RESUMO
INTRODUCTION AND OBJECTIVES: Primary immunodeficiency diseases (PIDs) are disorders associated mainly with recurrent and severe infection and an increase in susceptibility to autoimmune conditions and cancer. In Venezuela, PIDs are underdiagnosed and there is usually a delay in their diagnosis. Hence there are no data concerning the frequency and type of PIDs that occur. The aim of this study was to identify and quantify the types of PIDs that occur in Merida, a population within Venezuela. PATIENTS OR MATERIALS AND METHODS: Following an informative program designed to alert local health professionals to the warning signs for PIDs, patients with a history of recurrent infections were referred to the Instituto de Inmunologia Clinica, Universidad de Los Andes. RESULTS AND CONCLUSIONS: During the three-year period January 2014 to January 2017, thirty-two cases of PIDs were identified in pediatric patients, and 17 different types of PIDs, were identified. Predominantly antibody deficiencies were most frequent (40.6%), followed by immunodeficiencies affecting cellular and humoral immunity (21.8%), congenital defects of phagocyte (18.7%), CID with associated or syndromic features (9.3%), defects in intrinsic and innate immunity (6.4%) and diseases of immune dysregulation (3.2%). These results have important implications not only to the future approach for management of patients in our regions, but add important knowledge concerning PIDs in Latin America and worldwide.
Assuntos
Infecções/imunologia , Doenças da Imunodeficiência Primária/imunologia , Adolescente , Criança , Pré-Escolar , Controle de Doenças Transmissíveis , Progressão da Doença , Feminino , Humanos , Lactente , Recém-Nascido , Infecções/epidemiologia , Masculino , Doenças da Imunodeficiência Primária/epidemiologia , Recidiva , Venezuela/epidemiologiaRESUMO
Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite that can infect almost all warm-blooded species and induce a chronic infection in human hosts. The aim of this work was to investigate Th1, Th2, Th17 and Treg polarization, induced by four important T. gondii antigens (SAG1, ROP1, GRA8 and MAG1) in acutely and chronically infected patients. For this purpose, SAG1, ROP1, GRA8 and MAG1 were expressed as recombinant proteins, purified, and used to evaluate the proinflammatory and regulatory immune response profiles in seropositive and seronegative individuals. Our results show that SAG1 and ROP1 elicited a proinflammatory profile (INF-γ, IL-12 and IL-17) in individuals in the acute phase, whereas MAG1 and GRA8 induced a regulatory pattern (Treg and TGF-ß) in chronically infected patients. These results reveal fundamental differences in T-cell polarization induced by T. gondii antigens, which could have important implications in the immunopathogenesis of the disease and in future proposals of therapeutic strategies.
Assuntos
Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Adulto , Animais , Feminino , Humanos , Interferon gama/biossíntese , Subunidade p35 da Interleucina-12/biossíntese , Interleucina-17/biossíntese , Masculino , Proteínas de Membrana/imunologia , Camundongos , Proteínas de Protozoários/imunologia , Toxoplasmose/parasitologia , Fator de Crescimento Transformador beta1/biossínteseRESUMO
BACKGROUND: Mitoxantrone is highly efficacious in the treatment of severe multiple sclerosis (MS). Mitoxantrone therapy-related acute leukemia (TRAL) has recently become the focus of interest. METHODS: A case report of fatal TRAL following mitoxantrone therapy is presented with a discussion on the differential diagnosis and risk factors. The interdisciplinary development of diagnostic and therapeutic algorithms is presented from a haematological and neurological point of view. RESULTS: We describe the case of a 34-year-old MS patient who developed TRAL following mitoxantrone therapy (cumulative dose 45 mg/m(2) body surface). The patient died from endocarditis. TRAL is a rare but potentially fatal complication of mitoxantrone therapy with a wide variation of reported incidence. Thus far, no specific risk factors relating for example to preceding therapy and treatment regimens have been identified. Frequent laboratory controls and early bone marrow aspiration are mandatory for suspected TRAL as the condition is potentially curable. CONCLUSIONS: TRAL needs to be considered in the risk-benefit assessment of mitoxantrone therapy, however, the exact incidence and risk factors (e.g. dosage, treatment regimen) are still unclear. The risks are controllable under close surveillance and early diagnosis is important for prognosis. Future investigations need to concentrate on identification of potential risk factors.
Assuntos
Leucemia/induzido quimicamente , Mitoxantrona/efeitos adversos , Mitoxantrona/uso terapêutico , Esclerose Múltipla/complicações , Esclerose Múltipla/tratamento farmacológico , Trombocitopenia/induzido quimicamente , Adulto , Analgésicos/administração & dosagem , Analgésicos/efeitos adversos , Humanos , Leucemia/prevenção & controle , Masculino , Trombocitopenia/prevenção & controleRESUMO
Neutrophils from human immunodeficiency virus-positive (HIV+) patients have an increased susceptibility to undergo programmed cell death (PCD), which could explain neutropenia during advanced disease. In this work, key steps of PCD have been evaluated in neutrophils from HIV+ patients. The role of caspase-3, caspase-8, mitogen activated protein kinase (MAPK) and reactive oxygen species (ROS) was analysed. Spontaneous neutrophil death is dependent upon caspase-3 but independent of caspase-8, suggesting that the intrinsic pathway is involved as a pathogenic mechanism of PCD. Inhibition of ROS decreased spontaneous PCD and caspase-3 hydrolysis, connecting oxidative stress and caspase-3 activation with neutrophil PCD in HIV-infected patients. Additionally, an increased neutrophil death was observed in HIV+ patients, following inhibition of p38 MAPK, suggesting a role for p38 MAPK in cell survival during the disease. We conclude that oxidative stress secondary to HIV infection can accelerate neutrophil death.
Assuntos
Apoptose , Caspases/fisiologia , Infecções por HIV/imunologia , Neutrófilos/patologia , Espécies Reativas de Oxigênio/metabolismo , Adolescente , Adulto , Caspase 3/fisiologia , Sobrevivência Celular , Células Cultivadas , Feminino , Infecções por HIV/enzimologia , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Transdução de Sinais , Superóxidos/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologiaRESUMO
Human natural killer (NK) cells (CD56+ CD3-) represent crucial components of the innate immune system especially against viral infections and because their activation can modulate the outcome of the adaptive immune response. NKT cells (CD56+CD3+), a lymphocyte T population characterized by expression of surface markers of NK cells, are known to be abundant in the liver and their activation could be associated with hepatic injury. Using three-color flow cytometry to measure surface receptors and intracellular cytokines, we have explored early activation signals and cytokine production in NK and NKT cells within a group of hepatitis B vaccinated and non-vaccinated individuals. A specific increase of the CD56bright cell population, the activation receptor CD69 and IFN-gamma, was observed in NK cells following incubation with recombinant HBsAg in responders to vaccination. Comparable results were observed in NKT cells showing an increment of CD69, CD25, IL-2 and IFN-gamma expression in responder subjects. These parameters were statistically diminished in non-responder individuals (p<0.05) in both groups of cells. These results demonstrate a diminished activation of these cells in non-responders to the vaccine, suggesting that NK and NKT cells play an important role in the immune response following hepatitis B vaccination.
Assuntos
Citocinas/biossíntese , Vacinas contra Hepatite B/administração & dosagem , Células Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Vacinas Sintéticas/administração & dosagem , Adulto , Antígeno CD56/metabolismo , Hepatite B/imunologia , Hepatite B/prevenção & controle , Antígenos de Superfície da Hepatite B/administração & dosagem , Humanos , Imunidade Inata , Interferon gama/biossíntese , Interleucina-2/biossíntese , Ativação Linfocitária , Pessoa de Meia-IdadeRESUMO
Neutrophils represent an important line of innate host defence against invading microorganisms and their functional detriment during HIV infection, including accelerated spontaneous cell death, has been shown to contribute to AIDS development. Neutrophils are susceptible to apoptosis via Fas and an interaction between Fas and FasL was suggested originally as a mechanism to explain constitutive neutrophil apoptosis. We have explored some intracellular pathways leading to PMN apoptosis from 28 HIV-infected patients and 24 healthy volunteers. As previously reported, accelerated spontaneous apoptosis was observed in HIV+ patients, but this did not correlate with viral load. Furthermore, an increase in the level of spontaneous apoptosis was detected in neutrophils from HIV-infected patients following inhibition of ERK, suggesting an impairment of this kinase pathway during the early stages of infection which may contribute to PMN dysfunction. An elevated susceptibility to undergo apoptosis was observed following cross-linking of Fas, which correlated both with viral load and co-expression of Fas/FasL surface molecules. Different mechanisms for spontaneous and Fas-induced apoptosis are proposed which together contribute to the neutropenia and secondary infections observed during the progression to AIDS.
Assuntos
Apoptose/imunologia , Infecções por HIV/imunologia , Neutrófilos/imunologia , Receptor fas/imunologia , Adulto , Células Cultivadas , Humanos , Ligantes , Proteínas Quinases Ativadas por Mitógeno/imunologia , Carga Viral , Proteínas Quinases p38 Ativadas por MitógenoRESUMO
UNLABELLED: The aim of our study was to develop a rapid diagnostic urease test to demonstrate the presence of Helicobacter pylori in the Endoscopy room. MATERIALS AND METHODS: 200 consecutive patients referred to gastroscopy for different indications, were included in this study. One antral biopsy sample was obtained to be immersed in our test. The same sample was used for histological evaluation, considered to be the gold standard method for diagnose of Helicobacter pylori infection. RESULTS: 135 patients (67.5%) were found positives and 65 patients (32.5%) were negatives in our test. 128 patients (64%) showed Helicobacter pylori on histological examination. Our test showed a sensitivity of 91%, specificity of 88.1%, and positive and negative predictive values of 95% and 80% respectively. A remarkable correlation between density of Helicobacter pylori and reading time was also observed, where a high density of the bacteria reduced the reaction time in this liquid test. Furthermore, an overall accuracy of 90% was shown, which is comparable with other available commercial tests. CONCLUSION: LUT is easy to handle, cost effective and fast, with a high positive predictive value.
Assuntos
Ensaios Enzimáticos Clínicos , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/isolamento & purificação , Urease/análise , Ensaios Enzimáticos Clínicos/economia , Endoscopia Gastrointestinal , Feminino , Mucosa Gástrica/patologia , Helicobacter pylori/enzimologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Antro Pilórico/microbiologia , Antro Pilórico/patologia , Sensibilidade e Especificidade , Urease/metabolismoRESUMO
The aim of our study was to develop a rapid diagnostic urease test to demonstrate the presence of Helicobacter pylori in the Endoscopy room. MATERIALS AND METHODS: 200 consecutive patients referred to gastroscopy for different indications, were included in this study. One antral biopsy sample was obtained to be immersed in our test. The same sample was used for histological evaluation, considered to be the gold standard method for diagnose of Helicobacter pylori infection. RESULTS: 135 patients (67.5%) were found positives and 65 patients (32.5%) were negatives in our test. 128 patients (64%) showed Helicobacter pylori on histological examination. Our test showed a sensitivity of 91%, specificity of 88.1%, and positive and negative predictive values of 95% and 80% respectively. A remarkable correlation between density of Helicobacter pylori and reading time was also observed, where a high density of the bacteria reduced the reaction time in this liquid test. Furthermore, an overall accuracy of 90% was shown, which is comparable with other available commercial tests. CONCLUSION: LUT is easy to handle, cost effective and fast, with a high positive predictive value.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Ensaios Enzimáticos Clínicos , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/isolamento & purificação , Urease/análise , Ensaios Enzimáticos Clínicos , Endoscopia Gastrointestinal , Mucosa Gástrica/patologia , Helicobacter pylori/enzimologia , Estudos Prospectivos , Antro Pilórico/microbiologia , Antro Pilórico/patologia , Sensibilidade e Especificidade , Urease/metabolismoRESUMO
The past decade of research has led to a greater understanding of the pathogenesis of asthma and, in particular, the pivotal role of the underlying inflammatory process. Along with inheritance in atopic patients, the presence of inhaled triggering allergens are considered the predominant predisposing factors in the development of the disease. We have conducted a longitudinal clinical therapeutic study, which included 45 pediatrics patients with asthma, in order to evaluate whether the removal of any potential inhaled triggering factor, could decrease the requirement of drug based anti-inflammatory therapy. Patients admitted in this study presented at least, two monthly asthma attacks during the last four months. A single treatment with theophylline (group A), beclomethasone (group B) or salbutamol (group C), was prescribed during the first 2 weeks, along with specific instructions to avoid inhaled allergens. Regardless of the drug used, patients showed impressive and prolonged clinical improvement during 6 months, reduction of total IgE serum levels in the three groups (p < 0.02; 0.005 and 0.02 respectively) and favorable modification of force expiratory volume at the first second, forced vital capacity and flow expiratory peak. During the observation period a constant monitoring of mites allergens concentrations was performed, showing a decrease of these antigens, associated with clinical improvement, and only in those patients who remained symptomatic (group A 31%, group B 29% and group C 9%), failures performing the measures designed to reduce their exposure to environmental allergens, was demonstrated. These results suggest that reduction of inhaled triggering factors may decrease the requirement of anti-inflammatory drug therapy to control the symptoms in patients with asthma.
Assuntos
Alérgenos , Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Exposição por Inalação , Adolescente , Albuterol/administração & dosagem , Alérgenos/imunologia , Anti-Inflamatórios/administração & dosagem , Asma/fisiopatologia , Asma/prevenção & controle , Beclometasona/administração & dosagem , Broncodilatadores/administração & dosagem , Criança , Pré-Escolar , Interpretação Estatística de Dados , Poeira , Feminino , Humanos , Imunoglobulina E/sangue , Estudos Longitudinais , Masculino , Testes de Função Respiratória , Teofilina/administração & dosagem , Fatores de TempoRESUMO
Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency disease that leads to severe recurrent infections. CGD is caused by defects in the phagocyte NADPH oxidase, a multiprotein enzyme that reduces oxygen to superoxide, a precursor of microbicidal oxidants. Less than 6% of CGD patients have an autosomal recessive form of the disease caused by mutations in NCF-2. This gene encodes p67-phox, a cytosolic oxidase subunit that associates with membrane-bound flavocytochrome b558 and regulates electron transfer. We studied six patients from five families with p67-phox deficiency and identified seven different mutant alleles. Patients from three of the kindreds were homozygous for their respective mutation, although the parents of only one family were known to be related. Five of the mutations have not previously been identified: (1) a missense mutation (383C-->T) in exon 5, (2) a nonsense mutation (196C-->T) in exon 3, (3) a missense mutation (230G-->A) in exon 3, (4) a nonsense mutation (298C-->T) in exon 4, and (5) a dinucleotide deletion (835-836 AC) from exon 9. Phagocytes from each of the patients analyzed failed to generate a measurable respiratory burst and had no detectable p67-phox protein. Our results further demonstrate that there is great heterogeneity among the mutations in p67-phox-deficient CGD patients, with no evidence for mutational hot-spots or a founder effect. Our data also support the hypothesis that the stability of p67-phox is particularly sensitive to missense mutations that cause amino acid substitutions within its N-terminal domain. In contrast, mutations predicting single amino acid changes elsewhere in the protein generally represent benign polymorphisms.
Assuntos
Doença Granulomatosa Crônica/enzimologia , Doença Granulomatosa Crônica/genética , Mutação , NADPH Oxidases/genética , Fosfoproteínas/genética , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Criança , Pré-Escolar , Códon sem Sentido , DNA/genética , Estabilidade Enzimática/genética , Feminino , Genes Recessivos , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Mutação de Sentido Incorreto , NADPH Oxidases/deficiência , Fagócitos/enzimologia , Fosfoproteínas/deficiência , Deleção de SequênciaRESUMO
The immunopathogenesis of AIDS is associated with the development of opportunistic infections by intracellular pathogens that can invade and reproduce freely because of impaired cellular functions. Neutrophils from asymptomatic human immunodeficiency virus (HIV) type 1-infected persons and from symptomatic patients with AIDS were found to retain normal phagocytosis activity while producing significantly less superoxide than neutrophils from HIV-1-negative subjects, when stimulated through Fc receptors or protein kinase C. After priming with a synthetic HIV-1 envelope peptide and stimulation via the Fc receptor, the neutrophils from HIV-1-negative controls had suppressed superoxide production, reduced phosphorylation of two unidentified cellular proteins, and increased expression of a third phosphoprotein. These results suggest that HIV-1 can produce direct functional damage of neutrophils through binding of envelope components to the cell membrane.
Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Ativação de Neutrófilo , Superóxidos/metabolismo , Adolescente , Adulto , Feminino , Produtos do Gene env/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/imunologia , Fagocitose , Fosfoproteínas/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Receptores Fc/metabolismoRESUMO
Chronic Granulomatous Disease (CGD) is a primary immunodeficiency characterized by an unusual predisposition to develop bacterial and fungal infections due to a failure of phagocytic leukocytes to generate superoxide, required for the intracellular killing of microorganisms. The lack of superoxide production is secondary to a defect in the NADPH-oxidase enzymatic complex activation, as a result of mutations of any of the components. Both, X-linked and autosomal recessive patterns of inheritance have been demonstrated in this disease, being the X-linked the most frequent and characterized by mutations in gp91phox. Mutations in p47phox, p67phox and p22phox have been shown in the autosomal recessive pattern. The molecular and genetic characteristic of NADPH-oxidase complex and its pathology in CGD are reviewed along with a brief description of the preliminary findings in two families from Mérida, Venezuela.
Assuntos
Doença Granulomatosa Crônica/genética , NADPH Oxidases/metabolismo , Adolescente , Algoritmos , Criança , Pré-Escolar , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/enzimologia , Humanos , Masculino , Mutação , NADPH Oxidases/genética , Linhagem , VenezuelaRESUMO
En la evolución natural del cáncer colorrectal participan numerosos elementos entre los cuales, la acumulación progresiva de cambios genéticos representa la base patogénica fundamental. Pocos genes que afecten los fenómenos de muerte celular han sido identificados y el que ha sido mejor estudiado de ellos, p53, participa en las fases tardías del proceso tumoral. Las mutaciones en el gen de la Adenomatosis Poliposa Colónica (APC) están asociadas con los estadios más tempranos del carcinoma colorrectal. Los individuos quienes heredan mutaciones en la línea germinal de APC desarrollan cientos de tumores benignos, algunos de los cuales progresan hacia cáncer. Las mutaciones somáticas de APC están además asociadas con la incidencia de cáncer colorrectal en la población general por cuanto han sido demostradas en adenomas pequeños y en lesiones displásicas microscópicas. Elementos importantes en la historia natural de las neoplasias de colon y recto y sus repercusiones en el área clínica, son discutidos en esta revisión a la luz de los conocimientos más recientes derivados del estudio genético y molecular de la enfermedad
Assuntos
Humanos , Masculino , Feminino , Polipose Adenomatosa do Colo , Carcinoma , Colo , Neoplasias Colorretais , Reto , Gastroenterologia , VenezuelaRESUMO
BACKGROUND: It has been reported that the concentration of Dermatophagoides sp. population, the main trigger of asthma in sensitized atopic subjects, is inversely related with altitude and probably directly with humidity and that this population are scarcely found over 1750 m above sea level. OBJECTIVE: We studied the presence of Dermatophagoides sp. in a Venezuelan community between 2040 and 2600 m above sea level, and also the IgE response to D. pteronnyssinus and D. farinae in atopic subjects living on that region. METHODS: The presence of Dermatophagoides sp. was determined by microscopic identification of mites in dust, obtained by brushing the mattresses surface in 93 randomly selected houses between 2040 and 2600 m above sea level. The indoor relative humidity was also measured. The specific IgE serum levels were studied in 65 subjects classified as asthmatics, allergic non-asthmatics and non-allergic. RESULTS: A mean concentration of 188 mites/g of room dust was determined in 82.4% of houses with an indoor relative humidity ranging from 89% and 92% independently of altitude. The density of Dermatophagoides sp. was sufficiently high to sensitize the atopic subjects, IgE levels were 6.8 PRU mean value for asthmatic, against 0.38 PRU in non-atopic. CONCLUSIONS: We conclude that: (a) Dermatophagoides sp. can be found up to 2600 m above sea level in a Venezuelan neotropical region where a high indoor relative humidity is characteristic of most dwellings; (b) sensitization by D. pteronyssinus and D. farinae were demonstrated in atopic subjects resident at that region.
Assuntos
Alérgenos/imunologia , Altitude , Asma/imunologia , Glicoproteínas/imunologia , Imunoglobulina E/análise , Ácaros/imunologia , Animais , Antígenos de Dermatophagoides , Asma/epidemiologia , Humanos , Prevalência , Teste de Radioalergoadsorção , Distribuição Aleatória , Venezuela/epidemiologiaRESUMO
Se realizó un estudio transversal para conocer la prevalencia de anticuerpos contra el virus de la Hepatitis C en pacientes politransfundidos por: hemofilia, leucemia y anemia hemolítica, procedentes de la región andina. Se analizaron 39 muestras, 10 procedentes de pacientes hemofílicos, 12 de pacientes con leucemia, linfoma y anemia hemolítica, transfundidos por lo menos 6 meses antes del estudio. El resto de las muestras, 17, fueron controles sanos sin antecedentes de transfusion previa. Utilizando un ELISA de segunda generación, se detectaron 4 muestras positivas (10,26 por ciento), 3 de hemofílicos y la restante de un paciente con linfoma. Esto correponde a una positividad de 30 por ciento para el grupo de hemofilicos, lo cual contrasta con lo reportado en otros países. Se demostró una asociación estadísticamente significativa entre la positividad del ELISA y la cantidad de material transfundido (p< 0.0004), asi mismo con el tipo de material suministrado: Crioprecipitado (p= 0.000) y plasma (p= 0.000)
Assuntos
Humanos , Masculino , Ensaio de Imunoadsorção Enzimática/estatística & dados numéricos , Hemofilia A/diagnóstico , Hepatite C , Transfusão de Sangue/efeitos adversosRESUMO
We have done a study in order two know the prevalence of anti-hepatitis C virus antibodies in polytransfused patients with hemophilia, leukemia and hemolytic anemia, along with 17 healthy donors, without previous history of transfusions. We analyzed samples from 10 hemophilic patients and 12 from leukemia, lymphoma and hemolytic anemia, all of them had received blood or blood products, at least six months before the study. Using a second generation ELISA, 4 positive sample (3 hemophilic and 1 lymphoma) were detected (10.26%), which represent a prevalence of 30% in the hemophilic group, in contrast with the prevalence detected in other countries. A very significant statistic association was demonstrated, between the positive ELISA, the amount of the transfused product (P < 0.0004) and the type of blood product used for transfusion (crioprecipited, P = 0.000, plasma P = 0.000).
Assuntos
Transfusão de Sangue , Anticorpos Anti-Hepatite/sangue , Hepatite C/epidemiologia , Adolescente , Adulto , Anemia Hemolítica/terapia , Estudos Transversais , Hemofilia A/terapia , Hepatite C/sangue , Humanos , Leucemia/terapia , Masculino , Prevalência , Estudos SoroepidemiológicosRESUMO
How the T cell receptor (TcR)/CD3 complex mediates not only the induction of T cell activation but also suppressive effects like T cell anergy or apoptosis is not well understood. Here we describe a series of preincubation and restimulation experiments which demonstrate that primary stimulation of resting, unseparated human T cells with mitogenic doses of immobilized anti-CD3 antibodies induces hyporesponsiveness upon restimulation of the cells. Various costimuli can prevent this type of anergy to a variable degree if present during the preincubation period, phorbol 12-myristate 13-acetate (PMA) being the most and anti-CD4 antibody the least effective. If employed together with anti-CD3 antibody during the restimulation phase of the assay, interleukin (IL)-2, IL-4 and anti-CD28 antibody break anergy almost completely. Proliferation induced by a submitogenic dose of anti-CD3 antibody supplemented by costimulatory signals (anti-CD2, anti-CD4, anti-CD28, IL-2, IL-4 or PMA) does not result in hyporesponsiveness. Taken together, these results support a modified view of the two-signal model for T cell activation according to which anergy induction in resting T cells occurs if primary proliferation is induced by high density triggering of the TcR/CD3 complex in the absence of accessory signals. We discuss possible implications of these findings for the induction of peripheral tolerance.