RESUMO
BACKGROUND: Mortality following pancreatoduodenectomy is related to centre volume although the optimal volume is not defined. METHODS: Patients undergoing PD between 2001 and 2016 were identified from UK national databases. The effects of patient variables, centre volume and time period upon 90 day mortality were studied. RESULTS: 90 day mortality (970/14,935, 6.5%) was related to advanced age, comorbidity, diagnosis, ethnicity, deprivation, centre volume and time period. Mortality rates fell markedly from 10.0% in 2001-4 to 4.1% in 2013-16. There was no difference in 90 day mortality between high (36 -60 PD per year) and very high volume (>60) centres. However, patients operated upon at very high volume centres were more elderly (66, 58 -73 vs 65, 56 -72; median, IQR; p = 0.006), deprived (38.7 vs 34.6%; p < 0.001) and co morbid (48.9 vs 46.1%; p = 0.027). CONCLUSION: Although a plateau in the centre volume and mortality relationship appears to have been demonstrated those patients treated at the highest volume centres were at higher risk of mortality. This data suggests therefore that to further understand outcomes from specialist centres characteristics of the patient population should be defined, not just centre volume.
Assuntos
Hospitais com Alto Volume de Atendimentos/tendências , Hospitais com Baixo Volume de Atendimentos/tendências , Pancreaticoduodenectomia/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Inglaterra/epidemiologia , Feminino , Mortalidade Hospitalar/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Multiple myeloma (MM), an incurable plasma cell malignancy, requires localisation within the bone marrow. This microenvironment facilitates crucial interactions between the cancer cells and stromal cell types that permit the tumour to survive and proliferate. There is increasing evidence that the bone marrow mesenchymal stem cell (BMMSC) is stably altered in patients with MM-a phenotype also postulated to exist in patients with monoclonal gammopathy of undetermined significance (MGUS) a benign condition that precedes MM. In this study, we describe a mechanism by which increased expression of peptidyl arginine deiminase 2 (PADI2) by BMMSCs in patients with MGUS and MM directly alters malignant plasma cell phenotype. We identify PADI2 as one of the most highly upregulated transcripts in BMMSCs from both MGUS and MM patients, and that through its enzymatic deimination of histone H3 arginine 26, PADI2 activity directly induces the upregulation of interleukin-6 expression. This leads to the acquisition of resistance to the chemotherapeutic agent, bortezomib, by malignant plasma cells. We therefore describe a novel mechanism by which BMMSC dysfunction in patients with MGUS and MM directly leads to pro-malignancy signalling through the citrullination of histone H3R26.
Assuntos
Histonas/metabolismo , Interleucina-6/metabolismo , Células-Tronco Mesenquimais/metabolismo , Gamopatia Monoclonal de Significância Indeterminada/metabolismo , Mieloma Múltiplo/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/genética , Células Cultivadas , Análise por Conglomerados , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/genética , Modelos Biológicos , Gamopatia Monoclonal de Significância Indeterminada/tratamento farmacológico , Gamopatia Monoclonal de Significância Indeterminada/genética , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , TranscriptomaAssuntos
Biomarcadores Tumorais/análise , Medula Óssea/metabolismo , Gamopatia Monoclonal de Significância Indeterminada/metabolismo , Mieloma Múltiplo/metabolismo , Medula Óssea/patologia , Humanos , Espectroscopia de Ressonância Magnética , Metaboloma , Gamopatia Monoclonal de Significância Indeterminada/patologia , Análise de Componente PrincipalRESUMO
Cytomegalovirus (CMV) usually causes lifelong asymptomatic infection, but over time can distort immune profiles. Recent reports describe selective expansion of Vδ2(neg) γδ T cells in healthy and immunocompromised CMV carriers. Having shown previously that virus-specific CD8(+) and CD4(+) T cell responses are increased significantly in elderly CMV carriers, probably driven by chronic stimulation, we hypothesized that Vδ2(neg) γδ T cells may also be expanded with age. Our results show that Vδ2(neg) γδ T cells are increased significantly in CMV-seropositive healthy individuals compared to CMV-seronegative controls in all age groups. The differences were most significant in older age groups (P < 0·0001). Furthermore, while Vδ2(neg) γδ T- cells comprise both naive and memory cells in CMV-seronegative donors, highly differentiated effector memory cells are the dominant phenotype in CMV carriers, with naive cells reduced significantly in numbers in CMV-seropositive elderly. Although phenotypically resembling conventional CMV-specific T cells, Vδ2(neg) γδ T cells do not correlate with changes in magnitude of CMV-specific CD4(+) or CD8(+) T cell frequencies within those individuals, and do not possess ex-vivo immediate effector function as shown by CMV-specific CD4(+) and CD8(+) T cells. However, after short-term culture, Vδ2(neg) γδ T cells demonstrate effector T cell functions, suggesting additional requirements for activation. In summary, Vδ2(neg) γδ T cells are expanded in many older CMV carriers, demonstrating a further level of lymphocyte subset skewing by CMV in healthy individuals. As others have reported shared reactivity of Vδ2(neg) γδ T cells towards tumour cells, the composition of γδ T cell subsets may also have implications for risk of developing cancer in elderly people.
Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Infecções por Citomegalovirus/virologia , Epitopos de Linfócito T/imunologia , Humanos , Memória Imunológica , Imunofenotipagem , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
Advanced chronic lymphocytic leukaemia (CLL) is associated with profound immunodeficiency, including changes in T regulatory cells (T(regs)). We determined the pattern of expression of forkhead box P3 (FoxP3), CD25, CD27 and CD127 and showed that the frequency of CD4+ FoxP3+ T cells was increased in CLL patients (12% versus 8% in controls). This increase was seen only in advanced disease, with selective expansion of FoxP3-expressing cells in the CD4+ CD25(low) population, whereas the number of CD4+ CD25(high) FoxP3+ cells was unchanged. CD4+ CD25(low) cells showed reduced expression of CD127 and increased CD27, and this regulatory phenotype was also seen on all CD4 T cells subsets in CLL patients, irrespective of CD25 or FoxP3 expression. Incubation of CD4+ T cells with primary CLL tumours led to a sixfold increase in the expression of FoxP3 in CD4+ CD25- T cells. Patients undergoing treatment with fludarabine demonstrated a transient increase in the percentage of CD4+ FoxP3+ T cells, but this reduced to normal levels post-treatment. This work demonstrates that patients with CLL exhibit a systemic T cell dysregulation leading to the accumulation of CD4+ FoxP3+ T cells. This appears to be driven by interaction with malignant cells, and increased understanding of the mechanisms that are involved could provide novel avenues for treatment.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Fatores de Transcrição Forkhead/biossíntese , Leucemia Linfocítica Crônica de Células B/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Técnicas de Cocultura , Citometria de Fluxo , Humanos , Imunomodulação , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Subunidade alfa de Receptor de Interleucina-7/biossíntese , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Contagem de Linfócitos , Pessoa de Meia-Idade , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/biossíntese , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
Reactivation of CMV is a common complication following allogeneic haematopoietic SCT and is associated with significant morbidity and mortality. The relative importance of the CD4+ and CD8+ components of the CMV-specific immune response in protection from reactivation is unclear. The CMV-specific CD4+ and CD8+ immune response was measured at serial time points in 32 patients following allogeneic HSCT. Intracellular cytokine staining following CMV lysate stimulation and HLA-peptide tetramers were used to determine CMV-specific CD4+ and CD8+ responses, respectively. A deficient CMV-specific CD4+ T-cell immune response within the first 30-50 days post transplant was associated with high risk of viral reactivation. Patients with combined impairment of the CD4+ and CD8+ immune response within the first 100 days were susceptible to late viral reactivation. The frequency of CMV-specific CD4+ T cells correlated with CMV-specific CD8+ T cells, comprising 10% of the whole T-cell repertoire. Early CMV-specific CD4+ T-cell reconstitution was dominated by effector memory cells with normal levels of IL-2 resuming 6 months following transplantation. In summary, both CD4 and CD8 CMV-specific immune reconstitution is required for protection from recurrent activation. Measurement of the magnitude of the CMV-specific CD4+ immune response is useful in managing viral reactivation following HSCT.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Transplante de Células-Tronco Hematopoéticas , Memória Imunológica/imunologia , Adulto , Idoso , Anticorpos Monoclonais/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Homólogo , Adulto JovemRESUMO
There is increasing evidence that both circulating cells and free fetal DNA persist in the maternal circulation after delivery of the fetus. In some cases, this has been described many years after the end of the pregnancy. This article reviews the evidence for these cells being present, the potential methodologies used to identify such cells and the potential effects on maternal immunomodulation. Data relating to the potential beneficial and potentially harmful effects are discussed.
Assuntos
Quimerismo , Feto/citologia , Troca Materno-Fetal/fisiologia , Mães , DNA/análise , Feminino , Humanos , Masculino , GravidezRESUMO
We used SEREX technology to identify novel tumour-associated antigens in patients with primary hepatocellular carcinoma and found serological responses to the polycomb group (PcG) protein BMI-1, which is overexpressed in a range of different tumour types. Further studies identified T-cell responses to both BMI-1 and another PcG protein, EZH2, in cancer patients and at relatively lower levels in some normal donors. We next identified several CD8+ T-cell epitopes derived from BMI-1 and EZH2 and demonstrated that EZH2-derived peptides elicited more significant interferon-gamma (IFN-gamma) release than BMI-1-derived peptides. That CD8(+) T cells were responsible for the observed responses was confirmed for EZH2 by both IFN-gamma capture assays and tetramer staining using an HLA-A0201-restricted, EZH2-derived YMSCSFLFNL (aa 666-674) epitope. The ability of YMSCSFLFNL (aa 666-674) to stimulate the in vitro expansion of specific T cells from peripheral blood lymphocytes was greatly enhanced when the CD25(+) T-cell population was depleted. EZH2-specific cytotoxic T lymphocyte clones specific for two HLA-A0201 epitopes were generated and found to recognise endogenously processed EZH2 in both HLA-matched fibroblasts and tumour cell lines. Given the widespread overexpression of PcG proteins in cancer and their critical role in oncogenesis, these data suggest that they may be useful targets for cancer immunotherapy.
Assuntos
Proteínas de Ligação a DNA/genética , Neoplasias/patologia , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Fatores de Transcrição/genética , Sequência de Aminoácidos , Antígenos de Neoplasias/análise , Antígenos de Neoplasias/genética , Linhagem Celular Tumoral , Células Cultivadas , Citotoxicidade Imunológica/imunologia , Proteínas de Ligação a DNA/análise , Proteína Potenciadora do Homólogo 2 de Zeste , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Interferon gama/biossíntese , Subunidade alfa de Receptor de Interleucina-2/análise , Leucócitos Mononucleares/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Proteínas Nucleares/análise , Complexo Repressor Polycomb 1 , Complexo Repressor Polycomb 2 , Proteínas Proto-Oncogênicas/análise , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Transcrição/análiseRESUMO
Ageing is associated with evidence of immune deficiency and dysregulation. Key changes in the immune system with ageing include a progressive reduction in naive T cell output associated with thymic involution and peripheral expansion of oligoclonal memory T cells. These features are associated with evidence of impaired immune responsiveness both in vitro and in vivo, termed immune senescence. CD4+ CD25+ T cells have recently been recognized as mediators of peripheral immune regulation and play a role in the control of autoimmune and pathogen-specific immune responses. The significance of CD4+ CD25+ regulatory T cells in the context of immunosenescence is not known. We have investigated the number, phenotype and function of CD4+ CD25+ T cells in healthy volunteers over a wide age range. We demonstrate that the number of CD4+ CD25+ and CD4+ CD25high T cells in healthy volunteers increases with age. In both age groups CD4+ CD25+ T cells showed a phenotype consistent with that described for regulatory T cells. Further analysis of CD4+ CD25high T cells in young and elderly donors showed equivalent expression of intracellular CTLA-4 and surface expression of activation markers. In vitro, functional titration assays of CD4+ CD25high T cells demonstrated equivalent regulatory function in both young and elderly donors, with suppression of proliferation and cytokine production in response to polyclonal T cell stimulation. These observations demonstrate an increase in peripheral blood CD4+ CD25high regulatory T cells associated with ageing. The relevance of these expanded cells in relation to the immune senescence seen in the elderly as yet remains unclear.
Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Receptores de Interleucina-2/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD , Antígenos de Diferenciação/imunologia , Biomarcadores/análise , Antígeno CTLA-4 , Divisão Celular/imunologia , Citocinas/imunologia , Humanos , Imunofenotipagem/métodos , Imunossupressores/imunologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos/métodos , Pessoa de Meia-IdadeRESUMO
Viral infections remain a major problem for the patient who has undergone a stem cell transplant and the introduction of increasingly more intensive SCT regimens suggests that this will remain a significant concern for the immediate future. Advances in basic immunology have led to an improved understanding of how immune responses control individual viral infections and this information is now being directly applied to patient care with encouraging results. The application of cellular immunotherapy to the immunocompromised patient is one of the most exciting areas of clinical medicine and offers the prospect of significant clinical impact.
Assuntos
Imunoterapia Adotiva , Transplante de Células-Tronco , Viroses/terapia , Animais , Citocinas/metabolismo , Citomegalovirus/imunologia , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/terapia , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/terapia , Antígenos HLA/imunologia , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/fisiologia , Humanos , Hospedeiro Imunocomprometido , Transfusão de Leucócitos , Depleção Linfocítica/efeitos adversos , Camundongos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/transplante , Ativação Viral , Viroses/imunologiaRESUMO
Killer-cell immunoglobulin-like receptors (KIRs) can inhibit the killing activity of natural killer (NK) cells if they interact with their ligand, class I HLA. Using a modified polymerase chain reaction-sequence-specific primers (PCR-SSP) method for typing KIRs using genomic DNA, we compared KIR frequencies in three ethnic populations drawn from UK blood donors. We found a significantly lower frequency of the inhibitory KIRs KIR2DS1 and 3DS1 in Afro-Caribbean blood donors. Despite this, there was a (non-significant) increase in the B haplotype in Afro-Caribbean and Indian Asian donors. Some donors from each group tested negative for all non-inhibitory KIRs. In addition, we describe several new KIR profiles. Analysis of linkage disequilibrium was consistent with previously published findings.
Assuntos
Etnicidade , Frequência do Gene , Receptores Imunológicos/genética , Doadores de Sangue , Humanos , Índia , Desequilíbrio de Ligação , Receptores KIR , Receptores KIR2DL1 , Receptores KIR3DS1 , Reprodutibilidade dos Testes , Reino Unido/etnologia , População Branca/genéticaRESUMO
Patients with the autosomal recessive disorder ataxia telangiectasia (A-T) show the biallelic inactivation of the ataxia telangiectasia mutated (ATM) gene. A-T patients exhibit a predisposition to the development of a wide range of lymphoid tumours, suggesting that the ATM protein normally plays an important role in the prevention of both T and B cell malignancies. The ATM protein is a 370 kDa protein kinase implicated in the integration of different cellular responses to particular forms of DNA damage. Several recent studies have reported the possibility that the ATM gene can act as a tumour suppressor gene in non A-T individuals. Frequent ATM inactivation was confirmed in three sporadic lymphoid tumours of mature phenotype: T cell prolymphocytic leukaemia (T-PLL), B-cell chronic lymphocytic leukaemia (B-CLL) and mantle cell lymphoma (MCL). Here, we provide a summary of the published ATM mutations in sporadic lymphoid tumours, including our own study on the role of ATM mutations in the pathogenesis of sporadic B-CLL. The published results suggest possible differences in the origin, the nature and distribution of ATM mutations between sporadic B-CLL, MCL and T-PLL. While ATM mutations in mature B cell tumours (B-CLL and MCL) represent a mixture of missense and truncating errors distributed across the whole of the ATM coding sequence, mutations in sporadic T-PLL appear to be predominantly missense, clustering in the region encoding the PI-3 kinase catalytic domain of the protein. The reason for this difference is unclear, but the difference itself supports the notion that the pathogenesis of B and T cell tumours on an ATM deficient background might be different. In addition, in both B-CLL and MCL ATM mutation carriers have been reported, raising the possibility that ATM mutation carriers may have an increased risk of developing these tumours. The existence as well as magnitude of the risk, however, remains to be established. Furthermore, our own studies indicate that the presence of ATM mutations in sporadic B-CLL causes a distinctive defect in response to DNA damaging agents, offering a possible explanation for the poor response of ATM mutant tumours to standard treatment. Therefore, one of the future challenges will be to devise strategies to bypass the existing defect in response to DNA damage and activate apoptosis in ATM mutant sporadic lymphoid tumours.
Assuntos
Leucemia Linfocítica Crônica de Células B/genética , Leucemia Prolinfocítica/genética , Leucemia de Células T/genética , Linfoma de Célula do Manto/genética , Mutação , Proteínas Serina-Treonina Quinases/genética , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular , Proteínas de Ligação a DNA , Humanos , Fenótipo , Proteínas Supressoras de TumorRESUMO
The pathogenesis of pediatric B-precursor acute lymphoblastic leukemia is largely unknown, and even with nonrandom chromosomal translocations present, the precise order of clonal molecular events is undefined. We developed an in vitro system using cytokines interleukin (IL)-3, IL-7, IL-10, and FMS-like tyrosine kinase 3 ligand with CD40 ligand-expressing fibroblasts to obtain single blast colonies from which clonal immunoglobulin heavy chain (IgH), T-cell receptor delta gene rearrangements, and, in t(12;21)-positive cases, TEL-AML1 fusion transcripts could be simultaneously PCR amplified. The proliferation of early tumor progenitors increased subclone detection enabling us, in seven diagnostic samples, to determine the stage of differentiation at which each leukemia occurred. Four were derived from the stage before initiation of IgH rearrangement, one during recombination of variable, joining, and diversity segments of the heavy chain gene VDJ(H), and two after completion of IgH rearrangement. Furthermore, analysis of a t(12;21)-positive leukemia with unusually late onset, identified both TEL-AML1-positive and -negative colonies carrying a clonal T-cell receptor delta rearrangement, inferring the presence of clonal expansion before the occurrence of the t(12;21). In contrast, in a typical, early onset t(12;21)-positive leukemia, the t(12;21) appeared to be the first clonal event. In both leukemias, the t(12;21) occurred before recombination of variable, joining and diversity segments of the heavy chain gene VDJ.
Assuntos
Cromossomos Humanos Par 12 , Cromossomos Humanos Par 21 , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Linfócitos B/patologia , Diferenciação Celular/fisiologia , Divisão Celular/fisiologia , Rearranjo Gênico de Cadeia Pesada de Linfócito B , Rearranjo Gênico da Cadeia delta dos Receptores de Antígenos dos Linfócitos T , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
Cytomegalovirus (CMV) reactivation and disease remains an important clinical problem for patients after allogeneic stem cell transplantation. Impaired cellular immune control of viral replication is responsible for viral reactivation, and transfer of CMV-specific T cells from transplant donors can be effective in providing protection. Recent reports have indicated that the frequency of CMV-specific CD8(+) T cells in the peripheral blood of healthy donors is surprisingly high. Here we demonstrate that by using a combination of human leucocyte antigen (HLA) Class I-peptide tetramers and magnetic selection it is possible to select CMV-specific T cells from CMV antibody-positive individuals to high purity. Reliable purification of CMV-specific T cells up to 99.8% of CD8(+) cells was possible within hours, even when starting with a precursor frequency of < 0.1% of peripheral blood CD8(+) T cells. CMV-specific T cells remained functional after the selection process. This novel form of antigen-specific T-cell selection should facilitate the selection of T cells for cellular immunotherapy to treat or prevent CMV disease after transplantation. In addition, this technique could potentially be applied to many antigens including against other infective agents and tumour-specific antigens.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Antígenos HLA/imunologia , Transferência Adotiva , Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , Humanos , Epitopos Imunodominantes/imunologia , Separação Imunomagnética/métodos , Interferon gama/biossíntese , Fragmentos de Peptídeos/imunologiaRESUMO
We have shown that the dominance of CD8+ T cells expressing TCR Vbeta17 in the adult HLA-A*0201-restricted influenza A/M1(58-66)-specific response is acquired following first antigen exposure. Despite the acquired dominance of Vbeta17+ cells, subdominant M1(58-66)-specific clones expressing non-Vbeta17+ TCR persist in all individuals. To determine whether the affinity of the expressed TCR for the HLA-A*0201/M1(58-66) complex could influence functional properties, M1(58-66)-specific clones expressing subdominant (non-Vbeta17+) TCR were compared to cytotoxic T lymphocyte (CTL) clones expressing dominant (Vbeta17+) TCR. The Vbeta17+ CTL required up to 10,000-fold lower amounts of M1 peptide to mediate lysis compared to CTL clones expressing other Vbeta gene segments. All Vbeta17+ CTL clones tested bound HLA-A*0201/M1(58-66) tetramer, but two of three CTL clones expressing other TCR did not bind tetramer. The inability of non-Vbeta17+ CTL to bind tetramer did not correlate with phenotype, CD8 dependence or with cytokine production profiles. This suggests a limitation for the use of tetramers in examining subdominant T cell responses. Together these findings suggest that Vbeta17+ CTL which dominate the HLA-A*0201-restricted CTL response against influenza A are not functionally distinct from subdominant non-Vbeta17+ CTL. The dominance of Vbeta17+ CTL is likely to result from a competitive advantage due to superior CTL avidity for the HLA-A*0201/M1(58-66) complex.
Assuntos
Vírus da Influenza A/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T Citotóxicos/imunologia , Adulto , Células Clonais , Antígenos HLA-A/metabolismo , Humanos , Peptídeos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/virologia , Proteínas da Matriz Viral/imunologiaAssuntos
Genes Codificadores dos Receptores de Linfócitos T , Terapia Genética , Modelos Imunológicos , Neoplasias/imunologia , Proteínas Nucleares , Linfócitos T Citotóxicos/imunologia , Animais , Vetores Genéticos , Humanos , Imunoterapia Adotiva , Camundongos , Neoplasias/terapia , Proteínas Proto-Oncogênicas/imunologia , Proteínas Proto-Oncogênicas c-mdm2 , Retroviridae/genética , Transdução Genética , Viroses/terapiaRESUMO
Using HLA class I-viral epitope tetramers to monitor herpes virus-specific CD8(+) T cell responses in humans, we have shown that a significant fraction of responding cells revert from a CD45RO(+) to a CD45RA(+) state after priming. All tetramer-binding CD45RA(+) cells, regardless of epitope specificity, expressed a phenotype LFA-1(high)CCR7(low) that was stable for at least 10 years in infectious mononucleosis patients and indefinitely in asymptomatic carriers. CD8(+)CD45RA(+)LFA-1(high) cells were not present in cord blood but in adults account for up to 50% of CD8(+)CD45RA(+) cells. These CD45RA(+)LFA-1(high) cells have significantly shorter telomeres than CD45RA(+)LFA-1(low) cells, suggesting that the latter represent a naive population, while the former are memory cells. CD45RA(+) memory cells are a stable population of noncycling cells, but on stimulation they are potent producers of IFN-gamma, while naive CD8(+) cells produce only IL-2. The chemokine receptor profile and migratory potential of CD45RA(+) memory cells is very similar to CD45RO(+) cells but different to naive CD8 cells. In accord with this, CD45RA(+) memory cells were significantly underrepresented in lymph nodes, but account for virtually all CD8(+)CD45RA(+) T cells in peripheral tissues of the same individuals.
Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Movimento Celular/imunologia , Memória Imunológica , Imunofenotipagem , Antígenos Comuns de Leucócito/biossíntese , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Apoptose/imunologia , Linfócitos T CD8-Positivos/metabolismo , Divisão Celular/imunologia , Quimiotaxia de Leucócito/imunologia , Epitopos de Linfócito T/metabolismo , Antígeno HLA-A2/metabolismo , Antígeno HLA-B8/metabolismo , Humanos , Interfase/imunologia , Antígeno-1 Associado à Função Linfocitária/biossíntese , Especificidade de Órgãos/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Receptores CCR5/biossíntese , Receptores CCR7 , Receptores de Quimiocinas/biossíntese , Subpopulações de Linfócitos T/metabolismoRESUMO
Cytomegalovirus (CMV) remains an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT), but cytotoxic T lymphocytes (CTL) may play a critical role in controlling CMV reactivation. Fluorescent HLA-peptide tetramers containing immunodominant peptides from CMV were used to prospectively monitor the recovery of CMV CTL in recipients of allogeneic transplants from siblings (n = 13) or unrelated donors (n = 11). In patients given allografts from a sibling when both the patient and donor were seropositive for CMV before SCT, recovery of CMV-specific CTL was rapid and reached up to 21% of all CD8(+) T cells. Early reconstitution of CMV-specific immunity was not observed if either the donor or recipient was seronegative for CMV. In recipients of transplants from volunteer unrelated donors, recovery of CMV-specific CTL was delayed in comparison to that in recipients of transplants from siblings and no CTL were observed within the first 100 days after SCT. CTL numbers were increased after episodes of CMV reactivation but were suppressed by prednisolone therapy. Recovery of CMV-specific CTL to levels greater than 10 x 10(6)/L was associated with protection from CMV disease. It was concluded that use of HLA-peptide tetramers to quantify CMV CTL is valuable for studying T-cell responses after allogeneic SCT. It should allow prediction of CMV reactivation in individual patients and assist in the development of adoptive T-cell immunotherapy.