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Venenos de Abeja/inmunología , Apicultura , Abejas/fisiología , Mordeduras y Picaduras/inmunología , Factores de Transcripción Forkhead/metabolismo , Linfocitos T Reguladores/inmunología , Adulto , Animales , Venenos de Abeja/uso terapéutico , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Estaciones del AñoRESUMEN
Venom-specific immunotherapy (VIT) is well recognized by its efficacy, and compelling evidence implicates regulatory T cells (Tregs) in the underlying tolerogenic mechanisms. Additionally, hymenoptera venom has for a long time been claimed to modulate immunity. Here, we investigated the putative role of bee venom (Bv) in human FOXP3-expressing Treg homeostasis and differentiation, irrespective of the donors' allergic status. We found that Bv significantly enhanced the differentiation of FOXP3-expressing cells both from conventional naïve CD4 T cells and mature CD4 thymocytes, a property that may contribute to the VIT's capacity to expand circulating Tregs in allergic individuals. We expect that our data enlightening the Treg-mediated immunomodulatory properties of Bv regardless of TCR specificity, to have application in other allergies, as well as in other clinical settings, such as autoimmunity and transplantation.
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Venenos de Abeja/inmunología , Diferenciación Celular/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Antígenos de Superficie/metabolismo , Preescolar , Desensibilización Inmunológica , Femenino , Humanos , Inmunomodulación , Inmunofenotipificación , Lactante , Recién Nacido , Masculino , Receptores de Antígenos de Linfocitos T/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismoRESUMEN
Common variable immunodeficiency disorders (CVID), the most frequent cause of symptomatic primary immunodeficiency, are defined by impaired antibody production. Notwithstanding, T cell activation and granulomatous manifestations represent the main causes of CVID morbidity even in patients receiving immunoglobulin (Ig) G replacement therapy. Additionally, gut pathology is a frequent feature of CVID. In this study, we investigated monocyte imbalances and their possible relationship with increased microbial translocation in CVID patients. Monocyte subsets were defined according to CD14 and CD16 expression levels and evaluated in terms of human leucocyte antigen D-related (HLA-DR), CD86 and programmed death-1 molecule ligand 1 (PD-L1) expression by flow cytometry, in parallel with the quantification of plasma lipopolysaccharide (LPS) and serum levels of soluble CD14 (sCD14), LPS-binding protein (LBP) and anti-LPS antibodies. CVID patients (n=31) featured significantly increased levels of serum sCD14 and an expansion of CD14(bright) CD16(+) monocytes in direct correlation with T cell and B cell activation, the latter illustrated by the frequency of the CD21(low) CD38(low) subset. Such alterations were not observed in patients lacking B cells due to congenital agammaglobulinaemia (n=4). Moreover, we found no significant increase in circulating LPS or LBP levels in CVID patients, together with a relative preservation of serum anti-LPS antibodies, in agreement with their presence in commercial IgG preparations. In conclusion, CVID was associated with monocyte imbalances that correlated directly with T cell activation markers and with B cell imbalances, without an association with plasma LPS levels. The heightened monocyte activated state observed in CVID may represent an important target for complementary therapeutic strategies.
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Inmunodeficiencia Variable Común/inmunología , Lipopolisacáridos/sangre , Monocitos/inmunología , Subgrupos de Linfocitos T/inmunología , Proteínas de Fase Aguda , Adulto , Agammaglobulinemia Tirosina Quinasa , Agammaglobulinemia/sangre , Agammaglobulinemia/inmunología , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunología , Proteínas Portadoras/sangre , Inmunodeficiencia Variable Común/sangre , Citocinas/biosíntesis , Endotoxinas/inmunología , Femenino , Proteínas Ligadas a GPI/sangre , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Receptores de Lipopolisacáridos/sangre , Activación de Linfocitos , Masculino , Glicoproteínas de Membrana/sangre , Persona de Mediana Edad , Monocitos/química , Proteínas Tirosina Quinasas/deficiencia , Receptores de IgG/sangre , Subgrupos de Linfocitos T/patologíaAsunto(s)
Adenocarcinoma/complicaciones , Colonoscopía , Neoplasias Colorrectales/complicaciones , Absceso Piógeno Hepático/diagnóstico por imagen , Absceso Piógeno Hepático/etiología , Adenocarcinoma/patología , Neoplasias Colorrectales/patología , Humanos , Masculino , Persona de Mediana Edad , UltrasonografíaRESUMEN
BACKGROUND: Venom immunotherapy (VIT) induces long-lasting immune tolerance to hymenoptera venom antigens, but the underlying mechanisms are not yet clarified. Regulatory T cells are thought to play an important role in allergic diseases and tolerance induction during specific immunotherapy. AIM: Characterize longitudinally the impact of VIT on the pool of circulating regulatory T cells. METHODS: Fourteen hymenoptera venom-allergic patients with severe reactions (grades III-IV) were studied before, 6 and 12 months after starting ultra-rush VIT. Freshly isolated peripheral blood mononuclear cells were surface stained with a panel of markers of T cell differentiation and intracellularly for CTLA-4 and Foxp3 and analysed by flow cytometry. foxp3 mRNA was quantified by real-time PCR. VIT responses were assessed by measuring specific IgG4 and IgE levels. Eleven individuals with no history of insect venom allergy were studied as controls. RESULTS: VIT induces a significant progressive increase in both the proportion and the absolute numbers of regulatory T cells defined as CD25bright and/or Foxp3+ CD4+ T cells. These changes are not related to alterations in the expression of activation markers or imbalances in the naïve/memory T cell compartments. foxp3 mRNA levels also increased significantly during VIT. Of note, the increase in circulating regulatory T cell counts significantly correlates with the venom-specific IgG4/IgE ratio shift. CONCLUSION: VIT is associated with a progressive expansion of circulating regulatory T cells, supporting a role for these cells in tolerance induction.
Asunto(s)
Venenos de Abeja/inmunología , Desensibilización Inmunológica/métodos , Himenópteros/inmunología , Hipersensibilidad Inmediata/inmunología , Mordeduras y Picaduras de Insectos/inmunología , Linfocitos T Reguladores/inmunología , Venenos de Avispas/inmunología , Adolescente , Adulto , Anciano , Animales , Antígenos/inmunología , Venenos de Abeja/uso terapéutico , Antígenos CD4/análisis , Femenino , Factores de Transcripción Forkhead/análisis , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Humanos , Hipersensibilidad Inmediata/tratamiento farmacológico , Tolerancia Inmunológica , Inmunoglobulina E/sangre , Inmunoglobulina G/sangre , Memoria Inmunológica , Mordeduras y Picaduras de Insectos/tratamiento farmacológico , Subunidad alfa del Receptor de Interleucina-2/análisis , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Venenos de Avispas/uso terapéuticoRESUMEN
Paediatric studies may provide important insights into the immunopathology of Helicobacter pylori-associated gastritis, as mucosal changes reflect different stages of the immunoinflammatory response. We characterized, by quantitative immunohistochemistry, gastric mucosal lymphocyte phenotype and HLA-DR antigen expression and evaluated correlation with histopathology, in H. pylori-infected (Hp+ve) and uninfected children (Hp-ve). In the infected group, lamina propria CD3+ and IgA plasmocyte cell numbers were significantly higher and a trend for predominance of CD8+ over CD4+ was observed both in epithelium and lamina propria. A correlation of inflammation score with lamina propria CD3+ and CD4+ cell numbers and of CD45RO+ T lymphocytes with density of colonization was observed. The proportion of epithelial cells expressing HLA-DR antigen was significantly higher in the Hp+ve group and furthermore, glandular HLA-DR expression correlated with lamina propria CD3+ cell numbers, emphasizing the potential role of epithelial cells as antigen-presenting cells at this stage of infection.
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Mucosa Gástrica/inmunología , Gastritis/inmunología , Antígenos HLA-DR/análisis , Infecciones por Helicobacter/inmunología , Helicobacter pylori , Subgrupos de Linfocitos T/inmunología , Adolescente , Anticuerpos Antibacterianos/sangre , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Mucosa Gástrica/patología , Gastritis/patología , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Humanos , Inmunoglobulina G/sangre , Inmunohistoquímica/métodos , Inmunofenotipificación , Lactante , Recuento de Linfocitos , Masculino , Antro Pilórico/inmunología , Antro Pilórico/patología , Estadísticas no ParamétricasAsunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/tratamiento farmacológico , Terapia Antirretroviral Altamente Activa , VIH-1 , Infecciones por Helicobacter/tratamiento farmacológico , Helicobacter pylori , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Amoxicilina/administración & dosificación , Antibacterianos , Antiinfecciosos/administración & dosificación , Antiulcerosos/administración & dosificación , Quimioterapia Combinada , Humanos , Linfoma de Células B de la Zona Marginal/patología , Masculino , Omeprazol/administración & dosificación , Inducción de Remisión , Neoplasias Gástricas/patología , Tinidazol/administración & dosificaciónRESUMEN
Human immunodeficiency virus (HIV) type 2 infection is associated with a better clinical outcome, slower rates of CD4 T cell decline, and lower viremia than is HIV-1. This study compares HIV-1 and HIV-2 in regard to the percentages of interleukin (IL)-2-, interferon (IFN)-gamma-, and IL-4-producing cells at the single-cell level, as determined by flow cytometry. At a given degree of CD4 T cell depletion, the frequency of T cells able to produce IL-2 is better preserved in HIV-2 than in HIV-1 infection, particularly within the CD4 T cell subset. As described for HIV-1 immunodeficiency, HIV-2-positive patients exhibit a marked expansion of terminally differentiated effector CD8 T cells (CD28(-)CD27(-)IFN-gamma(+)). However, the proportion of CD8 T cells able to simultaneously produce IL-2 and IFN-gamma is higher in HIV-2 disease. Considering the central role of IL-2 as a lymphocyte proliferative and survival factor, these findings provide a possible immunologic basis for the distinct course of HIV-2 immunodeficiency.
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Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citocinas/biosíntesis , Infecciones por VIH/fisiopatología , VIH-1/inmunología , VIH-2/inmunología , Adolescente , Adulto , Anciano , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Femenino , Citometría de Flujo , Infecciones por VIH/epidemiología , Infecciones por VIH/inmunología , VIH-1/patogenicidad , VIH-2/patogenicidad , Humanos , Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Interleucina-4/metabolismo , Masculino , Persona de Mediana EdadAsunto(s)
Hipertensión Pulmonar/etiología , Lupus Eritematoso Sistémico/complicaciones , Adulto , Antiinflamatorios/uso terapéutico , Azatioprina/uso terapéutico , Femenino , Humanos , Hipertensión Pulmonar/diagnóstico , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Prednisona/uso terapéutico , Remisión EspontáneaRESUMEN
OBJECTIVE: HIV-1 envelope proteins have immunosuppressive properties and it is thought that they have a role in the establishment of immunodeficiency. This study characterizes the immunological effects of HIV-2 envelope protein gp105, a virus which is associated with a slower rate of disease progression. METHODS: The effects of recombinant baculovirus-expressed envelope proteins from HIV-IIIB HIV-1MN, HIV-2ROD and SIVmac251 on anti-CD3-stimulated peripheral blood mononuclear cells (PBMC) from healthy donors were evaluated by incorporation of 3H-thymidine, flow cytometric analysis of bromodeoxyuridine incorporation in different T cell subsets, kinetics of expression of costimulatory molecules (CD40L/OX40) and assessment of cell death by annexin V/propidium iodide staining. The effects on production of tumour necrosis factor alpha (TNF-alpha) by monocytes were assessed at the single-cell level after a 6 h culture of unstimulated PBMC. RESULTS: HIV-2 gp105 was more inhibitory than HIV-1 gp120 of T cell proliferation and the upregulation of CD40L and OX40; in the absence of signficant induction of apoptosis. This inhibition affected both CD4 and CD8 T cells and was only partially reversed by costimulation with interleukin 2 or CD28. gp105 strongly inducted TNF-alpha production by monocytes. CONCLUSION: The immunosuppressive properties of the HIV envelope proteins could be beneficial rather than detrimental to the host by interfering with the heightened state of immunocellular activation that characterizes HIV infection and by limiting the bursts of viral replication. This hypothesis could in part explain the slower decline of CD4 cell numbers in HIV-2 infection and deserves further exploration.
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Productos del Gen env/inmunología , Antígenos VIH/inmunología , VIH-2/inmunología , Terapia de Inmunosupresión , Receptores del Factor de Necrosis Tumoral , Linfocitos T/inmunología , Apoptosis , Antígenos CD28/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Ligando de CD40/biosíntesis , Ligando de CD40/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , División Celular , Células Cultivadas , ADN/biosíntesis , Citometría de Flujo , Proteína gp120 de Envoltorio del VIH/inmunología , VIH-1/inmunología , VIH-2/patogenicidad , Humanos , Interleucina-2/inmunología , Activación de Linfocitos/inmunología , Monocitos/metabolismo , Receptores OX40 , Virus de la Inmunodeficiencia de los Simios/inmunología , Linfocitos T/citología , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/biosíntesis , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/biosíntesis , Productos del Gen env del Virus de la Inmunodeficiencia HumanaRESUMEN
INTRODUCTION: Decrease in incidence of neurosyphilis over the last few decades implies that clinicians consider less frequently this diagnosis. On the other hand, some reports suggest an increase in atypical forms of this disease that represent an additional reason for missing this diagnosis. CLINICAL CASE: We report on a 16 year-old immunocompetent black female from Guinea-Bissau presented with headaches, ear pain, hearing loss and peripheral facial paralysis. A cranial CT scan showed a hypodense area in the left cortico-subcortical zone and a contrast enhancement on the left pontocerebellar angle and internal auditory meatus. On the third day of admission a diagnosis of meningitis was made, with high titles of VDRL and TPHA in CSF and serum, leading to a diagnosis of neurosyphilis. The epidemiological aspects of this case suggest either a late congenital syphilis or an infection as a result of a blood transfusion administered seven years earlier in Guinea-Bissau. CONCLUSION: This rare form of presentation of neurosyphilis emphasizes the importance of considering systematically this diagnosis, even in the context of atypical presentations.
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Dolor de Oído/diagnóstico , Dolor de Oído/etiología , Parálisis Facial/diagnóstico , Parálisis Facial/etiología , Cefalea/diagnóstico , Cefalea/etiología , Neurosífilis/complicaciones , Neurosífilis/diagnóstico , Adolescente , Nervio Coclear/fisiopatología , Diagnóstico Diferencial , Nervio Facial/fisiopatología , Parálisis Facial/fisiopatología , Femenino , Lateralidad Funcional/fisiología , Humanos , Neurosífilis/microbiología , Treponema pallidum/aislamiento & purificaciónRESUMEN
Cytokine imbalances play a major role in HIV immunopathogenesis. This study analyzes simultaneously the frequency of cytokine-producing cells at the single cell level by flow cytometry and the disturbances in cytokine secretion assessed by ELISA in a cohort of asymptomatic HIV1 patients in different stages of CD4 depletion and during antiretroviral therapy (HAART). Early in the disease, there is an increased frequency of IFN-gamma(+) lymphocytes and bulk IFN-gamma production, in parallel with a reduced proportion of IL4(+) cells and IL4 secreted. The two IL4 measurements are significantly correlated. No such correlation was found for IFN-gamma, which is consistent with a large variation in the amount of IFN-gamma released per individual cell. Moreover, HAART was associated with a reduction to normal levels in the bulk IFN-gamma secretion concomitant with a persistency of the overexpanded IFN-gamma(+) cell subset in the peripheral blood. This study emphasizes the importance of using a conjoint approach to assess the cytokine network in trials of antiretroviral and/or immune-based therapies to avoid missing significant effects which are possibly relevant in the clinical setting.
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Fármacos Anti-VIH/uso terapéutico , Citocinas/biosíntesis , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , VIH-1 , Adulto , Femenino , Humanos , Interleucina-10/biosíntesis , Interleucina-6/biosíntesis , Leucocitos Mononucleares/metabolismo , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Factores de TiempoAsunto(s)
Antiulcerosos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Ranitidina/efectos adversos , Anciano , Progresión de la Enfermedad , Hipersensibilidad a las Drogas/etiología , Resultado Fatal , Femenino , Hemorragia Gastrointestinal/inducido químicamente , Encefalopatía Hepática/inducido químicamente , Humanos , Ictericia/inducido químicamente , Choque/inducido químicamenteRESUMEN
Fas, CD40L and OX40 are members of the tumour necrosis factor (TNF) receptor superfamily with critical roles in T cell activation and death, B cell function, dendritic cell maturation and leucocyte traffic regulation. The aim of this study was to evaluate the effects of anti-retroviral therapy (HAART) on CD40L, OX40 and Fas expression on freshly isolated peripheral blood T cells by three-colour flow cytometry and compare them with lymphoproliferative responses, peripheral blood cell counts and viral load. Fourteen asymptomatic HIV-1+ patients treated with Lamivudine, Stavudine and Nelfinavir were prospectively investigated sequentially for 48 weeks. At baseline, patients exhibited significantly enhanced proportions and counts of CD40L+ and OX40+ cells within the CD4 subset which were corrected by weeks 8-16 of HAART. Interestingly, in the five patients showing viral load rebound during therapy in spite of increasing CD4 counts, the reduction of the levels of these costimulatory molecules was similarly maintained. Therapy induced a decrease in the over-expression of Fas, particularly in the CD4 subset where normal levels were reached at week 8. This reduction occurred in parallel with the major recovery of lymphoproliferative responses. Higher basal levels and lower reduction of Fas were associated with suboptimal suppression of viraemia. In conclusion, this previously undescribed increased expression of CD40L and OX40 may play a role in the HIV-associated pan-immune activation and represent a possible target for immunointervention, as suggested for several immunologically mediated diseases. Moreover, HAART induced an early correction of the over-expression of Fas, CD40L and OX40 in CD4 T cells which could be involved in the recovery of the cell traffic disturbances and in the T cell renewal capacity.
Asunto(s)
Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Fármacos Anti-VIH/uso terapéutico , VIH-1 , Glicoproteínas de Membrana/análisis , Receptores del Factor de Necrosis Tumoral , Linfocitos T/química , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/análisis , Receptor fas/análisis , Síndrome de Inmunodeficiencia Adquirida/inmunología , Síndrome de Inmunodeficiencia Adquirida/virología , Adulto , Recuento de Linfocito CD4 , Ligando de CD40 , Movimiento Celular , Quimioterapia Combinada , Femenino , Humanos , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Receptores OX40 , Linfocitos T/fisiologíaRESUMEN
The effects of highly active antiretroviral therapy on cytokine imbalances associated with HIV-1 infection have not been characterized. Using single cell analysis by flow cytometry, we show that a significant recovery in the frequency of IL-2-producing cells was only observed in patients with a sustained control of viral replication and that the overexpanded CD8 T cell population of CD28- IFN-gamma + cells was not significantly reduced after 1 yr of effective therapy. Moreover, a detrimental role of IL-4 is suggested by the association between an enhanced proportion of IL-4-producing cells within the CD4 and particularly the CD8 subset and viral load rebound. Finally, the kinetics of changes of cell subsets assessed for simultaneous production of different cytokines supports the view that cell reconstitution during highly active antiretroviral therapy is initially due to redistribution of terminally differentiated cells, followed by peripheral expansion of less differentiated ones and a late progressive increase of the proportion of functionally defined naive/memory precursor lymphocytes. These data bring new support for the role of cytokine imbalances in AIDS pathogenesis and may be relevant for the definition of immunointervention targets.
Asunto(s)
Fármacos Anti-VIH/farmacología , Citocinas/biosíntesis , Infecciones por VIH/inmunología , VIH-1/inmunología , Subgrupos Linfocitarios/metabolismo , Adulto , Femenino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Humanos , Inmunofenotipificación , Interferón gamma/análisis , Interferón gamma/biosíntesis , Interleucina-2/biosíntesis , Interleucina-4/análisis , Interleucina-4/biosíntesis , Cinética , Antígenos Comunes de Leucocito/análisis , Recuento de Linfocitos/efectos de los fármacos , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/virología , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
In this study we investigated at single-cell level by flow cytometry the potential of T cell cytokine production in asymptomatic HIV-1-infected subjects with > 200 CD4 counts and possible correlation with T helper cell depletion and viral load. Mitogen-stimulated peripheral blood mononuclear cells from 32 HIV-1+ patients and 16 healthy subjects were intracytoplasmically stained for IL-2, interferon-gamma (IFN-gamma), IL-4 or IL-10, and the frequency of cytokine-producing cells was assessed in total T cells, CD4, CD8 and CD45RO subsets as well as in CD69+CD3+ gated lymphocytes. HIV-1+ patients, irrespective of their degree of CD4 depletion, exhibited a major increase in IFN-gamma+ CD8 T cells, largely due to CD28- cells, as well as a decrease in the capacity of CD8 T cells to produce IL-2. Patients with > 500 CD4 counts showed a diminished frequency of IL-4 expression in CD4 T cells and a negative correlation was found between this parameter and the ex vivo CD4 counts in the 32 patients. Analysis of patients stratified according to viral load revealed a significantly higher proportion of IL-2-producing CD4 cells in the group with < 5000 RNA copies/ml. In short, using single-cell analysis and an antigen-presenting cell-independent stimulus, we have not been able to find any significant cytokine imbalances in the CD4 subset, suggesting that the well described T helper defects are not due to intrinsic alterations in the potential of CD4 T cells to produce cytokines. On the other hand, the major disturbances in the CD8 T lymphocytes agree with the marked activation and possible replicative senescence of CD8 T cells and emphasize the role of this subset in HIV immunopathogenesis.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , VIH-1 , Linfocinas/biosíntesis , Subgrupos de Linfocitos T/inmunología , Adulto , Recuento de Linfocito CD4 , Linfocitos T CD8-positivos/metabolismo , Femenino , Citometría de Flujo/métodos , Humanos , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Interleucina-2/biosíntesis , Interleucina-4/biosíntesis , Antígenos Comunes de Leucocito/análisis , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/metabolismo , Carga ViralRESUMEN
BACKGROUND: Diagnosis of drug induced liver injury is usually based on a temporal relation between drug intake and clinical picture as well as on the exclusion of alternative causes. More precise diagnosis has been attempted by using in vitro specific T cell reactivity to drugs but the test has never reached general acceptability because of frequent negative results which could be explained, in part, by prostaglandin producing suppressor cells (PPSC). AIM: To analyse the diagnostic value of a modified test where lymphocyte responses to drugs are detected in the presence of a prostaglandin inhibitor. PATIENTS: Ninety five patients with a clinical diagnosis of drug induced liver injury, 106 healthy controls, 35 individuals with recent exposure to the same drugs without adverse effects, and 15 patients with liver disease unrelated to drugs. METHODS: Peripheral blood mononuclear cells (PBMC) were cultured in the presence of drugs alone and in the presence of drugs and a prostaglandin inhibitor. Responses were assessed by 3H-thymidine incorporation in lymphocytes. Results were expressed as counts per minute and as stimulation indexes (SI). RESULTS: When PBMC were stimulated with drugs alone, lymphocyte sensitisation to drugs (SI > 2) was detected in 26% of the cases. This was noticeably increased (56%) when a prostaglandin inhibitor was added to the cultures. No reactivity was found in controls. In patients with possible sensitivity to several drugs, lymphocyte reactivity was detected to only one drug. The severity of the lesions, as assessed by aminotransferase concentrations and disease duration, was lower in patients with evidence of PPSC. CONCLUSIONS: This new approach is useful for the diagnosis of drug induced liver injury, particularly in patients exposed to more than one drug; furthermore, the presence of putative PPSC is associated with less severe forms of drug induced hepatitis.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/diagnóstico , Hipersensibilidad a las Drogas/diagnóstico , Linfocitos T/efectos de los fármacos , Adulto , División Celular/efectos de los fármacos , Células Cultivadas , Medios de Cultivo , Estudios de Evaluación como Asunto , Femenino , Humanos , Indometacina , Masculino , Persona de Mediana Edad , Antagonistas de Prostaglandina , Estadística como Asunto , Estadísticas no ParamétricasRESUMEN
The objective of this study is to present and validate a clinical scale for the diagnosis of drug-induced liver injury (DILI). Five components were selected to be included in the scale: temporal relationship between drug intake and the onset of clinical picture, exclusion of alternative causes, extrahepatic manifestations, rechallenge or accidental re-exposure, and previous report in medical literature. The relative importance of each component was weighed, and arbitrary scores were attributed. The probability of the diagnosis of DILI was expressed as a final score, which could vary from -6 to 20. Content validity, criterion validity, construct validity, and inter-rater reliability were studied. To analyze validity and reliability, a random sample of 50 cases of suspected DILI was drawn from a series of 120 cases reported to our unit. The classification of the 50 cases by three experts in DILI was used as the external standard in the study of criterion validity. Agreement between the scale and the standard, and agreement between two independent raters (inter-rater reliability) was analyzed by weighted kappa coefficient. There was agreement between the scale and the standard in 42 cases (84%) with a weighted kappa coefficient of 0.90. A good discriminatory capacity of the scale was found when construct validity was studied. Agreement between raters was observed in 86% of the cases, corresponding to the weighted kappa of 0.93. In conclusion, the clinical scale was shown to have a high-level of validity and inter-rater reliability as well as a good discriminatory capacity between different levels of probability. These data suggest that the scale is suitable for use in clinical practice and may contribute to overcome the difficulties in the process of causality assessment in DILI.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Sesgo , Diagnóstico Diferencial , Humanos , Probabilidad , Distribución Aleatoria , Reproducibilidad de los ResultadosRESUMEN
Non Hodgkin's lymphoma revealed by hepatic manifestations is extremely rare. We describe here a 82-year old male patient who presented with a right subphrenic abscess and a solitary liver tumour that was shown to be a centrocytic lymphoma. Furthermore, asymptomatic cryptogenic liver cirrhosis was diagnosed. This previously unreported form of clinical presentation of a non Hodgkin's lymphoma as well as the association with liver cirrhosis are discussed in the context of the recent literature.