOI: 10.1007/s10156-003-0263-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2003] [Indexed: 11/29/2022]
Abstract
In recent years, there has been an increase in the number of individuals with compromised immune systems. This is due to the rise in the numbers of aging people, patients receiving immunosuppressive treatment after organ transplantation, patients with hematological malignancies, and patients with AIDS. These individuals frequently fall into helper T cell (Th)1-Th2 cytokine imbalance due to a shift towards a Th2-dominant condition. Such a pathological condition puts them at a high risk for developing infectious diseases caused by a variety of microbial pathogens which are often refractory to conventional chemotherapy. Therefore, the administration of Th1-related cytokines is expected to be promising immunotherapy against these intractable infectious diseases. In a series of investigations, we have demonstrated the effectiveness of treatment with Th1-related cytokines, such as interferon (IFN)-gamma, interleukin (IL)-12, and IL-18, in protecting animals from experimental infectious diseases caused by Mycobacterium tuberculosis and Cryptococcus neoformans. Recently, several investigators reported successful clinical treatment with IFN-gamma or IL-12 in patients with intractable tuberculous and nontuberculous mycobacteriosis. Thus, now is an appropriate time for scientific evaluation to clinically confirm the effectiveness of these novel immunotherapies.
Collapse
Affiliation(s)
- Kazuyoshi Kawakami
- Division of Infectious Diseases, Department of Internal Medicine, Graduate School and Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
| |
Collapse
|
|
47
|
Macaubas C, de Klerk NH, Holt BJ, Wee C, Kendall G, Firth M, Sly PD, Holt PG. Association between antenatal cytokine production and the development of atopy and asthma at age 6 years. Lancet 2003; 362:1192-7. [PMID: 14568741 DOI: 10.1016/s0140-6736(03)14542-4] [Citation(s) in RCA: 183] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND Various lines of evidence suggest that antenatal factors are important in determining susceptibility to atopy and asthma. One possible mechanism is cytokines, production of which in the placenta is high throughout gestation and which protect placental integrity via control of local immunological homoeostasis. We investigated antenatal cytokine concentrations in a prospective birth cohort, intensively monitored for atopy and asthma outcomes at age 6 years. METHODS Cryopreserved cord-blood serum samples from 407 children were assayed for interleukins 4, 5, 6, 10, 12, and 13, interferon gamma, and tumour necrosis factor alpha (TNFalpha). Associations between family, antenatal, and perinatal factors, cord-blood cytokine concentrations, and atopy or asthma outcomes were analysed by logistic regression. Causal effects of cytokines on outcomes were estimated by propensity scores based on family, antenatal, and perinatal factors. FINDINGS Detectable cord-blood concentrations of interleukin 4 and interferon gamma were each associated with lower risk of physician-diagnosed asthma (adjusted odds ratios 0.60 [95% CI 0.37-0.99] and 0.60 [0.37-0.97] respectively), current asthma (0.59 [0.33-1.00] and 0.39 [0.22-0.71]), and current wheeze (0.55 [0.32-0.93] and 0.52 [0.31-0.90]) and atopy (sensitisation to some inhalant allergens) outcomes at 6 years. High concentrations of TNFalpha were associated with lower risk of atopy but not with asthma risk. These associations were broadly unaltered by propensity-score adjustment. Maternal smoking was associated with higher risk of both wheeze at 6 years and lower concentrations of interleukin 4 and interferon gamma in cord blood. INTERPRETATION The mechanism underlying attenuated T-helper-1/T-helper-2 cytokine production in high-risk children also apparently operates in control of cytokine production in the fetoplacental unit. The finding that this mechanism is dysregulated by maternal smoking suggests it is a target for antenatal environmental factors relevant to asthma aetiology.
Collapse
Affiliation(s)
- C Macaubas
- Telethon Institute for Child Health Research, and Centre for Child Health Research, Faculty of Medicine and Dentistry, University of Western Australia, Western Australia, Perth, Australia
| | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Yang DY, Lu FG, Tang XX, Zhao SP, Ouyang CH, Wu XP, Liu XW, Wu XY. Study on relationship between expression level and molecular conformations of gene drugs targeting to hepatoma cells in vitro. World J Gastroenterol 2003; 9:1954-8. [PMID: 12970883 PMCID: PMC4656651 DOI: 10.3748/wjg.v9.i9.1954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To increase exogenous gene expression level by modulating molecular conformations of targeting gene drugs.
METHODS: The full length cDNAs of both P40 and P35 subunits of human interleukin 12 were amplified through polymerase chain reaction (PCR) and cloned into eukaryotic expressing vectors pcDNA3.1 (±) to construct plasmids of P (+)/IL-12, P (+)/P40 and P (-)/P35. These plasmids were combined with ASOR-PLL to form two targeting gene drugs [ASOR-PLL-P (+)/IL-12 and ASOR-PLL-P (+)/P40 + ASOR-PLL-P (-)/P35] in optimal ratios. The conformations of these two drugs at various concentrations adjuvant were examined under electron microscope (EM) and the drugs were transfected into HepG2 (ASGr+) cells. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was performed with total RNA extracted from the transfected cells to determine the hIL12 mRNA transcript level. The hIL12 protein in the cultured supernatant was measured with enzyme-linked immunosorbent assay (ELISA) 48 hours after transfection.
RESULTS: Targeting gene drugs, whose structures were granular and circle-like and diameters ranged from 25 nm to 150 nm, had the highest hIL-12 expression level. The hIL-12 expression level in the group co-transfected with ASOR-PLL-P (+)/P40 and ASOR-PLL-P (-)/P35 was higher than that of ASOR-PLL-P (+)/IL-12 transfected group.
CONCLUSION: The molecular conformations of targeting gene drugs play an important role in exogenous gene expression level, the best structures are granular and circle-like and their diameters range from 25 nm to 150 nm. The sizes and linking styles of exogenous genes also have some effects on their expression level.
Collapse
Affiliation(s)
- Dong-Ye Yang
- Department of Gastroenterology, Xiangya Second Hospital, Central South University, Changsha 410011, Hunan, China
| | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Frassanito MA, Dammacco R, Fusaro T, Cusmai A, Guerriero S, Sborgia C. Combined cyclosporin-A /prednisone therapy of patients with active uveitis suppresses IFN-gamma production and the function of dendritic cells. Clin Exp Immunol 2003; 133:233-9. [PMID: 12869029 PMCID: PMC1808766 DOI: 10.1046/j.1365-2249.2003.02214.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
In this study, we assessed the Th1/Th2 polarization of the immune response and the involvement of dendritic cells (DC) and Th1 lymphocytes in the pathogenesis of uveitis. Thirty-seven patients with chronic idiopathic uveitis were enrolled: 21 of them had active uveitis and the remaining 16 were in complete remission. Patients with active uveitis were characterized as follows: 5 had intermediate uveitis, 5 panuveitis and the remaining 11 posterior uveitis. Thirteen healthy subjects were also studied as controls. Patients with active uveitis were treated with cyclosporin-A (CsA) associated to low doses of prednisone (PDS) and studied at baseline and after 6 months of therapy. Analysis of cytokine-producing CD3+ lymphocytes revealed a strong Th1 polarization of the immune response in patients with active uveitis. Th1 lymphocytes paralleled serum IL-12 levels and the response to therapy, which greatly reduced both IFN-gamma+/CD3+ lymphocytes and serum IL-12 levels, associated with a general clinical improvement. In vitro studies demonstrated that DC from untreated patients with active uveitis were mature and functionally active. In fact, they showed a higher ability to stimulate cell proliferation of allogeneic T cells in primary mixed lymphocyte reaction (MLR) and produced larger amounts of IL-12 than DC from CsA/PDS-treated patients and those in remission. These results demonstrate that CsA/PDS therapy impairs the capacity of mature DC to secrete IL-12 and inhibits their MLR activity.
Collapse
Affiliation(s)
- M A Frassanito
- Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
| | | | | | | | | | | |
Collapse
|
|
50
|
Martin M, Schifferle RE, Cuesta N, Vogel SN, Katz J, Michalek SM. Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2003; 171:717-25. [PMID: 12847238 DOI: 10.4049/jimmunol.171.2.717] [Citation(s) in RCA: 213] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Stimulation of the APC by Porphyromonas gingivalis LPS has been shown to result in the production of certain pro- and anti-inflammatory cytokines. However, the signaling pathways that regulate these processes are currently unknown. In the present study, the role of the phosphatidylinositol 3 kinase (PI3K)-Akt pathway in regulating P. gingivalis LPS-induced production of IL-10, IL-12 p40, and IL-12 p70 by human monocytes was investigated. P. gingivalis LPS selectively activates the PI3K-Akt pathway via Toll-like receptor 2, and inhibition of this pathway results in an abrogation of extracellular signal-regulated kinase 1/2 phosphorylation, whereas the activation of p38 and c-Jun N-terminal kinase 1/2 kinases were unaffected. Analysis of cytokine production following stimulation of monocytes with P. gingivalis LPS revealed that inhibition of the PI3K pathway differentially regulated IL-10 and IL-12 synthesis. IL-10 production was suppressed, whereas IL-12 levels were enhanced. Inhibition of P. gingivalis LPS-mediated activation of the PI3K-Akt pathway resulted in a pronounced augmentation of NF-kappaB p65 that was independent of IkappaB-alpha degradation. Furthermore, the ability of the PI3K-Akt pathway to modulate IL-10 and IL-12 production appears to be mediated by the selective suppression of extracellular signal-regulated kinase 1/2 activity, as the MEK1 inhibitor PD98059 closely mimicked the effects of wortmannin and LY294002 to differentially regulate IL-10 and IL-12 production by P. gingivalis LPS-stimulated monocytes. These studies provide new insight into how engagement of the PI3K-Akt pathway by P. gingivalis LPS affects the induction of key immunoregulatory cytokines that control both qualitative and quantitative aspects of innate and adaptive immunity.
Collapse
Affiliation(s)
- Michael Martin
- Department of Microbiology, University of Alabama, Birmingham, AL 35294, USA
| | | | | | | | | | | |
Collapse
|