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1.
Lab Chip ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32026889

RESUMO

Integration of microfluidics and biosensing functionalities on a single device holds promise in continuous health monitoring and disease diagnosis for point-of-care applications. However, the required functions of fluid handling and biomolecular sensing usually arise from different actuation mechanisms. In this work, we demonstrate that a single acoustofluidic device, based on a flexible thin film platform, is able to generate hybrid wave modes, which can be used for fluidic actuation (Lamb waves) and biosensing (thickness shear waves). On this integrated platform, we show multiple and sequential functions of mixing, transport and disposal of liquid volumes using Lamb waves, whilst the thickness bulk shear waves allow us to sense the chemotherapeutic Imatinib, using an aptamer-based strategy, as would be required for therapy monitoring. Upon binding, the conformation of the aptamer results in a change in coupled mass, which has been detected. This platform architecture has the potential to generate a wide range of simple sample-to-answer biosensing acoustofluidic devices.

3.
Invest New Drugs ; 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31240512

RESUMO

The anticancer activity of a series of novel synthesized, hydroxypyridone-based metal chelators (analogues of L-mimosine) was evaluated in an in vitro model of melanoma consisting of malignant melanoma (A375), non-melanoma epidermoid carcinoma (A431) and immortalized non-malignant keratinocyte (HaCaT) cells. More specifically, we have demonstrated that the L-enantiomer of a methylated analogue of L-mimosine (compound 22) can exert a potent anticancer effect in A375 cells when compared to either A431 or HaCaT cells. Moreover, we have demonstrated that this analogue has the ability to i) promote increased generation of reactive oxygen species (ROS), ii) activate both intrinsic and extrinsic apoptosis and iii) induce perturbations in cell cycle growth arrest. Our data highlights the potential of compound 22 to act as a promising therapeutic agent against an in vitro model of human malignant melanoma.

4.
Cells ; 8(3)2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30917514

RESUMO

Cellular therapies, including those based on T cells, are becoming approved options for clinicians treating a range of diseases. Cytotoxic T lymphocytes (CTLs) can be modified ex vivo to express receptors such as chimeric antigen receptors (CARs) or T cell receptors, allowing them to target tumour cells when infused back into patients with particular cancers. CTLs specific for viruses can be purified ex vivo and reinfused into patients transplanted with haematopoietic stem cells to help combat viral reactivation. Regulatory T cells (Tregs) can be expanded ex vivo for infusion into patients with autoimmunity or allergy, or into those at risk of rejecting transplanted cells or tissues, or suffering graft versus host disease. Effector and regulatory T cells can also be generated by infusion of patient-derived dendritic cells (DCs) conditioned in ways to elicit anti-tumour immunity (CTLs) or Tregs. All such therapies are resource-heavy (particularly in process regulation) and so must be initially targeted to patients that have limited treatment options, but also where they have a chance of being effective.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Linfócitos T/imunologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T/efeitos dos fármacos
5.
Cells ; 8(1)2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30646564

RESUMO

Adverse outcomes following virus-associated disease in patients receiving allogeneic haematopoietic stem cell transplantation (HSCT) have encouraged strategies to control viral reactivation in immunosuppressed patients. However, despite timely treatment with antiviral medication, some viral infections remain refractory to treatment, which hampers outcomes after HSCT, and are responsible for a high proportion of transplant-related morbidity and mortality. Adoptive transfer of donor-derived lymphocytes aims to improve cellular immunity and to prevent or treat viral diseases after HSCT. Early reports described the feasibility of transferring nonspecific lymphocytes from donors, which led to the development of cell therapy approaches based on virus-specific T cells, allowing a targeted treatment of infections, while limiting adverse events such as graft versus host disease (GvHD). Both expansion and direct selection techniques have yielded comparable results in terms of efficacy (around 70⁻80%), but efficacy is difficult to predict for individual cases. Generating bespoke products for each donor⁻recipient pair can be expensive, and there remains the major obstacle of generating products from seronegative or poorly responsive donors. More recent studies have focused on the feasibility of collecting and infusing partially matched third-party virus-specific T cells, reporting response rates of 60⁻70%. Future development of this approach will involve the broadening of applicability to multiple viruses, the optimization and cost-control of manufacturing, larger multicentred efficacy trials, and finally the creation of cell banks that can provide prompt access to virus-specific cellular product. The aim of this review is to summarise present knowledge on adoptive T cell manufacturing, efficacy and potential future developments.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoterapia Adotiva/métodos , Linfócitos T/transplante , Viroses/terapia , Adulto , Criança , Doação Dirigida de Tecido , Doença Enxerto-Hospedeiro/etiologia , Humanos , Viroses/etiologia
6.
Vaccines (Basel) ; 6(4)2018 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-30558246

RESUMO

Most immune responses associated with vaccination are controlled by specific T cells of a CD4+ helper phenotype which mediate the generation of effector antibodies, cytotoxic T lymphocytes (CTLs), or the activation of innate immune effector cells. A rapidly growing understanding of the generation, maintenance, activity, and measurement of such T cells is leading to vaccination strategies with greater efficacy and potentially greater microbial coverage.

7.
Mediators Inflamm ; 2018: 3972104, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29983634

RESUMO

Glucocorticoid receptor (GR) function may have aetiopathogenic significance in chronic fatigue syndrome (CFS), via its essential role in mediating inflammatory responses as well as in hypothalamic-pituitary-adrenal axis regulation. GR function can be estimated ex vivo by measuring dexamethasone (dex) modulation of cytokine response to lipopolysaccharide (LPS), and in vivo using the impact of dex on cortisol levels. This study aimed to compare the GR function between CFS (n = 48), primary Sjögren's syndrome (a disease group control) (n = 27), and sedentary healthy controls (HCs) (n = 20), and to investigate its relationship with clinical measures. In the GR ex vivo response assay, whole blood was diluted and incubated with LPS (to stimulate cytokine production), with or without 10 or 100 nanomolar concentrations of dex. Cytometric bead array (CBA) and flow cytometry enabled quantification of cytokine levels (TNFα, interleukin- (IL-) 6, and IL-10) in the supernatants. In the in vivo response assay, five plasma samples were taken for determination of total cortisol concentration using ELISA at half-hourly intervals on two consecutive mornings separated by ingestion of 0.5 mg of dex at 11 pm. The association of the data from the in vivo and ex vivo analyses with reported childhood adversity was also examined. CFS patients had reduced LPS-induced IL-6 and TNFα production compared to both control groups and reduced suppression of TNFα by the higher dose of dex compared to HCs. Cortisol levels, before or after dex, did not differ between CFS and HCs. Cortisol levels were more variable in CFS than HCs. In the combined group (CFS plus HC), cortisol concentrations positively and ex vivo GR function (determined by dex-mediated suppression of IL-10) negatively correlated with childhood adversity score. The results do not support the hypothesis that GR dysregulation is aetiopathogenic in CFS and suggest that current and future endocrine cross-sectional studies in CFS may be vulnerable to the confounding influence of childhood trauma which is likely increased by comorbid depression.


Assuntos
Síndrome de Fadiga Crônica/metabolismo , Receptores de Glucocorticoides/metabolismo , Adulto , Idoso , Análise de Variância , Dexametasona/farmacologia , Síndrome de Fadiga Crônica/patologia , Feminino , Citometria de Fluxo , Humanos , Hidrocortisona/metabolismo , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
8.
Respir Res ; 19(1): 106, 2018 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-29848315

RESUMO

BACKGROUND: As a way to determine markers of infection or disease informing disease management, and to reveal disease-associated immune mechanisms, this study sought to measure antibody and T cell responses against key lung pathogens and to relate these to patients' microbial colonization status, exacerbation history and lung function, in Bronchiectasis (BR) and Chronic Obstructive Pulmonary Disease (COPD). METHODS: One hundred nineteen patients with stable BR, 58 with COPD and 28 healthy volunteers were recruited and spirometry was performed. Bacterial lysates were used to measure specific antibody responses by ELISA and T cells by ELIspot. Cytokine secretion by lysate-stimulated T cells was measured by multiplex cytokine assay whilst activation phenotype was measured by flow cytometry. RESULTS: Typical colonization profiles were observed in BR and COPD, dominated by P.aeruginosa, H.influenzae, S.pneumoniae and M.catarrhalis. Colonization frequency was greater in BR, showing association with increased antibody responses against P.aeruginosa compared to COPD and HV, and with sensitivity of 73% and specificity of 95%. Interferon-gamma T cell responses against P.aeruginosa and S.pneumoniae were reduced in BR and COPD, whilst reactive T cells in BR had similar markers of homing and senescence compared to healthy volunteers. Exacerbation frequency in BR was associated with increased antibodies against P. aeruginosa, M.catarrhalis and S.maltophilia. T cell responses against H.influenzae showed positive correlation with FEV1% (r = 0.201, p = 0.033) and negative correlation with Bronchiectasis Severity Index (r = - 0.287, p = 0.0035). CONCLUSION: Our findings suggest a difference in antibody and T cell immunity in BR, with antibody being a marker of exposure and disease in BR for P.aeruginosa, M.catarrhalis and H.influenzae, and T cells a marker of reduced disease for H.influenzae.


Assuntos
Anticorpos Antibacterianos/imunologia , Bronquiectasia/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Doença Pulmonar Obstrutiva Crônica/imunologia , Linfócitos T/imunologia , Idoso , Anticorpos Antibacterianos/metabolismo , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Bronquiectasia/metabolismo , Feminino , Haemophilus influenzae/imunologia , Haemophilus influenzae/isolamento & purificação , Haemophilus influenzae/metabolismo , Humanos , Pulmão/metabolismo , Masculino , Pessoa de Meia-Idade , Pseudomonas aeruginosa/imunologia , Pseudomonas aeruginosa/isolamento & purificação , Pseudomonas aeruginosa/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Streptococcus pneumoniae/imunologia , Streptococcus pneumoniae/isolamento & purificação , Streptococcus pneumoniae/metabolismo , Linfócitos T/metabolismo
9.
Immunol Lett ; 195: 38-44, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28844771

RESUMO

Innate lymphoid cells (ILCs) are innate immune cells that do not possess B or T cell receptors but belong to the lymphoid lineage. While these cells have not yet been extensively investigated since their classification as a homogenous group, emerging evidence suggests that they exert significant regulatory roles in both tissue remodelling and inflammation, and are therefore, also involved in fibrotic regulation. The following review will serve to outline the transcription factors, surface markers, and cytokines that define each subgroup, and the process by which these cells differentiate. Furthermore, the diverse functions of these cells in non-pathogenic states will be discussed, in addition to the interactions between ILCs and other cells of the immune system, both innate and adaptive, and how these pathways can elicit both pro- and anti-inflammatory and -fibrotic effects in varying tissues.


Assuntos
Citocinas/metabolismo , Inflamação/imunologia , Linfócitos/imunologia , Animais , Fibrose , Regulação da Expressão Gênica , Humanos , Imunidade Inata , Imunomodulação , Fatores de Transcrição/metabolismo
10.
Clin Sci (Lond) ; 131(15): 1923-1940, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28705953

RESUMO

The skin is the largest organ of the integumentary system and possesses a vast number of functions. Due to the distinct layers of the skin and the variety of cells which populate each, a tightly regulated network of molecular signals control development and regeneration, whether due to programmed cell termination or injury. MicroRNAs (miRs) are a relatively recent discovery; they are a class of small non-coding RNAs which possess a multitude of biological functions due to their ability to regulate gene expression via post-transcriptional gene silencing. Of interest, is that a plethora of data demonstrates that a number of miRs are highly expressed within the skin, and are evidently key regulators of numerous vital processes to maintain non-aberrant functioning. Recently, miRs have been targeted as therapeutic interventions due to the ability of synthetic 'antagomiRs' to down-regulate abnormal miR expression, thereby potentiating wound healing and attenuating fibrotic processes which can contribute to disease such as systemic sclerosis (SSc). This review will provide an introduction to the structure and function of the skin and miR biogenesis, before summarizing the literature pertaining to the role of miRs. Finally, miR therapies will also be discussed, highlighting important future areas of research.


Assuntos
MicroRNAs/metabolismo , Fenômenos Fisiológicos da Pele , Animais , Homeostase , Humanos , MicroRNAs/genética , Regeneração
11.
Hum Vaccin Immunother ; 13(9): 2130-2134, 2017 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-28605295

RESUMO

The restimulation of an immune memory response by in vitro culture of blood cells with a specific antigen has been used as a way to gauge immunity to vaccines for decades. In this commentary we discuss a less appreciated application to support vaccine process development. We report that human whole blood from pre-primed subjects can generate a profound adjuvant-modulated, antigen-specific response to several different vaccine formulations. The response is able to differentiate subtle changes in the quality of an immune memory response to vaccine formulations and can be used to select optimal conditions relating to a particular manufacture process step. While questions relating to closeness to in vivo vaccination remain, the approach is another big step nearer to the more relevant human response. It has special importance for new adjuvant development, complementing other preclinical in vivo and in vitro approaches to considerably de-risk progression of novel vaccines before and throughout early clinical development. Broader implications of the approach are discussed.


Assuntos
Adjuvantes Imunológicos , Sangue/imunologia , Memória Imunológica , Vacinas/imunologia , Imunidade Adaptativa , Ensaios de Triagem em Larga Escala , Humanos , Interferon gama/biossíntese , Interferon gama/imunologia , Linfócitos T/imunologia , Vacinação
12.
PLoS One ; 11(2): e0148024, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26829555

RESUMO

INTRODUCTION: Gingival fibroblast-mediated extracellular matrix remodelling is implicated in the pathogenesis of periodontitis, yet the stimuli that regulate this response are not fully understood. The immunoregulatory adipokine leptin is detectable in the gingiva, human gingival fibroblasts express functional leptin receptor mRNA and leptin is known to regulate extracellular matrix remodelling responses in cardiac fibroblasts. We therefore hypothesised that leptin would enhance matrix metalloproteinase secretion in human gingival fibroblasts. METHODS AND RESULTS: We used in vitro cell culture to investigate leptin signalling and the effect of leptin on mRNA and protein expression in human gingival fibroblasts. We confirmed human gingival fibroblasts expressed cell surface leptin receptor, found leptin increased matrix metalloproteinase-1, -3, -8 and -14 expression in human gingival fibroblasts compared to unstimulated cells, and observed that leptin stimulation activated MAPK, STAT1/3 and Akt signalling in human gingival fibroblasts. Furthermore, leptin synergised with IL-1 or the TLR2 agonist pam2CSK4 to markedly enhance matrix metalloproteinase-1 and -3 production by human gingival fibroblasts. Signalling pathway inhibition demonstrated ERK was required for leptin-stimulated matrix metalloproteinase-1 expression in human gingival fibroblasts; whilst ERK, JNK, p38 and STAT3 were required for leptin+IL-1- and leptin+pam2CSK4-induced matrix metalloproteinase-1 expression. A genome-wide expression array and gene ontology analysis confirmed genes differentially expressed in leptin+IL-1-stimulated human gingival fibroblasts (compared to unstimulated cells) were enriched for extracellular matrix organisation and disassembly, and revealed that matrix metalloproteinase-8 and -12 were also synergistically upregulated by leptin+IL-1 in human gingival fibroblasts. CONCLUSIONS: We conclude that leptin selectively enhances the expression and secretion of certain matrix metalloproteinases in human gingival fibroblasts, and suggest that gingival fibroblasts may have an ECM-degrading phenotype during conditions of hyperleptinaemia (e.g., obesity, type 2 diabetes mellitus, exogenous leptin therapy).


Assuntos
Fibroblastos/metabolismo , Gengiva/citologia , Mediadores da Inflamação/metabolismo , Leptina/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Matriz Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Expressão Gênica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Mediadores da Inflamação/farmacologia , Interleucina-1/metabolismo , Interleucina-1/farmacologia , Leptina/farmacologia , Metaloproteinase 1 da Matriz/genética , Metaloproteinase 3 da Matriz/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fatores de Transcrição STAT/metabolismo , Transcriptoma , Vimentina/genética , Vimentina/metabolismo
13.
Physiol Rep ; 3(12)2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26660547

RESUMO

DNA methylation is modifiable by acute and chronic exercise. DNA methyltransferases (DNMT) catalyze this process; however, there is a lack of literature concerning the specific mechanisms by which exercise-induced modifications occur. Interleukin 6 (IL-6) stimulation of various cell lines has been shown to augment DNMT expression and nuclear translocation, which suggests a possible pathway by which exercise is able to elicit changes in epigenetic enzymes. The present study sought to elucidate the response of the de novo methyltransferases DNMT3A and DNMT3B to circulatory factors found in plasma isolated from whole blood before and after 120-min of treadmill running at an intensity of 60% of individual velocity at V˙O2max (vV˙O2max) interspersed with 30-sec sprints at 90% of vV˙O2max every 10-min. Peripheral blood mononuclear cells (PBMCs) isolated from a resting participant were incubated with plasma isolated from exercising participants (n = 10) or recombinant IL-6 (rIL-6), followed by nuclear protein extraction and quantification of DNMT3A and DNMT3B concentrations. Nuclear concentrations of DNMT3B significantly decreased following the experimental protocol (P = 0.03), with no change observed in DNMT3A (P = 0.514).Various concentrations of rIL-6 caused an elevation in both DNMT3A and DNMT3B nuclear concentration compared with the blank control. The conflicting results between exercising and rIL-6 conditions suggests that IL-6 does regulate DNMT nuclear transport, however, other plasma mediators may also exert significant influence on the nuclear concentrations of these enzymes.

14.
Sci Rep ; 5: 14938, 2015 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-26450665

RESUMO

This research proposes an intelligent decision support system for acute lymphoblastic leukaemia diagnosis from microscopic blood images. A novel clustering algorithm with stimulating discriminant measures (SDM) of both within- and between-cluster scatter variances is proposed to produce robust segmentation of nucleus and cytoplasm of lymphocytes/lymphoblasts. Specifically, the proposed between-cluster evaluation is formulated based on the trade-off of several between-cluster measures of well-known feature extraction methods. The SDM measures are used in conjuction with Genetic Algorithm for clustering nucleus, cytoplasm, and background regions. Subsequently, a total of eighty features consisting of shape, texture, and colour information of the nucleus and cytoplasm sub-images are extracted. A number of classifiers (multi-layer perceptron, Support Vector Machine (SVM) and Dempster-Shafer ensemble) are employed for lymphocyte/lymphoblast classification. Evaluated with the ALL-IDB2 database, the proposed SDM-based clustering overcomes the shortcomings of Fuzzy C-means which focuses purely on within-cluster scatter variance. It also outperforms Linear Discriminant Analysis and Fuzzy Compactness and Separation for nucleus-cytoplasm separation. The overall system achieves superior recognition rates of 96.72% and 96.67% accuracies using bootstrapping and 10-fold cross validation with Dempster-Shafer and SVM, respectively. The results also compare favourably with those reported in the literature, indicating the usefulness of the proposed SDM-based clustering method.


Assuntos
Algoritmos , Diagnóstico por Computador/métodos , Leucemia/diagnóstico , Leucócitos/patologia , Máquina de Vetores de Suporte , Núcleo Celular/metabolismo , Análise por Conglomerados , Citoplasma/metabolismo , Bases de Dados Factuais , Análise Discriminante , Humanos , Leucemia/sangue , Leucócitos/classificação , Leucócitos/metabolismo , Microscopia/métodos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Coloração e Rotulagem/métodos
15.
Immun Inflamm Dis ; 3(2): 56-70, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26029366

RESUMO

CMV infection is responsible for acceleration of immune senescence and linked to systemic pathologies, including cardiovascular diseases. In this study, we investigated differences in the immune response between CMV-seropositive and seronegative patients undergoing primary percutaneous coronary intervention (PPCI) for acute myocardial infarction (MI). Peripheral blood samples were taken at six different time points: pre-, 15, 30, 90 min, 24 h after PPCI and at 3 months after MI. Absolute counts of lymphocyte subpopulations, immune response to specific and nonspecific stimulation, serum cytokines and levels of CMV-IgG, cardiolipin-IgG, and anti-endothelial cell antibodies were assessed. CMV-seropositive patients with MI showed a twofold higher IFN-γ production to PHA-stimulation, up to 2.5-fold higher levels of IP-10 in serum and up to 30% lower serum levels of IL-16 compared to CMV-seronegative individuals. CMV-seropositive patients could be divided into two subgroups with high (IL-10Hi) and low (IL-10Lo) IL-10 serum levels during the acute stage of MI. The IL-10Hi CMV-seropositive subgroup showed an increased exit of late-differentiated T lymphocytes, NK and NKT-like cells from the circulation, which may potentially enhance cytotoxic damage in the ischemic myocardium. Finally, we did not observe an acceleration of autoimmunity by MI in CMV-seropositive individuals. The immune response during acute MI showed characteristic differences between CMV seronegative and seropositive patients, with a stronger pro-inflammatory response in seropositive patients. The effects of IP-10, IL-16, and IL-10 on characteristics of acute immune responses and formation of different immune profiles in CMV-seropositive individuals require further investigation.

16.
Immunology ; 145(1): 71-81, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25471322

RESUMO

This study examined specific antibody and T-cell responses associated with experimental malaria infection or malaria vaccination, in malaria-naive human volunteers within phase I/IIa vaccine trials, with a view to investigating inter-relationships between these types of response. Malaria infection was via five bites of Plasmodium falciparum-infected mosquitoes, with individuals reaching patent infection by 11-12 days, having harboured four or five blood-stage cycles before drug clearance. Infection elicited a robust antibody response against merozoite surface protein-119 , correlating with parasite load. Classical class switching was seen from an early IgM to an IgG1-dominant response of increasing affinity. Malaria-specific T-cell responses were detected in the form of interferon-γ and interleukin-4 (IL-4) ELIspot, but their magnitude did not correlate with the magnitude of antibody or its avidity, or with parasite load. Different individuals who were immunized with a virosome vaccine comprising influenza antigens combined with P. falciparum antigens, demonstrated pre-existing interferon-γ, IL-2 and IL-5 ELIspot responses against the influenza antigens, and showed boosting of anti-influenza T-cell responses only for IL-5. The large IgG1-dominated anti-parasite responses showed limited correlation with T-cell responses for magnitude or avidity, both parameters being only negatively correlated for IL-5 secretion versus anti-apical membrane antigen-1 antibody titres. Overall, these findings suggest that cognate T-cell responses across a range of magnitudes contribute towards driving potentially effective antibody responses in infection-induced and vaccine-induced immunity against malaria, and their existence during immunization is beneficial, but magnitudes are mostly not inter-related.


Assuntos
Anticorpos Antiprotozoários/imunologia , Formação de Anticorpos/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Citocinas/imunologia , Feminino , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/patologia , Malária Falciparum/prevenção & controle , Masculino , Proteína 1 de Superfície de Merozoito/administração & dosagem , Proteína 1 de Superfície de Merozoito/imunologia , Pessoa de Meia-Idade
17.
Circ Res ; 116(1): 87-98, 2015 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-25385851

RESUMO

RATIONALE: There is mounting evidence of a higher incidence of coronary heart disease in cytomegalovirus-seropositive individuals. OBJECTIVE: The aim of this study was to investigate whether acute myocardial infarction triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in cytomegalovirus-seropositive patients. METHODS AND RESULTS: Thirty-four patients with acute myocardial infarction undergoing primary percutaneous coronary intervention were longitudinally studied within 3 months after reperfusion (Cohort A). In addition, 54 patients with acute myocardial infarction and chronic myocardial infarction were analyzed in a cross-sectional study (Cohort B). Cytomegalovirus-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 minutes of reperfusion compared with cytomegalovirus-seronegative patients (-192 versus -63 cells/µL; P=0.008), correlating with the expression of programmed cell death-1 before primary percutaneous coronary intervention (r=0.8; P=0.0002). A significant proportion of TEMRA cells remained depleted for ≥3 months in cytomegalovirus-seropositive patients. Using high-throughput 13-parameter flow cytometry and human leukocyte antigen class I cytomegalovirus-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and cytomegalovirus-specific CD8(+) cells in cytomegalovirus-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic cytomegalovirus-seropositive postmyocardial infarction patients was associated with signs of terminal differentiation including an increase in killer cell lectin-like receptor subfamily G member 1 and shorter telomere length in CD8(+) T cells (2225 versus 3397 bp; P<0.001). CONCLUSIONS: Myocardial ischemia and reperfusion in cytomegalovirus-seropositive patients undergoing primary percutaneous coronary intervention leads to acute loss of antigen-specific, terminally differentiated CD8 T cells, possibly through programmed cell death-1-dependent programmed cell death. Our results suggest that acute myocardial infarction and reperfusion accelerate immunosenescence in cytomegalovirus-seropositive patients.


Assuntos
Antígenos CD8/sangue , Senescência Celular/fisiologia , Citomegalovirus/metabolismo , Síndromes de Imunodeficiência/sangue , Isquemia Miocárdica/sangue , Reperfusão Miocárdica/métodos , Idoso , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Estudos Transversais , Citomegalovirus/imunologia , Feminino , Humanos , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/virologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/virologia
18.
Hum Vaccin Immunother ; 10(4): 1129-35, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24401565

RESUMO

Understanding the relevant biological activity of any pharmaceutical formulation destined for human use is crucial. For vaccine-based formulations, activity must reflect the expected immune response, while for non-vaccine therapeutic agents, such as monoclonal antibodies, a lack of immune response to the formulation is desired. During early formulation development, various biochemical and biophysical characteristics can be monitored in a high-throughput screening (HTS) format. However, it remains impractical and arguably unethical to screen samples in this way for immunological functionality in animal models. Furthermore, data for immunological functionality lag formulation design by months, making it cumbersome to relate back to formulations in real-time. It is also likely that animal testing may not accurately reflect the response in humans. For a more effective formulation screen, a human whole blood (hWB) approach can be used to assess immunological functionality. The functional activity relates directly to the human immune response to a complete formulation (adjuvant/antigen) and includes adjuvant response, antigen response, adjuvant-modulated antigen response, stability, and potentially safety. The following commentary discusses the hWB approach as a valuable new tool to de-risk manufacture, formulation design, and clinical progression.


Assuntos
Sangue/imunologia , Química Farmacêutica/métodos , Vacinas/imunologia , Humanos
20.
Immunology ; 139(4): 407-15, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23551234

RESUMO

Heat-shock proteins (hsp) provide a natural link between innate and adaptive immune responses by combining the ideal properties of antigen carriage (chaperoning), targeting and activation of antigen-presenting cells (APC), including dendritic cells (DC). Targeting is achieved through binding of hsp to distinct cell surface receptors and is followed by antigen internalization, processing and presentation. An improved understanding of the interaction of hsp with DC has driven the development of numerous hsp-containing vaccines, designed to deliver antigens directly to DC. Studies in mice have shown that for cancers, such vaccines generate impressive immune responses and protection from tumour challenge. However, translation to human use, as for many experimental immunotherapies, has been slow partly because of the need to perform trials in patients with advanced cancers, where demonstration of efficacy is challenging. Recently, the properties of hsp have been used for development of prophylactic vaccines against infectious diseases including tuberculosis and meningitis. These hsp-based vaccines, in the form of pathogen-derived hsp-antigen complexes, or recombinant hsp combined with selected antigens in vitro, offer an innovative approach against challenging diseases where broad antigen coverage is critical.


Assuntos
Imunidade Adaptativa , Vacinas Bacterianas/imunologia , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Proteínas de Choque Térmico/imunologia , Imunidade Inata , Vacinas Virais/imunologia , Animais , Vacinas Bacterianas/metabolismo , Vacinas Anticâncer/metabolismo , Células Dendríticas/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Ativação Linfocitária , Receptores de Superfície Celular/metabolismo , Linfócitos T/imunologia , Vacinas Sintéticas/imunologia , Vacinas Virais/metabolismo
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