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1.
J Thromb Thrombolysis ; 51(1): 17-24, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32592081

RESUMO

After an initial treatment period for venous thromboembolism (VTE), indefinite anticoagulation may be considered, depending upon individual risks. The aim of the study was to determine if there is consensus amongst clinicians that manage VTE regarding which patients require 3-6 months versus indefinite anticoagulation. The importance of VTE site and severity in decision making was also evaluated. An international survey of clinicians involved in VTE management was undertaken. Respondents were asked about long-term treatment of six patients that had completed 3-6 months initial anticoagulation. These included four cases of VTE not associated with a major reversible risk factor and two control cases; one unprovoked VTE and one VTE associated with a major reversible risk factor. For consensus, there was a pre-defined equivalence boundary whereby at least 70% of clinicians had to decide either to stop or consider indefinite anticoagulation for each case. 351 responses were collected. In the control cases, there was a ≥ 95% consensus on long-term management (stop versus indefinite anticoagulation). In three of the four test cases, there was no consensus about duration of anticoagulation. In case 3, 78% (99% confidence interval 73-84%) would stop anticoagulation after 3-6 months. When analysed by grade or specialty of doctor, a lack of consensus remained. Opinion on whether site or severity of VTE influenced decision making was variable. For patients with unprovoked VTE or VTE associated with a major transient risk factor there is treatment consensus. For the remainder, there is a lack consensus regarding the need for indefinite anticoagulation.


Assuntos
Anticoagulantes/uso terapêutico , Tromboembolia Venosa/tratamento farmacológico , Adulto , Idoso , Anticoagulantes/administração & dosagem , Gerenciamento Clínico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Fatores de Tempo
2.
Occup Med (Lond) ; 71(6-7): 250-254, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34455444

RESUMO

BACKGROUND: The first COVID-19-positive patient was identified in Ireland on 29 February 2020 (Department of Health, Government of Ireland; https://www.gov.ie/en/pressrelease/2f75fd-statement-from-the-national-public-healthemergency-team-sat-29-feb/). Healthcare worker (HCW) quarantining became a core intervention for those identified as 'close contacts' to reduce onward transmission within the workplace to patients and colleagues. Whether a quarantining strategy could be justified at a time when there was an increased demand for the services of HCWs remained unknown. AIMS: To establish whether quarantining staff away from a healthcare setting during a pandemic is justified. METHODS: This retrospective study examined close contacts of COVID-19-positive index cases (both residents and HCWs) in a community hospital over a 4-week period from 1 to 28 April 2020. Close contacts were identified in accordance with national guidelines. Zones of the hospital were examined to determine the number of COVID-positive index cases and their close contacts. A cumulative result for the hospital was recorded. RESULTS: While outcomes varied over time, per zone and per HCW category, the overall conversion rate from close contact to an index case was 30%. CONCLUSIONS: This study vindicates the policy of quarantining close contact HCWs from their workplaces as they pose a significant threat to both their patients and fellow workers.


Assuntos
COVID-19 , Quarentena , Atenção à Saúde , Pessoal de Saúde , Humanos , Estudos Retrospectivos , SARS-CoV-2
4.
Transfus Med ; 27(1): 66-71, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27714877

RESUMO

BACKGROUND: Real-world studies of the emergency reversal of warfarin using 4-factor prothrombin complex concentrate (PCC) report unwarranted delays. The delay to receiving PCC was ≥ 8 h in 46·7% of patients with warfarin-associated bleeding (PWAB) treated with a variable PCC dosing protocol in our retrospective audit. OBJECTIVE: To report the impact of a simplified PCC dosing protocol on the interval to reversal of anticoagulation. METHODS: We developed a PCC dosing protocol standardising the initial PCC dose and simplifying dosing calculations. Study end points were the proportion of PWAB achieving international normalised ratio (INR) ≤1·5 and treated within 8 h of presentation, respectively. RESULTS: Of 17, 15 (88·2%) PWABs achieved a post-treatment INR ≤ 1·5; 14 of 17 (82·4%) PWABs were reversed within 8 h. Median intervals between triage and PCC request and PCC request and start of infusion (administration interval) were 126 min (range 39-520) and 30 min (range 5-100), respectively. Compared with the retrospective cohort, RAPID is associated with an improved administration interval (mean 37·7 vs 76 min, P = 0·031) and the proportion of PWABs treated within 30 min (58·8 vs 6·7%, P = 0·009). CONCLUSION: The RAPID protocol reduces unwarranted delays without compromising efficacy.


Assuntos
Fatores de Coagulação Sanguínea/administração & dosagem , Fatores de Coagulação Sanguínea/farmacocinética , Coeficiente Internacional Normatizado , Varfarina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Tempo , Varfarina/administração & dosagem , Varfarina/farmacocinética
5.
Ir Med J ; 110(5): 567, 2017 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-28737308

RESUMO

Venous thromboembolism (VTE) is a leading cause of maternal mortality. The risk increases with increasing maternal age, mode of delivery and medical co-morbidities. Thromboprophylaxis with low molecular weight heparin (LMWH) has been shown to be both safe and efficacious. The aim of this study was to prospectively investigate the incidence of maternal risk factors in pregnant women admitted to hospital, to calculate their VTE risk status and to investigate if they were receiving appropriate thromboprophylaxis. All patients admitted to the participating hospitals on the day of investigation were assessed for risk of VTE on the basis of hospital chart review. Five Hundred and forty women were recruited from 16 hospitals. Almost 32% (31.7%) were receiving thromboprophylaxis with LMWH. Just under 80% of patients were on the correct thromboprophylaxis strategy as defined by the RCOG guideline but 49% were under-dosed. The odds of receiving appropriate thromboprophylaxis were significantly increased if the woman was >35 years 0or with parity>3.


Assuntos
Anticoagulantes/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Complicações Cardiovasculares na Gravidez/prevenção & controle , Tromboembolia Venosa/prevenção & controle , Adulto , Fatores Etários , Feminino , Humanos , Gravidez , Estudos Prospectivos , Fatores de Risco
6.
Scott Med J ; 60(2): 90-4, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25922413

RESUMO

BACKGROUND: Recent violence reduction initiatives in Glasgow have led to a reduction in recorded levels of violent crime.(1) This study evaluates the impact of these initiatives on assault-related emergency department attendances and admissions. METHODS: A retrospective observational study conducted in Glasgow Royal Infirmary's emergency department comparing assault-related emergency department attendances and hospital admissions over two 30-day study periods (April 2010 and April 2012). The primary outcome measure was the change in assault-related emergency department attendances. The secondary outcome measure was the impact on assault-related hospital and critical care admissions. RESULTS: In April 2010, there were 6098 emergency department attendances, 301 (4.9%) were due to assault. In April 2012, there were 7236 emergency department attendances, 263 (3.6%) were due to assault, representing a significant reduction in assault-related attendances (p < 0.01). There were significant reductions in level 1 admissions 2010 n = 56 (19.2%), 2012 n = 36 (14.0%) p = 0.04 and critical care admissions, 2010 n = 5 (1.7%), 2012 n = 1 (0.4%) p = 0.04. CONCLUSIONS: Violence reduction initiatives in Glasgow have contributed to a reduction in assault-related emergency department attendance at Glasgow Royal Infirmary. The reduction in hospital admissions, in particular critical care admissions, suggests a reduction in morbidity and cost to the National Health Service.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Vítimas de Crime/estatística & dados numéricos , Serviço Hospitalar de Emergência/estatística & dados numéricos , Violência/prevenção & controle , Ferimentos e Lesões/prevenção & controle , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Consumo de Bebidas Alcoólicas/prevenção & controle , Feminino , Humanos , Masculino , Estudos Retrospectivos , Escócia/epidemiologia , Medidas de Segurança , Controle Social Formal , Violência/legislação & jurisprudência , Ferimentos e Lesões/epidemiologia
7.
Ir Med J ; 107(9): 281-4, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25417387

RESUMO

Patients with myeloma are at high risk of venous thromboembolism (VTE). There is no consensus about what agent to use or what haematologists are doing in clinical practice. A survey was sent to haematologists treating patients with myeloma in Ireland. 32/45 (71%) responded. 13/28 (46%) felt that VTE affected < 5% of patients. However, 8/28 (29%) felt it affected 10-19%. Thromboprophylaxis was most commonly used in patients on lenalidomide; 25/28 (89%) and thalidomide; 23/28 (82%). 23/28 (82%) used LMWH and 20/28 (71%) used aspirin either very frequently or frequently. 3/28 (11%) had used dabigatran/rivaroxaban despite there being little evidence to support their use. Efficacy was the most important factor in choosing an agent for 25/28 (89%). Bleeding was not felt to be an issue 15/29 (52%) were not using thromboprophylaxis guidelines. This survey demonstrated wide variation in the beliefs and practices regarding the burden of VTE in patients with myeloma and the need for thromboprophylaxis.


Assuntos
Fármacos Hematológicos , Mieloma Múltiplo/complicações , Padrões de Prática Médica , Serviços Preventivos de Saúde , Tromboembolia Venosa , Atitude do Pessoal de Saúde , Pesquisas sobre Atenção à Saúde , Fármacos Hematológicos/classificação , Fármacos Hematológicos/uso terapêutico , Hematologia/métodos , Hematologia/estatística & dados numéricos , Humanos , Irlanda , Participação do Paciente , Padrões de Prática Médica/normas , Padrões de Prática Médica/estatística & dados numéricos , Serviços Preventivos de Saúde/métodos , Serviços Preventivos de Saúde/normas , Medição de Risco , Resultado do Tratamento , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Tromboembolia Venosa/psicologia
8.
Front Genet ; 15: 1362977, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38933924

RESUMO

Women with maturity-onset diabetes of the young (MODY) need tailored antenatal care and monitoring of their offspring. Each MODY subtype has different implications for glycaemic targets, treatment choices and neonatal management. Hyperglycaemia of MODY is often first diagnosed in adolescence or early adulthood and therefore is clinically relevant to pregnant women. MODY remains an under-recognised and undiagnosed condition. Pregnancy represents an opportune time to make a genetic diagnosis of MODY and provide precision treatment. This review describes the nuance of antenatal care in women with MODY and the implications for pregnancies affected by a positive paternal genotype. Mutations in hepatic nuclear factor 1-alpha (HNF1A) and 4-alpha (HNF4A) genes are associated with progressive ß-cell dysfunction resulting in early onset diabetes. Patients are largely managed with sulphonylureas outside of pregnancy. Macrosomia and persistent neonatal hypoglycaemia are reported in 54% and 15% of HNF4A genotype positive offspring respectively with a median increase in birthweight of 790 g. Close observation of foetal growth in utero allows optimal timing of delivery to minimise peri- and postpartum materno-foetal complications. Glucokinase (GCK)-MODY causes mild fasting hyperglycaemia which does not require treatment outside of pregnancy. Birthweight of offspring of maternal carriers is dependent on foetal genotype; heterozygous mutation carriers are usually normal weight while genotype negative offspring are large for gestational age (600 g heavier). Affected offspring of paternal carriers may be small for gestational age (500 g lighter). Serial growth scans with measurement of the abdominal circumference indirectly differentiate foetal genotype. Measurement of cell free foetal DNA in maternal blood from the late first trimester is superior to traditionally used ultrasound to distinguish foetal genotype. Cost and accessibility may limit its use.

9.
Ann Surg Oncol ; 19(3): 973-80, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21879273

RESUMO

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) is implicated in carcinogenesis. In this study we examined the expression of ICAM-1 in papillary thyroid cancer (PTC). We hypothesized that ICAM-1 correlates with indicators of tumor aggressiveness in PTC. METHODS: Thirty-five primary and metastatic PTCs, five follicular adenomas, five Hashimoto thyroiditis, five nodular hyperplasia, and eight normal thyroid tissue samples were analyzed for ICAM-1 gene expression using quantitative reverse-transcription polymerase chain reaction (RT-PCR). ICAM-1 gene expression was analyzed at protein level by immunohistochemistry (IHC) using a semiquantitative score. Gene expression and intensity levels were correlated with markers of tumor aggressiveness including BRAF V600E mutation, tumor size, extrathyroidal extension (ETE), angiolymphatic invasion, and lymph node metastasis. RESULTS: ICAM-1 gene expression was higher in PTC (p = 0.01) and lymph node metastases (p = 0.03) when compared with benign tumors and Hashimoto's. Furthermore, PTCs exhibiting BRAF V600E mutation (p = 0.01), ETE (p < 0.01), and lymph node metastasis (p = 0.02) were associated with higher ICAM-1 levels. Gene expression correlated with protein levels on IHC. Additionally, poorly differentiated thyroid carcinoma had a higher ICAM-1 intensity score compared with well-differentiated carcinoma (p = 0.03). CONCLUSIONS: ICAM-1 expression is upregulated in papillary thyroid carcinoma. Furthermore, ICAM-1 upregulation correlated with aggressive tumor features such as BRAF V600E mutation, ETE, and lymph node metastasis, suggesting that ICAM-1 plays a role in thyroid cancer progression.


Assuntos
Carcinoma Papilar/metabolismo , Regulação Neoplásica da Expressão Gênica , Molécula 1 de Adesão Intercelular/metabolismo , Neoplasias da Glândula Tireoide/metabolismo , Regulação para Cima , Adolescente , Adulto , Idoso , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Feminino , Doença de Hashimoto/genética , Doença de Hashimoto/metabolismo , Humanos , Molécula 1 de Adesão Intercelular/genética , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Mutação , Análise Serial de Proteínas , Proteínas Proto-Oncogênicas B-raf/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Adulto Jovem
10.
Thromb Update ; 5: 100086, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38620810

RESUMO

Since the beginning of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) virus pandemic, several highly effective and safe vaccines have been produced at remarkable speed. Following global implementation of vaccination programmes, cases of thrombosis with thrombocytopenia following administration of adenoviral vector-based vaccines started being reported. In this review we discuss the known pathogenesis and epidemiology of so-called vaccine induced thrombocytopenia and thrombosis (VITT). We consider the available guidelines, diagnostic laboratory tests and management options for these patients. Finally, we discuss important unanswered questions and areas for future research in this novel pathoclinical entity.

11.
J Exp Med ; 172(1): 383-6, 1990 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-1694226

RESUMO

We monitored the APC function of cells taken from the spleen and peritoneal cavity of mice that had been given protein antigens via the intravenous or intraperitoneal routes. Using the mAb 33D1 and N418 to negatively and positively select dendritic cells, we obtained evidence that dendritic cells are the main cell type in spleen that carries the protein in a form that is immunogenic for antigen-specific T cells. In vivo pulsed macrophages were not immunogenic and did not appear capable of transferring peptide fragments to dendritic cells.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Células Dendríticas/imunologia , Baço/citologia , Animais , Células Clonais , Epitopos/imunologia , Feminino , Macrófagos/imunologia , Masculino , Camundongos , Fragmentos de Peptídeos/imunologia , Cavidade Peritoneal/citologia , Linfócitos T/imunologia
12.
J Exp Med ; 172(2): 631-40, 1990 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-2373994

RESUMO

T cells recognize peptides that are bound to MHC molecules on the surface of different types of antigen-presenting cells (APC). Antigen presentation most often is studied using T cells that have undergone priming in situ, or cell lines that have been chronically stimulated in vitro. The use of primed cells provides sufficient numbers of antigen-reactive lymphocytes for experimental study. A more complete understanding of immunogenicity, however, requires that one develop systems for studying the onset of a T cell response from unprimed lymphocytes, especially in situ. Here it is shown that mouse T cells can be reliably primed in situ using dendritic cells as APC. The dendritic cells were isolated from spleen, pulsed with protein antigens, and then administered to naive mice. Antigen-responsive T cells developed in the draining lymphoid tissue, and these T cells only recognized protein when presented on cells bearing the same MHC products as the original priming dendritic cells. In contrast, little or no priming was seen if antigen-pulsed spleen cells or peritoneal cells were injected. Since very small amounts of the foreign protein were visualized within endocytic vacuoles of antigen-pulsed dendritic cells, it is suggested that dendritic cells have a small but relevant vacuolar system for presenting antigens over a several day period in situ.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Conalbumina/imunologia , Células Dendríticas/imunologia , Proteínas do Ovo/imunologia , Complexo Principal de Histocompatibilidade , Mioglobina/imunologia , Linfócitos T/imunologia , Animais , Células Cultivadas , Conalbumina/metabolismo , Replicação do DNA , Endocitose , Feminino , Cinética , Linfonodos/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos , Mioglobina/metabolismo , Pinocitose
13.
J Exp Med ; 194(7): 953-66, 2001 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-11581317

RESUMO

It has been proposed that two different antigen-experienced T cell subsets may be distinguishable by their preferential ability to home to lymphoid organs (central memory cells) or nonlymphoid tissues (effector memory/effector cells). We have shown recently that murine antigen-primed CD8(+) T cells cultured in interleukin (IL)-15 (CD8(IL-15)) resemble central memory cells in phenotype and function. In contrast, primed CD8(+) T cells cultured in IL-2 (CD8(IL-2)) become cytotoxic effector cells. Here, the migratory behavior of these two subsets was investigated. Naive, CD8(IL-15) cells and, to a lesser degree, CD8(IL-2) cells localized to T cell areas in the spleen, but only naive and CD8(IL-15) cells homed to lymph nodes (LNs) and Peyer's patches. Intravital microscopy of peripheral LNs revealed that CD8(IL-15) cells, but not CD8(IL-2) cells, rolled and arrested in high endothelial venules (HEVs). Migration of CD8(IL-15) cells to LNs depended on L-selectin and required chemokines that bind CC chemokine receptor (CCR)7. Both antigen-experienced populations, but not naive T cells, responded to inflammatory chemokines and accumulated at sites of inflammation. However, CD8(IL-2) cells were 12 times more efficient in migrating to inflamed peritoneum than CD8(IL-15) cells. Furthermore, CD8(IL-15) cells proliferated rapidly upon reencounter with antigen at sites of inflammation. Thus, central memory-like CD8(IL-15) cells home avidly to lymphoid organs and moderately to sites of inflammation, where they mediate rapid recall responses, whereas CD8(IL-2) effector T cells accumulate in inflamed tissues, but are excluded from most lymphoid organs.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Quimiotaxia de Leucócito/imunologia , Memória Imunológica , Subpopulações de Linfócitos T/imunologia , Animais , Circulação Sanguínea , Divisão Celular , Feminino , Inflamação/imunologia , Interleucina-15/imunologia , Interleucina-2/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Sistema Linfático/citologia , Sistema Linfático/imunologia , Masculino , Camundongos , Nódulos Linfáticos Agregados/citologia , Nódulos Linfáticos Agregados/imunologia , Baço/citologia , Baço/imunologia
14.
J Exp Med ; 169(3): 1153-68, 1989 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-2522496

RESUMO

Resting T cells enter cell cycle when challenged with anti-CD3 mAb and accessory cells that bear required Fc receptors (FcR). Presentation of anti-CD3 is thought to be a model for antigens presented by accessory cells to the TCR complex. We have obtained evidence that the number of anti-CD3 molecules that are associated with the accessory cell can be very small. We first noticed that thymic dendritic cells and cultured, but not freshly isolated, epidermal Langerhans cells (LC) were active accessory cells for responses to anti-CD3 mAb. DNA synthesis was abrogated by a mAb to the FcR but not by mAb to other molecules used in clonally specific antigen recognition, i.e., class I and II MHC products or CD4 and CD8. The requisite FcR could be identified on the LC but in small numbers. Freshly isolated LC had 20,000 FcR per cell, while the more active cultured LC had only 2,000 sites, using 125I-anti-FcR mAb in quantitative binding studies. Individual LC had similar levels of FcR, as evidenced with a sensitive FACS. FcR could not be detected on T cells or within the dendritic cell cytoplasm, at the start of or during the mitogenesis response. When the response was assessed at 30 h with single cell assays, at least 20 T cells became lymphoblasts per added LC, and at least 8 T cells were synthesizing DNA while in contact with the LC in discrete cell clusters. To the extent that anti-CD3 represents a polyclonal model for antigen presentation to specific T cell clones, these results suggest two conclusions. First, only 200-300 molecules of ligand on dendritic cells may be required to trigger a T cell. Second, the maturation of LC in culture entails "sensitizing" functions other than ligand presentation (anti-CD3 on FcR) to clonotypic T cell receptors.


Assuntos
Anticorpos Monoclonais/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , DNA/biossíntese , Células de Langerhans/imunologia , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Complexo CD3 , Células Cultivadas , Concanavalina A/farmacologia , Células Dendríticas/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Imunoensaio , Teste de Cultura Mista de Linfócitos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Mitose , Receptores Fc/análise , Receptores Fc/imunologia , Linfócitos T/imunologia
15.
J Exp Med ; 185(7): 1223-30, 1997 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-9104809

RESUMO

Recent studies have shown that many nonclassical major histocompatibility complex (MHC) (class 1b) molecules have distinct antigen-binding capabilities, including the binding of nonpeptide moieties and the binding of peptides that are different from those bound to classical MHC molecules. Here, we show that one of the H-2T region-encoded molecules, T10, when produced in Escherichia coli, can be folded in vitro with beta2-microglobulin (beta2m) to form a stable heterodimer in the absence of peptide or nonpeptide moieties. This heterodimer can be recognized by specific antibodies and is stimulatory to the gammadelta T cell clone, G8. Circular dichroism analysis indicates that T10/beta2m has structural features distinct from those of classical MHC class I molecules. These results suggest a new way for MHC-like molecules to adopt a peptide-free structure and to function in the immune system.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Complexo Principal de Histocompatibilidade , Dobramento de Proteína , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/imunologia , Microglobulina beta-2/imunologia , Células Clonais , Dimerização , Antígenos de Histocompatibilidade Classe I/genética , Conformação Proteica , Desnaturação Proteica , Proteínas Recombinantes/imunologia
16.
J Exp Med ; 168(6): 2279-94, 1988 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-3264326

RESUMO

The thymus gland is important for the formation of competent T lymphocytes. However, there is long-standing evidence that greater than 95% of newly formed thymocytes do not emigrate to peripheral lymphoid tissues but instead die locally. We have identified a rapid and selective pathway for thymocyte turnover in vitro. The mechanism entails binding, uptake, and digestion by macrophages. The susceptible cells are a subpopulation of double-positive thymocytes. These thymocytes can be enriched by virtue of their high buoyant density in Percoll and prove to have low levels of surface CD3 and little or no surface TCR. However TCR-alpha and -beta genes have undergone rearrangement, and full length alpha and beta transcripts are abundant. Therefore many double-positive cells rearrange and express TCR genes but do not have normal levels of TCR on the cell surface. We propose that thymocytes that undergo high turnover in situ are unable to form receptors that can be selected by MHC molecules in the thymus, and that these cells are recognized and cleared by the macrophage.


Assuntos
Macrófagos/imunologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Timo/citologia , Rearranjo Gênico do Linfócito T , Fagocitose
17.
J Exp Med ; 169(3): 1169-78, 1989 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-2522497

RESUMO

The capacity of dendritic cells to present protein antigens has been studied with two MHC class II-restricted, myoglobin-specific, T cell clones. Spleen dendritic cells and cultured epidermal Langerhans cells (LC) presented native myoglobin weakly and often not at all. These same populations were powerful stimulators of allogeneic T cells in the primary MLR. Freshly isolated LC were in contrast very active in presenting proteins to T cell clones but were weak stimulators of the MLR. Both fresh and cultured LC could present specific peptide fragments of myoglobin to the clones. These results suggest that dendritic cells in nonlymphoid tissues like skin can act as sentinels for presenting antigens in situ, their accessory function developing in two phases. First antigens are captured and appropriately presented. Further handling of antigen then is downregulated while the cells acquire strong sensitizing activity for the growth and function of resting T lymphocytes. The potent MLR stimulating activity of cultured epidermal LC and lymphoid dendritic cells probably reflects prior handling of antigens leading to the formation of allogeneic MHC-peptide complexes.


Assuntos
Antígenos/imunologia , Células Dendríticas/imunologia , Mioglobina/imunologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Clonais/imunologia , Células Epidérmicas , Feminino , Antígenos H-2/imunologia , Haplótipos , Antígenos de Histocompatibilidade Classe II/imunologia , Células de Langerhans/imunologia , Teste de Cultura Mista de Linfócitos , Linfoma/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Camundongos Endogâmicos DBA , Fragmentos de Peptídeos/imunologia , Baço/citologia , Células Tumorais Cultivadas
18.
J Exp Med ; 191(4): 669-82, 2000 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-10684859

RESUMO

Macrophage Fcgamma receptors (FcgammaRs) mediate the uptake and destruction of antibody-coated viruses, bacteria, and parasites. We examined FcgammaR signaling and phagocytic function in bone marrow-derived macrophages from mutant mice lacking the major Src family kinases expressed in these cells, Hck, Fgr, and Lyn. Many FcgammaR-induced functional responses and signaling events were diminished or delayed in these macrophages, including immunoglobulin (Ig)G-coated erythrocyte phagocytosis, respiratory burst, actin cup formation, and activation of Syk, phosphatidylinositol 3-kinase, and extracellular signal-regulated kinases 1 and 2. Significant reduction of IgG-dependent phagocytosis was not seen in hck(-)(/)-fgr(-)(/)- or lyn(-)(/)- cells, although the single mutant lyn(-)(/)- macrophages did manifest signaling defects. Thus, Src family kinases clearly have roles in two events leading to FcgammaR-mediated phagocytosis, one involving initiation of actin polymerization and the second involving activation of Syk and subsequent internalization. Since FcgammaR-mediated phagocytosis did occur at modest levels in a delayed fashion in triple mutant macrophages, these Src family kinases are not absolutely required for uptake of IgG-opsonized particles.


Assuntos
Macrófagos/fisiologia , Fagocitose/imunologia , Proteínas Tirosina Quinases/metabolismo , Proteínas Tirosina Quinases/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Fc/fisiologia , Quinases da Família src/metabolismo , Actinas/metabolismo , Animais , Células da Medula Óssea/citologia , Macrófagos/citologia , Macrófagos/imunologia , Camundongos , Camundongos Knockout , Modelos Biológicos , Proteínas Tirosina Quinases/deficiência , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-fyn , Proteínas Proto-Oncogênicas c-hck , Transdução de Sinais , Quinases da Família src/deficiência , Quinases da Família src/genética
19.
J Exp Med ; 171(5): 1753-71, 1990 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-2185332

RESUMO

Hybridoma fusions with hamster hosts were undertaken to generate mAbs to mouse spleen dendritic cells. Two mAb were obtained and used to uncover the distinct integrins of these APC. One, 2E6, bound a determinant common to all members of the CD11/CD18 family, most likely the shared 90 kD CD18 beta chain. 2E6 immunoprecipitated the characteristic beta 2 integrin heterodimers from lymphocytes (p180, 90; CD11a) and macrophages (p170,90; CD11b), but from dendritic cells, a p150,90 (presumably CD11c) integrin was the predominant species. 2E6 inhibited the binding function of the CD11a and CD11b integrins on B cells and macrophages in appropriate assays, but 2E6 exerted little or no inhibition on the clustering of dendritic cells to T cells early in primary MLR, suggesting a CD11/CD18-independent mechanism for this binding. The second mAb, N418, precipitated a 150, 90 kD heterodimer that shared the 2E6 CD18 epitope. This N418 epitope may be the murine homologue of the previously characterized human CD11c molecule, but the epitope was only detected on dendritic cells. N418 did not react with peritoneal macrophages, anti-Ig-induced spleen B blasts, or bulk lymph node cells. When used to stain sections of spleen, N418 stained dendritic cells in the T-dependent areas, much like anti-class II mAbs that were also generated in these fusions. In addition, N418 revealed nests of dendritic cells that punctuated the rim of marginal zone macrophages between red and white pulp. This localization positioned most dendritic cells at regions where arterial vessels and T cells enter the white pulp. We conclude that the p150, 90 heterodimer is the major beta 2 integrin of spleen dendritic cells, and we speculate that it may function to localize these APC at sites that permit access to the recirculating pool of resting T cells.


Assuntos
Anticorpos Monoclonais , Células Dendríticas/imunologia , Integrinas/análise , Leucócitos/imunologia , Baço/imunologia , Animais , Anticorpos Monoclonais/isolamento & purificação , Complexo Antígeno-Anticorpo , Células Cultivadas , Cricetinae , Feminino , Citometria de Fluxo , Hibridomas/imunologia , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Endogâmicos
20.
J Exp Med ; 172(5): 1459-69, 1990 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-2121888

RESUMO

Two prior studies with a small number of T cell lines have shown that the presentation of native protein antigens by epidermal Langerhans cells (LC) is regulated. When freshly isolated, LC are efficient antigen-presenting cells (APC), but after a period of culture LC are inefficient or even inactive. The deficit in culture seems to be a selective loss in antigen processing, since cultured LC are otherwise rich in major histocompatibility complex (MHC) class II products and are active APC for alloantigens and mitogens, which do not require processing. We have extended the analysis by studying presentation to bulk populations of primed lymph node and a T-T hybrid. Only freshly isolated LC can be pulsed with the protein antigens myoglobin and conalbumin, but once pulsed, antigen is retained in an immunogenic form for at least 2 d. The acquisition of antigen, presumably as MHC-peptide complexes, is inhibited if the fresh LC are exposed to foreign protein in the presence of chloroquine or cycloheximide. The latter, in contrast, improves the efficacy of antigen pulsing in anti-Ig-stimulated B blasts. In additional studies of mechanism, we noted that both fresh and cultured LC endocytose similar amounts of an antigen, rhodamineovalbumin, into perinuclear granules. However, freshly isolated LC synthesize high levels class II MHC molecules and express higher amounts of the class II-associated invariant chain. Fresh LC are at least 5-10 times more active than many other cells types in the level of biosynthesis of MHC class II products. These findings provide a physiologic model in which newly synthesized MHC class II molecules appear to be the principal vehicle for effective antigen processing by APC of the dendritic cell lineage. Another APC, the B lymphoblast, does not appear to require newly synthesized MHC class II molecules for presentation.


Assuntos
Células Apresentadoras de Antígenos/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Cadeias gama de Imunoglobulina/metabolismo , Células de Langerhans/metabolismo , Animais , Células Apresentadoras de Antígenos/fisiologia , Células Cultivadas , Cloroquina/farmacologia , Cicloeximida/farmacologia , Células Dendríticas/metabolismo , Regulação para Baixo/fisiologia , Feminino , Expressão Gênica/fisiologia , Antígenos de Histocompatibilidade Classe II/genética , Hibridomas/metabolismo , Cadeias gama de Imunoglobulina/genética , Células de Langerhans/fisiologia , Linfócitos/metabolismo , Camundongos , Microscopia de Fluorescência/métodos , Ovalbumina , Rodaminas , Linfócitos T/imunologia , Linfócitos T/metabolismo
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