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Khan GH, Veltkamp F, Scheper M, Hoebe RA, Claessen N, Butter L, Bouts AHM, Florquin S, Guikema JEJ. Levamisole suppresses activation and proliferation of human T cells by the induction of a p53-dependent DNA damage response. Eur J Immunol 2023; 53:e2350562. [PMID: 37597325 DOI: 10.1002/eji.202350562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/17/2023] [Accepted: 08/18/2023] [Indexed: 08/21/2023]
Abstract
Levamisole (LMS) is a small molecule used in the treatment of idiopathic nephrotic syndrome (INS). The pathogenesis of INS remains unknown, but evidence points toward an immunological basis of the disease. Recently, LMS has been shown to increase the relapse-free survival in INS patients. While LMS has been hypothesized to exert an immunomodulatory effect, its mechanism of action remains unknown. Here, we show that LMS decreased activation and proliferation of human T cells. T-cell activation-associated cytokines such as IL-2, TNF-α, and IFN-γ were reduced upon LMS treatment, whereas IL-4 and IL-13 were increased. Gene expression profiling confirmed that the suppressive effects of LMS as genes involved in cell cycle progression were downregulated. Furthermore, genes associated with p53 activation were upregulated by LMS. In agreement, LMS treatment resulted in p53 phosphorylation and increased expression of the p53 target gene FAS. Accordingly, LMS sensitized activated T cells for Fas-mediated apoptosis. LMS treatment resulted in a mid-S phase cell cycle arrest accompanied by γH2AX-foci formation and phosphorylation of CHK1. Our findings indicate that LMS acts as an immunosuppressive drug that directly affects the activation and proliferation of human T cells by induction of DNA damage and the activation of a p53-dependent DNA damage response.
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Affiliation(s)
- Gerarda H Khan
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Floor Veltkamp
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Mirte Scheper
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Ron A Hoebe
- Department of Medical Biology, Amsterdam UMC and Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Nike Claessen
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Loes Butter
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Antonia H M Bouts
- Department of Pediatric Nephrology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Sandrine Florquin
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Jeroen E J Guikema
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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2
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Antitumor and immune-modulatory efficacy of dual-treatment based on levamisole and/or taurine in Ehrlich ascites carcinoma-bearing mice. Biomed Pharmacother 2018; 106:43-49. [DOI: 10.1016/j.biopha.2018.06.113] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Revised: 06/19/2018] [Accepted: 06/19/2018] [Indexed: 01/10/2023] Open
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Jeong HS, Layher H, Cao L, Vandergriff T, Dominguez AR. Pyoderma gangrenosum (PG) associated with levamisole-adulterated cocaine: Clinical, serologic, and histopathologic findings in a cohort of patients. J Am Acad Dermatol 2016; 74:892-8. [PMID: 26785804 DOI: 10.1016/j.jaad.2015.11.040] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 11/26/2015] [Accepted: 11/30/2015] [Indexed: 11/17/2022]
Abstract
BACKGROUND Recently, isolated reports of pyoderma gangrenosum (PG) secondary to levamisole-contaminated cocaine have been described, with similar serologic findings to the vasculopathic presentation. OBJECTIVE We sought to describe clinical, histopathological, and serologic findings in 8 patients with PG associated with levamisole-contaminated cocaine. METHODS Eight consecutive patients presenting with this disease spanning the period from 2011 to 2015 were included for the cohort. Observed variables included: lesion distribution, morphology, serologic titers, and histopathologic evaluation for vasculitis and vasculopathy. RESULTS All patients reported cocaine exposure prior to the onset of lesions resembling PG. Lesions appeared primarily on the upper (6 of 8 patients) and lower (all 8 patients) extremities. Most patients demonstrated elevated titers for p-ANCA and antiphospholipid antibodies, and a diffuse dermal infiltrate dominated by neutrophils was seen in all biopsy specimens. Lesions improved or remained stable with conservative management or short courses of steroids, and recurrence was only noted on re-exposure to adulterated cocaine. LIMITATIONS The study is limited by sample size. CONCLUSIONS PG may occur after exposure to levamisole-adulterated cocaine. Clinical and histopathological findings resemble those seen in conventional forms of PG, whereas serologic findings mirror those seen in other levamisole-associated vasculopathic or vasculitic eruptions. Cocaine avoidance represents a cornerstone of management in these patients.
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Affiliation(s)
- Haneol S Jeong
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Heather Layher
- Brooke Army Medical Center, San Antonio Uniformed Services Health Education Consortium, Dermatology Residency Program, San Antonio, Texas
| | - Lauren Cao
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Travis Vandergriff
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Arturo R Dominguez
- Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas.
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4
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Zhang Y, Chen H, Zeng X, Wang P, Li J, Wu W. Levamisole enhances immunity in ducklings vaccinated againstRiemerella anatipestifer. Microbiol Immunol 2014; 58:456-62. [PMID: 24931647 DOI: 10.1111/1348-0421.12169] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 06/10/2014] [Accepted: 06/12/2014] [Indexed: 01/02/2023]
Affiliation(s)
- Yuewei Zhang
- Key Laboratory of Rapid Diagnostic Technology for Animal Disease; Ministry of Agriculture; College of Veterinary Medicine; China Agricultural University; No. 2 Yuanmingyuan West Road Beijing 100193 China
| | - Huiling Chen
- Beijing General Station of Animal Husbandry and Veterinary Service; Beijing Municipal Bureau of Agriculture; A15 Beiyuan Road Beijing 100107 China
| | - Xiangfan Zeng
- Key Laboratory of Rapid Diagnostic Technology for Animal Disease; Ministry of Agriculture; College of Veterinary Medicine; China Agricultural University; No. 2 Yuanmingyuan West Road Beijing 100193 China
| | - Peng Wang
- Animal Health Inspection Institute; No. 3 ShangYuanCun Beijing 100044 China
| | - Jinxiang Li
- Chinese Academy of Agricultural Sciences; No. 12 Zhongguancun South Street Beijing 100081 China
| | - Wenxue Wu
- Key Laboratory of Rapid Diagnostic Technology for Animal Disease; Ministry of Agriculture; College of Veterinary Medicine; China Agricultural University; No. 2 Yuanmingyuan West Road Beijing 100193 China
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Magliocca KR, Coker NA, Parker SR. The head, neck, and systemic manifestations of levamisole-adulterated cocaine use. J Oral Maxillofac Surg 2013; 71:487-92. [PMID: 23298805 DOI: 10.1016/j.joms.2012.10.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 10/29/2012] [Indexed: 11/26/2022]
Abstract
Systemic complications of levamisole-adulterated cocaine (LAC) use have recently been described. The objective of this review is to increase awareness of these manifestations among oral and maxillofacial surgeons. LAC exposure through inhalation, nasal insufflation, or injection can induce cutaneous vasculopathy and hematologic abnormalities such as neutropenia or agranulocytosis. Unlike other vasculopathies involving the skin, LAC-induced vascular injury frequently manifests with purpuric and necrotic lesions that involve the face and ears. Oral manifestations have also been reported but are not yet well characterized. The aforementioned hematologic manifestations are not uncommon, and patients exposed to LAC are potentially at higher risk for infectious complications. When manifestations of LAC affect the head, neck, and oral cavity, oral and maxillofacial surgeons may be the first providers to encounter the patient. Early recognition of the clinical signs and laboratory abnormalities will better allow for distinguishing LAC-related effects from various clinical mimics, will facilitate appropriate patient management, and may further contribute to the understanding of the biological effects of LAC.
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Affiliation(s)
- Kelly R Magliocca
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA.
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Sanadgol H. Levamisole usage as an adjuvant to hepatitis B vaccine in hemodialysis patients, yes or no? Nephrourol Mon 2012; 5:673-8. [PMID: 23577329 PMCID: PMC3614321 DOI: 10.5812/numonthly.3985] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2011] [Revised: 01/30/2012] [Accepted: 02/24/2012] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is much more common in hemodialysis patients than the general population. These patients have an impaired immune response to HBV vaccination; to that end there are certain studies that have evaluated levamisole as an immunomodulator agent improving HBV vaccination response rate in hemodialysis patients. OBJECTIVES In the current review, we have assembled all of the results to determine whether lavamisole is of value as an adjuvant to HBV vaccination in hemodialysis patients. MATERIALS AND METHODS Science Direct (Elsevier), ProQuest, Springer, MD Consult, BMJ Journals, Pubmed and Wiley were searched for levamisole application to HBV vaccination in hemodialysis patients. All studies revealed a seroconversion response level between levamisole plus HBV vaccine versus HBV vaccine alone. RESULTS From 10 relevant studies, 5 studies fulfilled our inclusion criteria. Three of them suggested the significant benefit of adding levamisole to the HBV vaccine to increase augment seroprotection level in hemodialysis patients. Another study reported a decrease in seroprotection level and another study showed no significant difference caused by levamisole administration. CONCLUSIONS Due to the limited number of studies evaluated, it is challenging to perform a definite decision about routinely administering levamisole in addition to the HBV vaccine for all hemodialysis patients. However, it does seem reasonable to recommend administration of levamisole for impaired immune response patients.
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Affiliation(s)
- Houshang Sanadgol
- Department of Nephrology, Faculty of Medicine, Zahedan Medical University, Zahedan, IR Iran
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Ali SH, Abdel-Fattah YES, Shaimaa AM. Biochemical, immunomodulatory and antioxidant properties of levamisole at different storage conditions and administration routes. Pak J Biol Sci 2012; 15:986-991. [PMID: 24199477 DOI: 10.3923/pjbs.2012.986.991] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/02/2023]
Abstract
Levamisole is a broad-spectrum nicotinic anthelmintic drug; widely used in veterinary medicine. Levamisole actions are variable depending on storage temperature and administration route. The present study was conducted to test levamisole effects on immune responses and antioxidant status of rats at different storage temperature and administration routs. The experimental rats were allocated into four experimental groups and two controls. Group 1 was given levamisole orally. Group 2 was injected levamisole intramuscularly. In group 1 and 2 levamisole was stored at 4 degrees C for 72 h and given every two days for three weeks at a dose of 2.5 mg kg(-1) body weight. Group 3 and 4 were treated same as group 1 and 2 but levamisole was stored at 37 degrees C. Serum levels of total IgG and IgA and plasma levels of glutathione reductase (GSSG-R), TAC concentrations in addition to GST and GSH-Px activities were measured. The results indicated that the storage of levamisole at 4 degrees C significantly increased serum IgG and IgA levels in rats and improved rat's antioxidant status through significant increase in glutathione related enzymes (GSSG-R, GST and GSH-Px) and the TAC. Levamisole stored at 37 degrees C increased measured antioxidant biomarkers but decreased the rats' non-specific humoral immunity. Moreover, the intramuscular administration induced better antioxidant properties than oral administration of levamisole. In conclusion, levamisole actions could be specifically directed towards certain types of immune responses due to changes in storage temperature with better response to injectable routes than oral routs with more antioxidant activities.
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Affiliation(s)
- Samy Hussein Ali
- Biochemistry Department, Faculty of Veterinary Medicine, Moshtohor, Benha University, Egypt
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Somi MH, Hajipour B. Improving hepatitis B vaccine efficacy in end-stage renal diseases patients and role of adjuvants. ISRN GASTROENTEROLOGY 2012; 2012:960413. [PMID: 23029621 PMCID: PMC3458294 DOI: 10.5402/2012/960413] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/18/2012] [Accepted: 08/01/2012] [Indexed: 12/18/2022]
Abstract
Hepatitis B virus (HBV) infection is a serious global health problem.The prevalence of viral hepatitis is higher in dialysis patients than in the general population because of the opportunity for exposure during the dialysis procedure. Immunization is the most effective way to prevent transmission of hepatitis B virus (HBV) and hence the development of acute or chronic hepatitis B. It is well established that patients with end-stage renal disease including dialysis-dependent patients, have an impaired immune response to hepatitis B vaccine. End stage renal diseases (ESRD) patients have lower seroconversion rates compared with the subjects with intact renal function. Moreover, even after the completion of vaccination schedule anti-hepatitis B (anti-HBs) titers of responder dialysis, patients are low and decline logarithmically with time. The impaired efficacy of HBV vaccine in patients with ESRD has been attributed to numerous factors such as immune compromise because of uremia and some other factors. One approach to improve the immunogenicity of existing HBV vaccines is adjuvantation, and it's very important to find more effective adjutants for improving HBV vaccine efficacy. In this paper we have a brief review on recently known new ways for improving HBV vaccine efficacy.
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Affiliation(s)
- Mohammad Hossein Somi
- Liver and Gastroenterology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Effects of oral levamisole as an adjuvant to hepatitis B vaccine in adults with end-stage renal disease: a meta-analysis of controlled clinical trials. Clin Ther 2010; 32:1-10. [PMID: 20171406 DOI: 10.1016/j.clinthera.2010.01.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/04/2009] [Indexed: 12/14/2022]
Abstract
BACKGROUND Many patients receiving long-term dialysis do not produce protective antibodies to hepatitis B virus (HBV) surface antigen (HBsAg) after HBV vaccination. The results from several studies have suggested benefit of oral levamisole as an adjuvant to HBV vaccination in patients with end-stage renal disease (ESRD). However, reliable information is still lacking. OBJECTIVE This meta-analysis assessed the efficacy and safety profile of oral levamisole as an adjuvant to HBV vaccine in patients with ESRD. METHODS This meta-analysis included prospective controlled clinical trials identified using literature searches of MEDLINE, SCOPUS, Institute for Scientific Information bibliographic database, and Cochrane Collaboration's Central Register of Controlled Clinical Trials for controlled clinical trials that weighted the seroprotection rate in patients with ESRD who received oral levamisole + HBV vaccine versus those who received the HBV vaccine alone (control). The fixed-effects Mantel-Haenszel model was applied with the heterogeneity and sensitivity analyses. The response rate, defined as the proportion of patients with seroprotective concentrations of antibodies to HBsAg (>10 mIU/mL) at completion and 6 to 10 months after completion of the HBV vaccine schedule, was the end point of interest and was also analyzed separately. For the tolerability assessment, studies that reported dose reduction, levamisole discontinuation, and their adverse effects including laboratory abnormalities were included. RESULTS The literature search identified 4 studies that fulfilled the inclusion criteria (328 patients). The mean ages of the patients in these studies ranged from 41 to 53 years, and sex distribution ranged from 52.6% to 68.0% male. Twenty-two patients received oral levamisole 100 mg/d for 12 days (from 6 days before to 6 days after each vaccination). A total of 106 patients received oral levamisole 80 to 120 mg for 4 to 6 months. Aggregation of study results suggested a significant increase in response rate in the group that received levamisole + HBV vaccine compared with the control group (pooled odds ratio [OR] = 2.77 [95% CI, 1.56-4.94]) after completion and 6 to 10 months after the vaccination period (pooled OR = 3.96 [95% CI, 1.71-9.18]). The test of heterogeneity was not statistically significant in either group. Five patients underwent dose reduction due to mild adverse events. In one trial, 3 patients died, 1 of whom was receiving levamisole; however, the authors did not provide the causes of death. No other serious adverse events were reported with levamisole administration. CONCLUSION The results from this meta-analysis suggest significant benefit in the administration of levamisole as an adjuvant to HBV vaccine to increase seroprotection in patients with ESRD.
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Yin J, Jin H, Kang Y, Xiao C, Zhao L, Li X, Ding Z, Yang F, Zhu Q, Wang B. Efficacy of Modified Levamisole Adjuvant on Inactivated Virus Vaccine. Viral Immunol 2006; 19:525-35. [PMID: 16987070 DOI: 10.1089/vim.2006.19.525] [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] [Indexed: 11/12/2022] Open
Abstract
To improve efficacy, especially for the cell-mediated response to inactivated viral vaccines, a modified levamisole (LMS) adjuvant formulation, designated LMS+, was evaluated for its efficacy in mice and chickens, using Newcastle Disease Virus (NDV) as a model pathogen. Compared with oil adjuvant, the killed NDV in LMS+ induced a significantly higher helper T cell type 1 response, as shown by higher levels of interleukin-2, interferon-gamma, T cell proliferation, and delayed-type hypersensitivity responses, without sacrificing the level of IgG production in mice. In addition, vaccine in LMS+ formulation increased the expression of MHC and costimulatory molecules as well as the number of CD11c+ dendritic cells, suggesting that the better response to the LMS+ formulation occurs partly via the maturation of dendritic cells and activation of MHC-antigen presentation and costimulation. Furthermore, this formulation provides 100% protection in chickens after challenge with a lethal dose of virulent NDV strain F48E9 at 1000 ELD50 (50% egg lethal dose). These results demonstrated that modified LMS+ adjuvant could be used to improve both humoral and cell-mediated responses for inactivated viral vaccines and its development as an effective inactivated viral vaccine is warranted.
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Affiliation(s)
- Jiangmei Yin
- State Key Laboratory for Agro-Biotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
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Wang KX, Zhang LH, Peng JL, Liang Y, Wang XF, Zhi H, Wang XX, Geng HX. Effect of liniment levamisole on cellular immune functions of patients with chronic hepatitis B. World J Gastroenterol 2006; 11:7208-10. [PMID: 16437674 PMCID: PMC4725075 DOI: 10.3748/wjg.v11.i45.7208] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To explore the effects of liniment levamisole on cellular immune functions of patients with chronic hepatitis B. METHODS The levels of T lymphocyte subsets and mIL-2R in peripheral blood mononuclear cells (PBMCs) were measured by biotin-streptavidin (BSA) technique in patients with chronic hepatitis B before and after the treatment with liniment levamisole. RESULTS After one course of treatment with liniment levamisole, the levels of CD3(+), CD4(+), and the ratio of CD4(+)/CD8(+) increased as compared to those before the treatment but the level of CD8(+) decreased. The total expression level of mIL-2R in PBMCs increased before and after the treatment with liniment levamisole. CONCLUSION Liniment levamisole may reinforce cellular immune functions of patients with chronic hepatitis B.
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Affiliation(s)
- Ke-Xia Wang
- Department of Pathogenic Biology, School of Medicine, Anhui University of Science and Technology, Huainan 232001, Anhui Province, China.
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Kang Y, Jin H, Zheng G, Xie Q, Yin J, Yu Y, Xiao C, Zhang X, Chen A, Wang B. The adjuvant effect of levamisole on killed viral vaccines. Vaccine 2005; 23:5543-50. [PMID: 16095767 DOI: 10.1016/j.vaccine.2005.07.017] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2005] [Revised: 06/22/2005] [Accepted: 07/06/2005] [Indexed: 10/25/2022]
Abstract
To explore adjuvants that are capable of promoting Th1-biased immune response, we investigated the usefulness of levamisole (LMS) as one such adjuvant for two different preparations of killed viral vaccines, derived from the foot mouth disease virus (FMDV) or the porcine respiratory reproductive syndrome virus (PRRSV) and tested respectively in BALB/c or C57 BL/6 mice. The results showed that LMS induced different types of immune responses in the host, depending on its dosage. While a high level of serum IgG was induced by using LMS at 2%, the most robust T cell proliferation was induced with LMS at 0.5%. The Th1 and Th2 cytokine profiles, which tracked well with the antibody and T cell responses, were similarly influenced by the dose of LMS. Moreover, the enhanced T cell response correlated with increased expression of MHC and co-stimulatory molecules and decreased expression of the suppressors of cytokine signaling molecules (SOCS1 and SOCS3) in the spleen, suggesting that it is mediated by the antigen presentation, co-stimulator signaling, and cytokine production pathways. These results establish that LMS can be used to induce Th1-biased immune responses when combined with killed-virus-based antiviral vaccines and that such adjuvant effect depends on the optimal LMS dosage.
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Affiliation(s)
- Youmin Kang
- State Key Laboratory for Agro-Biotechnology, Department of Physiology, College of Biology, China Agricultural University, Beijing 100094, China
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Liu CY, Lai YY, Lo CJ. Levamisole modulates prostaglandin E2 production and cyclooxygenase II gene expression in human colonic cancer cells. J Surg Res 2004; 117:223-31. [PMID: 15047127 DOI: 10.1016/j.jss.2003.11.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2003] [Indexed: 01/31/2023]
Abstract
BACKGROUND Colorectal adenocarcinoma is one of the leading causes of cancer mortality in the world. Recent studies have demonstrated that prostaglandin E(2) (PGE(2)) and cyclooxygenase (COX) are involved in the early development of colorectal cancer. Levamisole together with 5-fluorouracil has been shown to improve the survival of patients with Duke's C colon cancer. This study examined the effect of levamisole on PGE(2) production and COX-2 gene activation in immortalized human colon cells. MATERIALS AND METHODS Colon 205 cells, a human colonic cancer cell line, were exposed to Escherichia coli LPS (1 microg/mL) in the presence of levamisole (1 microm to 1 mm). The PGE(2) production was determined by enzyme-linked immunosorbent assay. In addition, cyclooxygenase II (COX-2) mRNA expression and COX-2 protein were measured by the real-time reverse transcription polymerase chain reaction and Western blot assay, respectively. Transcription factor nuclear factor (NF)-kappaB activity of the nuclear and cytoplasmic proteins was determined by Western blot assay with a P65 antibody. RESULTS Colon 205 cells produced significantly more PGE(2) when stimulated by LPS. Levamisole inhibited PGE(2) production by LPS-stimulated colon 205 cells in a dose-dependent fashion. In addition, COX-2 mRNA expression and COX-2 protein induced by LPS were also reduced by levamisole. Finally, NF-kappaB activation of LPS-stimulated colon cells was inhibited by levamisole. CONCLUSION Levamisole inhibits PGE(2) production by LPS-stimulated colon 205 cells. The inhibition of levamisole occurs at the transcription level of COX-2 gene and is regulated through NF-kappaB activation.
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Affiliation(s)
- Chin-Yen Liu
- Department of Education and Research, Changhua Christian Hospital, 135 Nanhsiao Street, Changhua, 500 Taiwan
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Sett S, Mishra SK, Siddiqui KA. Avirulent mutants of Macrophomina phaseolina and Aspergillus fumigatus initiate infection in Phaseolus mungo in the presence of phaseolinone; levamisole gives protection. J Biosci 2000; 25:73-80. [PMID: 10824201 DOI: 10.1007/bf02985184] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
To evaluate the role of phaseolinone, a phytotoxin produced by Macrophomina phaseolina, in disease initiation, three nontoxigenic avirulent mutants of the fungus were generated by UV-mutagenesis. Two of them were able to initiate infection in germinating Phaseolus mungo seeds only in the presence of phaseolinone. The minimum dose of phaseoli-none required for infection in 30% seedlings was 2 5 mg/ml. A human pathogen, Aspergillus fumigatus was also able to infect germinating seeds of P. mungo in the presence of 5 mg/ml concentration of phaseolinone. Phaseolinone seemed to facilitate infection by A. fumigatus, which is not normally phytopathogenic, by reducing the immunity of germinating seedlings in a nonspecific way. Levamisole, a non-specific immunopotentiator gave protection against infection induced by A. fumigatus at an optimum dose of 50 mg/ml. Sodium malonate prevented the effects of levamisole.
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Affiliation(s)
- S Sett
- Indian Institute of Chemical Biology, 4, Raja S C Mullick Road, Jadavpur, Calcutta 700 032, India
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Volpe CM, Mehta N, Kim U, Hordines J, Doerr RJ, Cohen SA. AsGM1+ NK cells prevent metastasis of invading LD-MCA-38 tumor cells in the nude mouse. J Surg Res 1999; 84:157-61. [PMID: 10357913 DOI: 10.1006/jsre.1999.5631] [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] [Indexed: 11/22/2022]
Abstract
BACKGROUND Although the liver is a potent tumor cell killing organ it is frequently the site of lethal metastases often signifying the endstage for patients with colorectal cancers. Enhancing hepatic-associated immunity remains elusive until the interactions among hepatic nonparenchymal cells (NPC) are deciphered. We sought to modulate the cellular components of the hepatic immune system of mice with anti-NK and anti-T-cell-neutralizing antibodies in order to determine the cell type most efficacious in preventing liver metastasis. MATERIALS AND METHODS Liver-derived murine colon adenocarcinoma (LD-MCA-38) cells were injected into the ileocolic vein (ICV) of immunocompetent and immunodeficient C57BL/6 mice. Mice were pretreated 1 day prior to tumor cell injection with one of three antibodies: anti-AsGM1, Anti-NK1.1, or Anti-Thy1.2. On Day 21 laparotomy was performed to determine the extent of hepatic tumor foci. The number of hepatic tumor foci was recorded and compared by the Wilcoxon rank sum test. RESULTS Mice pretreated with anti-AsGM1 or Anti-NK1.1 developed a massive increase in the number of hepatic tumor foci and decreased survival compared to the control treated mice. Pretreatment with anti-Thy1.2 antibody resulted in a significant decrease in the number of hepatic tumor foci. LD-MCA-38 tumor cells were unable to colonize the liver of C57BL/6 athymic nude mice; however, anti-AsGM1 antibody abolished this antimetastatic effect. There was no difference in the extent of hepatic metastasis and survival between immunodeficient C57BL/6 bg/bg and their conventional littermates bg/+. CONCLUSION AsGM1+ NK cells exhibit a significant antitumor response in the absence of T-cells. The concept of stimulating NK cell activity and suppressing T-cell function may enhance liver-associated immunity and serve as a deterrent for blood-borne tumor cells metastasizing to the liver.
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MESH Headings
- Adenocarcinoma/prevention & control
- Adenocarcinoma/secondary
- Animals
- Antibodies/pharmacology
- Antibodies, Monoclonal/pharmacology
- Antigens/immunology
- Antigens, Ly
- Antigens, Surface
- Colonic Neoplasms/pathology
- G(M1) Ganglioside/immunology
- G(M1) Ganglioside/metabolism
- Immunocompetence/physiology
- Killer Cells, Natural/metabolism
- Killer Cells, Natural/physiology
- Lectins, C-Type
- Liver Neoplasms/prevention & control
- Liver Neoplasms/secondary
- Lymphocyte Count/drug effects
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL/genetics
- Mice, Nude/immunology
- NK Cell Lectin-Like Receptor Subfamily B
- Neoplasm Invasiveness/prevention & control
- Neoplasm Transplantation
- Proteins/immunology
- T-Lymphocytes/pathology
- Thy-1 Antigens/immunology
- Tumor Cells, Cultured
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Affiliation(s)
- C M Volpe
- Department of Surgery, Buffalo VA Medical Center and CGF Health Systems, Buffalo, New York, 14203, USA.
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