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2.
Nat Commun ; 10(1): 3106, 2019 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-31308374

RESUMO

Immune responses need to be controlled tightly to prevent autoimmune diseases, yet underlying molecular mechanisms remain partially understood. Here, we identify biallelic mutations in three patients from two unrelated families in differentially expressed in FDCP6 homolog (DEF6) as the molecular cause of an inborn error of immunity with systemic autoimmunity. Patient T cells exhibit impaired regulation of CTLA-4 surface trafficking associated with reduced functional CTLA-4 availability, which is replicated in DEF6-knockout Jurkat cells. Mechanistically, we identify the small GTPase RAB11 as an interactor of the guanine nucleotide exchange factor DEF6, and find disrupted binding of mutant DEF6 to RAB11 as well as reduced RAB11+CTLA-4+ vesicles in DEF6-mutated cells. One of the patients has been treated with CTLA-4-Ig and achieved sustained remission. Collectively, we uncover DEF6 as player in immune homeostasis ensuring availability of the checkpoint protein CTLA-4 at T-cell surface, identifying a potential target for autoimmune and/or cancer therapy.

3.
BMJ Open ; 9(2): e024917, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787089

RESUMO

OBJECTIVES: Increased morbidity and mortality have been associated with weekend and night-time clinical activity. We sought to compare the outcomes of liver transplantation (LT) between weekdays and weekends or night-time and day-time to determine if 'out-of-hours' LT has acceptable results compared with 'in-hours'. DESIGN, SETTING AND PARTICIPANTS: We conducted a retrospective analysis of patient outcomes for all 8816 adult, liver-only transplants (2000-2014) from the UK Transplant Registry. OUTCOME MEASURES: Outcome measures were graft failure (loss of the graft with or without death) and transplant failure (either graft failure or death with a functioning graft) at 30 days, 1 year and 3 years post-transplantation. The association of these outcomes with weekend versus weekday and day versus night transplantation were explored, following the construction of a risk-adjusted Cox regression model. RESULTS: Similar patient and donor characteristics were observed between weekend and weekday transplantation. Unadjusted graft failure estimates were 5.7% at 30 days, 10.4% at 1 year and 14.6% at 3 years; transplant failure estimates were 7.9%, 15.3% and 21.3% respectively.A risk-adjusted Cox regression model demonstrated a significantly lower adjusted HR (95% CI) of transplant failure for weekend transplant of 0.77 (0.66 to 0.91) within 30 days, 0.86 (0.77 to 0.97) within 1 year, 0.89 (0.81 to 0.99) within 3 years and for graft failure of 0.81 (0.67 to 0.97) within 30 days. For patients without transplant failure within 30 days, there was no weekend effect on transplant failure. Neither night-time procurement nor transplantation were associated with an increased hazard of transplant or graft failure. CONCLUSIONS: Weekend and night-time LT outcomes were non-inferior to weekday or day-time transplantation, and we observed a possible small beneficial effect of weekend transplantation. The structure of LT services in the UK delivers acceptable outcomes 'out-of-hours' and may offer wider lessons for weekend working structures.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30471454

RESUMO

INTRODUCTION: & Aims: Small studies have found that black patient with autoimmune hepatitis (AIH) patients present with more aggressive disease. We aimed to characterize the presentation and outcome in black and white patients with AIH. METHODS: We performed a retrospective study, collecting information from databases of patients with AIH attending the Institute of Liver studies at King's College Hospital, London (1971-October 2015, the Royal Free Hospital, London (1982 through December 2016) and the multicenter Dutch Autoimmune Hepatitis Study Group cohort (2006-August 2016). We identified 88 black patients with AIH and we compared their clinical characteristics and outcomes to 897 white patients with AIH. RESULTS: Black patients presented at a younger age (median 38 years vs 45 years) (P=.007), had higher IgG levels (mean 31.0 mg/dL vs 27.5 mg/dL) (P=.04), but there were no significant differences between groups in auto-antibody profiles, international AIH Group scores, or sex distribution of disease. A higher proportion of black patients had systemic lupus erythematosus (10%) than white patients (2%) (P=<.001). There was no significant difference in proportions of patients with a response to standard therapy (86% for black patients vs 91% for white patients; P=.20) or in rate of relapse (57% vs 50%; P=.3). Despite this, black patients had an increased risk of liver transplantation and liver-related death (hazard ratio 2.4, 95% CI, 1.4-4.0; P<.001). Overall mortality was similar between the two groups. CONCLUSION: In a comparison of black and white patients with AIH in Europe, we found that black patients present at a younger age, have higher levels of IgG levels, and a greater proportion have SLE. We also found black patients to have a greater risk of liver transplantation and liver-related mortality, indicating more aggressive disease.

5.
Biophys J ; 115(7): 1330-1343, 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30219287

RESUMO

CTLA4 is an essential negative regulator of T-cell immune responses and a key checkpoint regulating autoimmunity and antitumor responses. Genetic mutations resulting in quantitative defects in the CTLA4 pathway are also associated with the development of immune dysregulation syndromes in humans. It has been proposed that CTLA4 functions to remove its ligands CD80 and CD86 from opposing cells by a process known as transendocytosis. A quantitative characterization of CTLA4 synthesis, endocytosis, degradation, and recycling and how these affect its function is currently lacking. In a combined in vitro and in silico study, we developed a mathematical model and identified these trafficking parameters. Our model predicts optimal ligand removal in an intermediate affinity range. The intracellular CTLA4 pool as well as fast internalization, recovery of free CTLA4 from internalized complexes, and recycling is critical for sustained functionality. CD80-CTLA4 interactions are predicted to dominate over CD86-CTLA4. Implications of these findings in the context of control of antigen-presenting cells by regulatory T cells and of pathologic genetic deficiencies are discussed. The presented mathematical model can be reused in the community beyond these questions to better understand other trafficking receptors and study the impact of CTLA4 targeting drugs.

6.
Blood ; 131(1): 58-67, 2018 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-29118008

RESUMO

CD28 and CTLA-4 are members of a family of immunoglobulin-related receptors that are responsible for various aspects of T-cell immune regulation. The family includes CD28, CTLA-4, and ICOS as well as other proteins, including PD-1, BTLA, and TIGIT. These receptors have both stimulatory (CD28, ICOS) and inhibitory roles (CTLA-4, PD-1, BTLA, and TIGIT) in T-cell function. Increasingly, these pathways are targeted as part of immune modulatory strategies to treat cancers, referred to generically as immune checkpoint blockade, and conversely to treat autoimmunity and CTLA-4 deficiency. Here, we focus on the biology of the CD28/CTLA-4 pathway as a framework for understanding the impacts of therapeutic manipulation of this pathway.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Animais , Antígeno CTLA-4/imunologia , Humanos
8.
Br J Hosp Med (Lond) ; 78(5): 278-285, 2017 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-28489436

RESUMO

Medical care for patients following liver transplantation is complex and requires a holistic approach to management. Patients and clinicians are faced with multiple challenges: immunosuppressive regimens must be optimized to avoid and treat graft rejection, the risk and atypical features of sepsis in the immunocompromised patient must be recognized, steps are required to reduce the recurrence of liver disease and the long-term increased risks of malignancy, renal failure and metabolic complications need managing. Despite the benefits of liver transplantation there are additional concerns regarding the impact upon quality of life. This review will focus upon the care of patients following liver transplantation. As these patients will present to a broad range of clinicians, an understanding of the common drugs used post-transplantation and general approach to management of these patients will be of benefit to the general clinical audience.


Assuntos
Transplante de Fígado , Cuidados Pós-Operatórios/métodos , Complicações Pós-Operatórias/terapia , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/uso terapêutico , Qualidade de Vida
9.
Br J Hosp Med (Lond) ; 78(5): 252-259, 2017 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-28489446

RESUMO

Chronic or acute liver failure and primary liver cancers can be effectively managed with liver transplantation. The range of indications for liver transplantation is increasing but there is a mismatch between the numbers of available donations and current needs. Specific criteria for listing patients exist but, at minimum, the predicted mortality without transplantation must exceed that with transplantation, coupled with a 50% predicted 5-year survival following liver transplantation. The risk posed by liver disease must be weighed against the risk of liver transplantation, considering the patient's comorbidities, age, nutritional status and behavioural factors in a complex assessment process. This article reviews current UK practice in the selection and care of patients being assessed for liver transplantation.


Assuntos
Hepatopatias/cirurgia , Transplante de Fígado , Fatores Etários , Comorbidade , Humanos , Estado Nutricional , Seleção de Pacientes , Cuidados Pré-Operatórios , Fatores de Risco , Análise de Sobrevida , Obtenção de Tecidos e Órgãos , Reino Unido , Listas de Espera
10.
J Allergy Clin Immunol ; 140(6): 1660-1670.e16, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28400115

RESUMO

BACKGROUND: Thymus transplantation is a promising strategy for the treatment of athymic complete DiGeorge syndrome (cDGS). METHODS: Twelve patients with cDGS underwent transplantation with allogeneic cultured thymus. OBJECTIVE: We sought to confirm and extend the results previously obtained in a single center. RESULTS: Two patients died of pre-existing viral infections without having thymopoiesis, and 1 late death occurred from autoimmune thrombocytopenia. One infant had septic shock shortly after transplantation, resulting in graft loss and the need for a second transplant. Evidence of thymopoiesis developed from 5 to 6 months after transplantation in 10 patients. Median circulating naive CD4 counts were 44 × 106/L (range, 11-440 × 106/L) and 200 × 106/L (range, 5-310 × 106/L) at 12 and 24 months after transplantation and T-cell receptor excision circles were 2,238/106 T cells (range, 320-8,807/106 T cells) and 4,184/106 T cells (range, 1,582-24,596/106 T cells). Counts did not usually reach normal levels for age, but patients were able to clear pre-existing infections and those acquired later. At a median of 49 months (range, 22-80 months), 8 have ceased prophylactic antimicrobials, and 5 have ceased immunoglobulin replacement. Histologic confirmation of thymopoiesis was seen in 7 of 11 patients undergoing biopsy of transplanted tissue, including 5 showing full maturation through to the terminal stage of Hassall body formation. Autoimmune regulator expression was also demonstrated. Autoimmune complications were seen in 7 of 12 patients. In 2 patients early transient autoimmune hemolysis settled after treatment and did not recur. The other 5 experienced ongoing autoimmune problems, including thyroiditis (3), hemolysis (1), thrombocytopenia (4), and neutropenia (1). CONCLUSIONS: This study confirms the previous reports that thymus transplantation can reconstitute T cells in patients with cDGS but with frequent autoimmune complications in survivors.


Assuntos
Doenças Autoimunes/imunologia , Síndrome de DiGeorge/terapia , Transplante de Órgãos , Complicações Pós-Operatórias/imunologia , Linfócitos T/imunologia , Timo/transplante , Doenças Autoimunes/etiologia , Células Cultivadas , Criança , Pré-Escolar , Síndrome de DiGeorge/imunologia , Europa (Continente) , Feminino , Humanos , Reconstituição Imune , Lactente , Masculino , Técnicas de Cultura de Órgãos , Transplante Homólogo , Resultado do Tratamento
11.
Blood ; 129(11): 1458-1468, 2017 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-28159733

RESUMO

Heterozygous CTLA-4 deficiency has been reported as a monogenic cause of common variable immune deficiency with features of immune dysregulation. Direct mutation in CTLA-4 leads to defective regulatory T-cell (Treg) function associated with impaired ability to control levels of the CTLA-4 ligands, CD80 and CD86. However, additional mutations affecting the CTLA-4 pathway, such as those recently reported for LRBA, indirectly affect CTLA-4 expression, resulting in clinically similar disorders. Robust phenotyping approaches sensitive to defects in the CTLA-4 pathway are therefore required to inform understanding of such immune dysregulation syndromes. Here, we describe assays capable of distinguishing a variety of defects in the CTLA-4 pathway. Assessing total CTLA-4 expression levels was found to be optimal when restricting analysis to the CD45RA-Foxp3+ fraction. CTLA-4 induction following stimulation, and the use of lysosomal-blocking compounds, distinguished CTLA-4 from LRBA mutations. Short-term T-cell stimulation improved the capacity for discriminating the Foxp3+ Treg compartment, clearly revealing Treg expansions in these disorders. Finally, we developed a functionally orientated assay to measure ligand uptake by CTLA-4, which is sensitive to ligand-binding or -trafficking mutations, that would otherwise be difficult to detect and that is appropriate for testing novel mutations in CTLA-4 pathway genes. These approaches are likely to be of value in interpreting the functional significance of mutations in the CTLA-4 pathway identified by gene-sequencing approaches.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Antígeno CTLA-4/genética , Mutação , Antígeno CTLA-4/metabolismo , Linhagem Celular , Imunodeficiência de Variável Comum/genética , Fatores de Transcrição Forkhead/análise , Humanos , Fenômenos do Sistema Imunológico/genética , Ligantes , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
12.
Transpl Int ; 27(8): 838-46, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24750406

RESUMO

Therapeutic immunosuppression following solid organ transplantation increases the risk of Epstein-Barr (EBV) viraemia, which is implicated in post-transplant lymphoproliferative disease (PTLD). We retrospectively analysed the incidence of EBV viraemia and clinical outcomes in 98 liver transplant recipients. Patients underwent EBV DNA monitoring by whole-blood PCR: EBV levels were correlated with clinical parameters and outcomes for a median of 249 days. 67% patients developed EBV viraemia (EBV DNA ≥100 copies/ml) and 30% had sustained viraemia. There was a trend towards higher hazard ratios for viraemia with exposure to aciclovir (HR 1.57, P = 0.12) or in recipients of a poorly HLA-matched graft (HR 1.62, P = 0.10). These associations became significant in the subgroup with >90 days surveillance; HR 2.54 (P = 0.0015) for aciclovir and HR 1.99 (P = 0.03) for poorly matched grafts. The converse was true with ganciclovir (HR 0.56 P = 0.13). Viraemia was more prolonged in men (median duration 7 days vs 1; P = 0.01) and in those with lower UKELD scores (11 days vs 1 day; P = 0.001) but shortened with ganciclovir exposure (P = 0.06). Younger patients were more likely to have high peak viral loads (P = 0.07). No clinical signs or symptoms or adverse outcomes were associated with EBV reactivation.


Assuntos
Infecções por Vírus Epstein-Barr/epidemiologia , Transplante de Fígado/efeitos adversos , Viremia/epidemiologia , Adulto , Idoso , Estudos de Coortes , DNA Viral/sangue , Infecções por Vírus Epstein-Barr/etiologia , Feminino , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Carga Viral , Viremia/etiologia
13.
Pediatr Res ; 72(3): 299-304, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22785446

RESUMO

BACKGROUND: The balance between endothelial injury and repair in childhood is poorly understood. We examined this relationship in healthy children, in adults, and in children with familial hypercholesterolemia (FH). METHODS: Circulating endothelial cells (CECs) were measured as a marker of vascular injury, with vascular repair assessed by counting colony-forming units (CFUs), also known as endothelial progenitor cells. RESULTS: CEC number increased with age. Children with FH had elevated CECs as compared with healthy children, with similar levels numerically to those found in healthy adults. CFU numbers were higher in healthy children than either healthy adults or children with FH. Endothelium-dependent vascular function, measured by flow-mediated dilatations, was positively associated with CFU number, even after adjustment for confounding risk variables. CONCLUSION: Levels of CECs increase and CFUs decrease with age. In childhood, before the onset of clinically detectable cardiovascular dysfunction, children with a major risk factor for atherosclerotic disease have levels of these indexes of vascular injury and repair approaching those seen in adults.


Assuntos
Fatores Etários , Dislipidemias/patologia , Células Endoteliais , Células-Tronco , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Humanos , Pessoa de Meia-Idade , Adulto Jovem
14.
Transplantation ; 93(5): 551-4, 2012 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-22245874

RESUMO

BACKGROUND: Concern that pandemic H1N1 swine influenza could be transmitted by solid organ transplantation led to the publication of guidance advising screening of donors, restriction of use of organs under certain conditions, and prophylaxis of recipients. We have reviewed the outcomes for cases of solid organ graft recipients from H1N1 influenza-positive donors in the United Kingdom up to May 2010. METHODS: The Organ Donation and Transplantation Directorate supplied a list of five known H1N1 influenza-positive donors, one of whom died from active H1N1 infection. Transplanting teams were contacted to gain information on clinical outcomes. RESULTS: Thirteen organs were grafted from the donors. None of the 13 recipients developed suspected or confirmed H1N1 influenza. There was variable use of antiviral chemoprophylaxis and screening of recipients for H1N1 influenza. CONCLUSIONS: No cases of transplant-related H1N1 influenza transmission were demonstrated in this series. It remains prudent that transplanting teams have a high index of suspicion for H1N1 influenza infection in donors and offer prophylaxis to and undertake active surveillance of recipients.


Assuntos
Vírus da Influenza A Subtipo H1N1/patogenicidade , Influenza Humana/transmissão , Doadores de Tecidos/provisão & distribução , Transplantes/efeitos adversos , Antivirais/uso terapêutico , Humanos , Influenza Humana/diagnóstico , Influenza Humana/mortalidade , Influenza Humana/prevenção & controle , Influenza Humana/virologia , Guias de Prática Clínica como Assunto , Sistema de Registros , Medição de Risco , Fatores de Risco , Obtenção de Tecidos e Órgãos , Reino Unido/epidemiologia
15.
Cell ; 122(5): 789-801, 2005 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-16143108

RESUMO

Dietary heme iron is an important nutritional source of iron in carnivores and omnivores that is more readily absorbed than non-heme iron derived from vegetables and grain. Most heme is absorbed in the proximal intestine, with absorptive capacity decreasing distally. We utilized a subtractive hybridization approach to isolate a heme transporter from duodenum by taking advantage of the intestinal gradient for heme absorption. Here we show a membrane protein named HCP 1 (heme carrier protein 1), with homology to bacterial metal-tetracycline transporters, mediates heme uptake by cells in a temperature-dependent and saturable manner. HCP 1 mRNA was highly expressed in duodenum and regulated by hypoxia. HCP 1 protein was iron regulated and localized to the brush-border membrane of duodenal enterocytes in iron deficiency. Our data indicate that HCP 1 is the long-sought intestinal heme transporter.


Assuntos
Duodeno/metabolismo , Heme/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Bactérias/metabolismo , Células CHO , Proteínas de Transporte/metabolismo , Clonagem Molecular , Cricetinae , Duodeno/citologia , Células Epiteliais/metabolismo , Células HeLa , Humanos , Hipóxia/metabolismo , Absorção Intestinal/fisiologia , Ferro/deficiência , Ferro/metabolismo , Proteínas de Membrana Transportadoras/genética , Camundongos , Dados de Sequência Molecular , Oócitos/metabolismo , Transportador de Folato Acoplado a Próton , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Coelhos , Ratos , Alinhamento de Sequência , Transferrina/metabolismo , Xenopus , Peixe-Zebra
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