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Dynamic changes of cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and natural killer T (NKT) cells in patients with acute hepatitis B infection
Jun Li, Yaping Han, Ke Jin, Yufeng Wan, Shixia Wang, Bo Liu, Yuan Liu, Shan Lu, Zuhu Huang
Virology Journal , 2011, DOI: 10.1186/1743-422x-8-199
Abstract: Dynamic profiles on the frequency of HLA-A0201-restricted HBcAg18-27 pentamer complex (MHC-Pentamer)-specific CTLs and lymphocyte subsets in AHB patients were analyzed in addition to liver function tests, HBV serological markers, and HBV DNA levels. ELISPOT was used to detect interferon-gamma (INF-γ) secretion in specific CTLs stimulated with known T cell epitope peptides associated with HBV surface protein, polymerase, and core protein.HBV-specific CTL frequencies in AHB patients were much higher than in patients with chronic hepatitis B (CHB) (p < 0.05). HBeAg and HBV DNA disappeared earlier in AHB patients with a high frequency of HBV-specific CTLs compared with those with a low frequency of HBV-specific CTLs (p = 0.001 and 0.024, respectively). INF-γ spots of effector cells stimulated by Pol575-583, Env348-357, or Core18-27 epitope peptides were significantly greater in AHB patients than in CHB patients (p < 0.01). CD3+CD8+ T cell numbers in AHB patients was more than observed in the healthy control group from the first to the fourth week after admission (p = 0.008 and 0.01, respectively); the number of CD3+CD8+ T cells and frequency of HBcAg18-27-specific CTLs in AHB patients reached peak levels at the second week after admission. NK and NKT cell numbers were negatively correlated with the frequency of HBcAg-specific CTLs (r = -0.266, p = 0.05).Patients with AHB possess a higher frequency of HBcAg-specific CTLs than CHB patients. The frequency of specific CTLs in AHB patients is correlated with HBeAg clearance indicating that HBV-specific CTLs play an important role in viral clearance and the self-limited process of the disease. Furthermore, NK and NKT cells are likely involved in the early, non-specific immune response to clear the virus.The clinical manifestations and outcomes of hepatitis B virus (HBV) infection depend mainly on the intensity and type of anti-viral immunity produced by the infected individual. In patients with acute HBV infection, the specif
Phase I clinical trial of the vaccination for the patients with metastatic melanoma using gp100-derived epitope peptide restricted to HLA-A*2402
Toshiyuki Baba, Marimo Sato-Matsushita, Akira Kanamoto, Akihiko Itoh, Naoki Oyaizu, Yusuke Inoue, Yutaka Kawakami, Hideaki Tahara
Journal of Translational Medicine , 2010, DOI: 10.1186/1479-5876-8-84
Abstract: The phase I clinical protocol to test a HLA-A*2402 gp100 peptide-based cancer vaccine was designed to evaluate safety as the primary endpoint and was approved by The University of Tokyo Institutional Review Board. Information related to the immunologic and antitumor responses were also collected as secondary endpoints. Patients that were HLA-A*2402 positive with stage IV melanoma were enrolled according to the criteria set by the protocol and immunized with a vaccine consisting of epitope peptide (VYFFLPDHL, gp100-in4) emulsified with incomplete Freund's adjuvant (IFA) for the total of 4 times with two week intervals. Prior to each vaccination, peripheral blood mononuclear cells (PBMCs) were separated from the blood and stored at -80°C. The stored PBMCs were thawed and examined for the frequency of the peptide specific T lymphocytes by IFN-γ- ELISPOT and MHC-Dextramer assays.No related adverse events greater than grade I were observed in the six patients enrolled in this study. No clinical responses were observed in the enrolled patients although vitiligo was observed after the vaccination in two patients. Promotion of peptide specific immune responses was observed in four patients with ELISPOT assay. Furthermore, a significant increase of CD8+ gp100-in4+ CTLs was observed in all patients using the MHC-Dextramer assay. Cytotoxic T lymphocytes (CTLs) clones specific to gp100-in4 were successfully established from the PBMC of some patients and these CTL clones were capable of lysing the melanoma cell line, 888 mel, which endogenously expresses HLA-restricted gp100-in4.Our results suggest this HLA-restricted gp100-in4 peptide vaccination protocol was well-tolerated and can induce antigen-specific T-cell responses in multiple patients. Although no objective anti-tumor effects were observed, the effectiveness of this approach can be enhanced with the appropriate modifications.Multiple tumor associated antigens (TAAs) have been identified and examined for their immunogeni
Experimental HTLV-I and associated myelopathy
COSTA, CARLOS M. DE CASTRO;FIGUEIREDO, EBERVAL G. DE;SANTOS, TEREZINHA J.T.;FROTA, CARINA H.;LOBO, CARMEN C.G.;SANTOS, FRANKLIN J.C.;ALC?NTARA, RAIMUNDO N.;RAMOS, RODRIGO S.N.;ROCHA, TARCíSIO T.S.;NOGUEIRA, TRíCIA F.;
Arquivos de Neuro-Psiquiatria , 1998, DOI: 10.1590/S0004-282X1998000300024
Abstract: htlv-i infection and associated myelopathy has been reproduced experimentally in vitro and in vivo and these studies have shown the possibility of creating several lines of infective cells and of detecting minor and major clinical expressions of htlv-i associated myelopathy in rabbits and rats.
Experimental HTLV-I and associated myelopathy
COSTA CARLOS M. DE CASTRO,FIGUEIREDO EBERVAL G. DE,SANTOS TEREZINHA J.T.,FROTA CARINA H.
Arquivos de Neuro-Psiquiatria , 1998,
Abstract: HTLV-I infection and associated myelopathy has been reproduced experimentally in vitro and in vivo and these studies have shown the possibility of creating several lines of infective cells and of detecting minor and major clinical expressions of HTLV-I associated myelopathy in rabbits and rats.
Discovery of novel targets for multi-epitope vaccines: Screening of HIV-1 genomes using association rule mining
Sinu Paul, Helen Piontkivska
Retrovirology , 2009, DOI: 10.1186/1742-4690-6-62
Abstract: Using a set of 189 best-defined HIV-1 CTL/CD8+ epitopes from 9 different protein-coding genes, as described by Frahm, Linde & Brander (2007), we examined the complete genomic sequences of 62 reference HIV sequences (including 13 subtypes and sub-subtypes with approximately 4 representative sequences for each subtype or sub-subtype, and 18 circulating recombinant forms). The results showed that despite inclusion of recombinant sequences that would be expected to break-up associations of epitopes in different genes when two different genomes are recombined, there exist particular combinations of epitopes (epitope associations) that occur repeatedly across the world-wide population of HIV-1. For example, Pol epitope LFLDGIDKA is found to be significantly associated with epitopes GHQAAMQML and FLKEKGGL from Gag and Nef, respectively, and this association rule is observed even among circulating recombinant forms.We have identified CTL epitope combinations co-occurring in HIV-1 genomes including different subtypes and recombinant forms. Such co-occurrence has important implications for design of complex vaccines (multi-epitope vaccines) and/or drugs that would target multiple HIV-1 regions at once and, thus, may be expected to overcome challenges associated with viral escape.In the course of viral infection, recognition of viral peptides by class I major histocompatibility complex (MHC) molecules and subsequent interactions of the peptide/MCH complex with the cytotoxic T lymphocytes (CTLs, or CD8+ T cells) plays an important role in the control of the infection [1,2]. Viral CTL epitopes (which are short viral peptides recognized by the immune system components, CTL and MHC class I molecules) are an integral – and critical – part of this recognition process, and amino acid changes at CTL epitopes have been shown to play a role in viral "escape" (in other words, evading recognition by the immune system) in human (HIV) and simian (SIV) immunodeficiency viruses [3-8]. In part
Extracellular conversion of adiponectin hexamers into trimers  [cached]
Jeong?a Kim,Martha Nu?ez,David?B. Briggs,Bethany?L. Laskowski
Bioscience Reports , 2012, DOI: 10.1042/bsr20120067
Abstract: Adiponectin is an adipocyte-secreted hormone that exists as trimers, hexamers and larger species collectively referred to as HMW (high-molecular-weight) adiponectin. Whether hexamers or HMW adiponectin serve as precursors for trimers outside the circulation is currently unknown. Here, we demonstrate that adiponectin trimers can be generated from larger oligomers secreted from primary rat adipose cells or differentiated 3T3-L1 adipocytes. Purified hexameric, but not HMW, adiponectin converted into trimers in conditioned media separated from 3T3-L1 adipocytes or, more efficiently, when enclosed in the dialysis membrane in the presence of adipocytes. Several lines of evidence indicate that the conversion is mediated by an extracellular redox system. First, N-terminal epitope-tagged hexamers converted into trimers without proteolytic removal of the tag. Secondly, appearance of trimers was associated with conversion of disulfide-bonded dimers into monomers. Thirdly, thiol-reactive agents inhibited conversion into trimers. Consistent with a redox-based mechanism, purified hexamers reductively converted into trimers in defined glutathione redox buffer with reduction potential typically found in the extracellular environment while the HMW adiponectin remained stable. In addition, conversion of hexamers into trimers was enhanced by NADPH, but not by NADP+. Collectively, these data strongly suggest the presence of an extracellular redox system capable of converting adiponectin oligomers.
Pulmonary function testing in HTLV-I and HTLV-II infected humans: a cohort study
Edward L Murphy, Helen E Ownby, James W Smith, George Garratty, Sheila T Hutching, Ying Wu, Dannie I Ameti
BMC Pulmonary Medicine , 2003, DOI: 10.1186/1471-2466-3-1
Abstract: We performed pulmonary function testing on HTLV-I, HTLV-II and HTLV seronegative subjects from the HTLV outcomes study (HOST), including vital capacity (VC), forced expiratory volume in one second (FEV1), and diffusing lung capacity for carbon monoxide (DLCO) corrected for hemoglobin and lung volume. Multivariable analysis adjusted for differences in age, gender, race/ethnicity, height and smoking history.Mean (standard deviation) pulmonary function values among the 257 subjects were as follows: FVC = 3.74 (0.89) L, FEV1 = 2.93 (0.67) L, DLCOcorr = 23.82 (5.89) ml/min/mmHg, alveolar ventilation (VA) = 5.25 (1.20) L and DLCOcorr/VA = 4.54 (0.87) ml/min/mmHg/L. There were no differences in FVC, FEV1 and DLCOcorr/VA by HTLV status. For DLCOcorr, HTLV-I and HTLV-II subjects had slightly lower values than seronegatives, but neither difference was statistically significant after adjustment for confounding.There was no difference in measured pulmonary function and diffusing capacity in generally healthy HTLV-I and HTLV-II subjects compared to seronegatives. These results suggest that previously described HTLV-associated abnormalities in bronchoalveolar cells and fluid may not affect pulmonary function.Human T-lymphotropic virus type I (HTLV-I) has been associated with sporadic cases of chronic bronchiolitis and alveolitis, especially in patients with concurrent HTLV associated myelopathy (HAM) [1,2]. HTLV type II (HTLV-II) has been epidemiologically associated with increased incidences of bronchitis and pneumonia among HTLV-II infected persons [3,4].Biological studies have demonstrated increased levels of CD3+/CD25+ lymphocytes [5], HTLV-I proviral load and HTLV-I tax/rex mRNA expression [6,7], HTLV-I specific IgA [8], soluble interleukin-2 receptors [9], beta-chemokines [7] and soluble intracellular adhesion molecule-1 (ICAM-1) [10], in bronchoalveolar lavage fluid from HTLV-I infected humans. In addition, mice transgenic for HTLV-I p40 tax had lymphocytic infiltration of
Induction of galectin-1 expression by HTLV-I Tax and its impact on HTLV-I infectivity
Sonia Gauthier, Isabelle Pelletier, Michel Ouellet, Amandine Vargas, Michel J Tremblay, Sachiko Sato, Benoit Barbeau
Retrovirology , 2008, DOI: 10.1186/1742-4690-5-105
Abstract: Herein, we demonstrate that galectin-1 expression and release are higher in HTLV-I-infected T cells in comparison to uninfected T cells. Furthermore, galectin-1 expression was activated in various cell lines expressing the wild type viral Tax protein while this induction was minimal upon expression of NF-κB activation-defective TaxM22. Cotransfection of these Tax expression vectors with galectin-1 promoter-driven luciferase constructs confirmed that Tax upregulated galectin-1 promoter activity. However, a NF-κB-independent mechanism was strongly favoured in this induction of galectin-1 expression as no activation of the promoter was apparent in Jurkat cells treated with known NF-κB activators. Using HTLV-I envelope pseudotyped HIV-1 virions, galectin-1 was shown to increase infectivity. In addition, a co-culture assay with HTLV-I-infected cells also indicated an increase in cell fusion upon addition of galectin-1. This effect was not mediated by factors present in the supernatant of the HTLV-I-infected cells.These data suggest that HTLV-I Tax increases galectin-1 expression and that this modulation could play an important role in HTLV-I infection by stabilizing both cell-to-cell and virus-cell interactions.Human T-cell Leukemia Virus type I (HTLV-I) is the etiological agent of adult T cell leukemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) [1-3]. It has been estimated that 20 million individuals are infected worldwide [4]. The in vivo target cells are mature CD4+CD45RO T lymphocytes and CD8+ T lymphocytes [5], although other cell types have been suggested to be potential target including lung epithelial cells, as recently demonstrated [6]. HTLV-I is transmitted between individuals by the transfer of infected lymphocytes and is thought to require repeated contacts as only one out of 1 × 105 to 1 × 106 viruses is infectious [7-9]. During viral transmission, a contact is established between an uninfected and an infected T cell by the
Tuberculous meningoencephalomyelitis and coinfection with HTLV-I + HTLV-II: case report
Menna-Barreto, Marcio;Machado, Denise C.;
Arquivos de Neuro-Psiquiatria , 2006, DOI: 10.1590/S0004-282X2006000100026
Abstract: htlv-i and htlv-ii are endemic in some areas of brazil, where an associated disease, htlv-i-associated myelopathy/tropical spastic paraparesis (ham/tsp) have been diagnosed in significant number of infected individuals. tuberculosis has been demonstrated among those individuals, with higher prevalence than in the general population, suggesting that there is an increased risk for this comorbidity. we report the case of an individual coinfected with htlv-i and htlv-ii, suffering from an insidious meningoencephalomyelitis caused by mycobacterium tuberculosis. the patient was a 44 years old man successfully treated with steroids and antituberculous drugs, improving clinically and turning to a negative pcr and to a normal blood-cerebrospinal fluid barrier.
Tuberculous meningoencephalomyelitis and coinfection with HTLV-I + HTLV-II: case report
Menna-Barreto Marcio,Machado Denise C.
Arquivos de Neuro-Psiquiatria , 2006,
Abstract: HTLV-I and HTLV-II are endemic in some areas of Brazil, where an associated disease, HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) have been diagnosed in significant number of infected individuals. Tuberculosis has been demonstrated among those individuals, with higher prevalence than in the general population, suggesting that there is an increased risk for this comorbidity. We report the case of an individual coinfected with HTLV-I and HTLV-II, suffering from an insidious meningoencephalomyelitis caused by Mycobacterium tuberculosis. The patient was a 44 years old man successfully treated with steroids and antituberculous drugs, improving clinically and turning to a negative PCR and to a normal blood-cerebrospinal fluid barrier.
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