RESUMEN
Relapse after allogeneic hematopoietic cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) entering HCT with poor-risk features1-3. When HCT does produce prolonged relapse-free survival, it commonly reflects graft-versus-leukemia effects mediated by donor T cells reactive with antigens on leukemic cells4. As graft T cells have not been selected for leukemia specificity and frequently recognize proteins expressed by many normal host tissues, graft-versus-leukemia effects are often accompanied by morbidity and mortality from graft-versus-host disease5. Thus, AML relapse risk might be more effectively reduced with T cells expressing receptors (TCRs) that target selected AML antigens6. We therefore isolated a high-affinity Wilms' Tumor Antigen 1-specific TCR (TCRC4) from HLA-A2+ normal donor repertoires, inserted TCRC4 into Epstein-Bar virus-specific donor CD8+ T cells (TTCR-C4) to minimize graft-versus-host disease risk and enhance transferred T cell survival7,8, and infused these cells prophylactically post-HCT into 12 patients ( NCT01640301 ). Relapse-free survival was 100% at a median of 44 months following infusion, while a concurrent comparative group of 88 patients with similar risk AML had 54% relapse-free survival (P = 0.002). TTCR-C4 maintained TCRC4 expression, persisted long-term and were polyfunctional. This strategy appears promising for preventing AML recurrence in individuals at increased risk of post-HCT relapse.
Asunto(s)
Genes Codificadores de los Receptores de Linfocitos T , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide Aguda/terapia , Proteínas WT1/genética , Adulto , Anciano , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia , Trasplante HomólogoRESUMEN
Background: The purpose of this study was to investigate the acute effects of a single oral administration of an essential amino acids enriched mixture (EAA) on myoelectric descriptors of fatigue and maximal force production after a resistance exercise protocol (REP). Methods: Twenty adult males (age: 27 ± 6 years; body mass: 72.7 ± 7.50 kg; height: 1.76 ± 0.06 m) were enrolled in a double-blind crossover placebo-controlled study. Subjects were randomized to receive EAA mix (0.15 g/kg BM) or a placebo (PLA) in two successive trials 7 days apart. In both trials subjects completed a REP 2 h after the ingestion of the EAA mix or PLA. Before ingestion and after REP subjects performed isometric contractions of the dominant upper limb with the elbow joint at 120 degrees: (1) two maximal voluntary contractions (MVCs) for 2-3 s; (2) at 20% MVC for 90 s; (3) at 60% MVC until exhaustion. Mean values of MVC, conduction velocity initial values (CV), fractal dimension initial values (FD), their rates of change (CV slopes, FD slopes) and the Time to perform the Task (TtT) were obtained from a multichannel surface electromyography (sEMG) recording technique. Basal blood lactate (BL) and BL after REP were measured. Results: Following REP a significant decrease of MVC was observed in PLA (P < 0.05), while no statistical differences were found in EAA between pre-REP and post-REP. After REP, although a significant increase in BL was found in both groups (P < 0.0001) a higher BL Δ% was observed in PLA compared to EAA (P < 0.05). After REP, at 60% MVC a significant increase of CV rate of change (P < 0.05) was observed in PLA but not in EAA. At the same force level TtT was longer in EAA compared to PLA, with a significant TtT Δ% between groups (P < 0.001). Conclusion: Acute EAA enriched mix administration may prevent the loss of force-generating capacity during MVC following a REP. During isometric contraction at 60% MVC after REP the EAA mix may maintain CV rate of change values with a delay in the TtT failure.
RESUMEN
Myelin presentation to T cells in the central nervous system (CNS) sustains inflammation in multiple sclerosis (MS). CD4(+) and CD8(+) T cells contribute to MS, but only cells that present myelin to CD4(+) T cells have been identified. We show that MHC class I-restricted myelin basic protein (MBP) was presented by oligodendrocytes and cross-presented by Tip-dendritic cells (DCs) during experimental autoimmune encephalomyelitis (EAE), an animal model of MS initiated by CD4(+) T cells. Tip-DCs activated naive and effector CD8(+) T cells ex vivo, and naive MBP-specific CD8(+) T cells were activated in the CNS during CD4(+) T cell-induced EAE. These results demonstrate that CD4(+) T cell-mediated CNS autoimmunity leads to determinant spreading to myelin-specific CD8(+) T cells that can directly recognize oligodendrocytes.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Reactividad Cruzada , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Proteína Básica de Mielina/inmunología , Animales , Presentación de Antígeno , Autoinmunidad/inmunología , Antígeno CD11c/metabolismo , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular , Sistema Nervioso Central/inmunología , Epítopos/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C3H , Ratones Transgénicos , Monocitos/citología , Monocitos/metabolismo , Esclerosis Múltiple/inmunología , Oligodendroglía/inmunologíaRESUMEN
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by inflammatory, demyelinating lesions localized in the brain and spinal cord. Experimental autoimmune encephalomyelitis (EAE) is an animal model of MS that is induced by activating myelin-specific T cells and exhibits immune cell infiltrates in the CNS similar to those seen in MS. Both MS and EAE exhibit disease heterogeneity, reflecting variations in clinical course and localization of lesions within the CNS. Collectively, the differences seen in MS and EAE suggest that the brain and spinal cord function as unique microenvironments that respond differently to infiltrating immune cells. This review addresses the roles of the cytokines interferon-γ and interleukin-17 in determining the localization of inflammation to the brain or spinal cord in EAE.
Asunto(s)
Autoinmunidad , Sistema Nervioso Central/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Inflamación/inmunología , Animales , Encéfalo/inmunología , Encéfalo/patología , Linfocitos T CD4-Positivos/inmunología , Microambiente Celular , Citocinas/inmunología , Humanos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Transducción de Señal , Médula Espinal/inmunología , Médula Espinal/patología , Células TH1/inmunología , Células Th17/inmunologíaRESUMEN
The regulatory T (Treg) cells restrain immune responses through suppressor-function elaboration that is dependent upon expression of the transcription factor Foxp3. Despite a critical role for Treg cells in maintaining lympho-myeloid homeostasis, it remains unclear whether a single mechanism or multiple mechanisms of Treg cell-mediated suppression are operating in vivo and how redundant such mechanisms might be. Here we addressed these questions by examining the role of the immunomodulatory cytokine IL-10 in Treg cell-mediated suppression. Analyses of mice in which the Treg cell-specific ablation of a conditional IL-10 allele was induced by Cre recombinase knocked into the Foxp3 gene locus showed that although IL-10 production by Treg cells was not required for the control of systemic autoimmunity, it was essential for keeping immune responses in check at environmental interfaces such as the colon and lungs. Our study suggests that Treg cells utilize multiple means to limit immune responses. Furthermore, these mechanisms are likely to be nonredundant, in that a distinct suppressor mechanism most likely plays a prominent and identifiable role at a particular tissue and inflammatory setting.
Asunto(s)
Mediadores de Inflamación/fisiología , Interleucina-10/fisiología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Animales , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/prevención & control , Colitis/genética , Colitis/inmunología , Colitis/prevención & control , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/fisiología , Mediadores de Inflamación/metabolismo , Integrasas/genética , Interleucina-10/deficiencia , Interleucina-10/genética , Proteínas Luminiscentes/genética , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Piel/inmunología , Piel/metabolismo , Piel/patología , Linfocitos T Reguladores/patologíaRESUMEN
Human ICOS is a T cell costimulatory molecule supporting IL10 secretion. A pilot study investigating variations of the ICOS gene 3'UTR detected 8 polymorphisms forming three haplotypes (A, B, C). Haplotype-A and -C displayed the highest difference. Activated T cells from healthy AA homozygotes expressed significantly less ICOS and secreted more IL10 than AC heterozygotes, whereas AB heterozygotes displayed intermediate levels. Analysis of 441 multiple sclerosis patients and 793 controls showed that frequency of AA homozygosity was significantly lower in MS patients with relapsing-remitting onset (N=416) than in controls (OR=0.70). Moreover, AA patients with relapsing-remitting onset had lower relapse rate and multiple sclerosis severity score than non-AA patients.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/genética , Predisposición Genética a la Enfermedad , Haplotipos/genética , Interleucina-10/metabolismo , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Regiones no Traducidas 3'/genética , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles , Leucocitos Mononucleares/metabolismo , Desequilibrio de Ligamiento , Masculino , Estadísticas no ParamétricasRESUMEN
Arachidonic acid metabolites, the eicosanoids, are key mediators of allergen-induced airway inflammation and remodeling in asthma. The availability of free arachidonate in cells for subsequent eicosanoid biosynthesis is controlled by phospholipase A(2)s (PLA(2)s), most notably cytosolic PLA(2)-alpha. 10 secreted PLA(2)s (sPLA(2)s) have also been identified, but their function in eicosanoid generation is poorly understood. We investigated the role of group X sPLA(2) (sPLA(2)-X), the sPLA(2) with the highest in vitro cellular phospholipolysis activity, in acute and chronic mouse asthma models in vivo. The lungs of sPLA(2)-X(-/-) mice, compared with those of sPLA(2)-X(+/+) littermates, had significant reduction in ovalbumin-induced infiltration by CD4(+) and CD8(+) T cells and eosinophils, goblet cell metaplasia, smooth muscle cell layer thickening, subepithelial fibrosis, and levels of T helper type 2 cell cytokines and eicosanoids. These data direct attention to sPLA(2)-X as a novel therapeutic target for asthma.
Asunto(s)
Alérgenos/inmunología , Asma/enzimología , Asma/inmunología , Modelos Animales de Enfermedad , Fosfolipasas A/metabolismo , Animales , Asma/genética , Asma/patología , Citocinas/metabolismo , Eicosanoides/metabolismo , Regulación Enzimológica de la Expresión Génica , Fosfolipasas A2 Grupo X , Inflamación/enzimología , Inflamación/genética , Inflamación/inmunología , Metaplasia/enzimología , Metaplasia/patología , Ratones , Ratones Noqueados , Fosfolipasas A/deficiencia , Fosfolipasas A/genética , Fosfolipasas A2 , Células Th2/enzimologíaRESUMEN
Several sets of data indicate that ICOS regulates cytokine production in activated T cells, but is less effective on naïve T cells. This work evaluates ICOS function in human naïve CD4+ T cells through an assessment of the effect of soluble forms of the ICOS and CD28 physiological ligands on activation driven by anti-CD3 mAb. ICOS strikingly potentiated secretion of IL-2, IFN-gamma, IL-10, and TNF-alpha, but not IL-4, promoted by optimal stimulation of CD3+CD28, and it was the key switching-factor of activation when cells received suboptimal stimulation of CD3+CD28 or stimulation of CD3 alone in the presence of exogenous IL-2. In these conditions, blockade of IL-2 and IFN-gamma showed that ICOS builds up a positive feedback loop with IFN-gamma, which required IL-2 and was inhibited by IL-4. By contrast, in the absence of CD28 triggering or exogenous IL-2, ICOS-induced costimulation mainly supported expression of TGF-beta1 and FoxP3 and differentiation of regulatory T cells capable to inhibit proliferation of naïve CD4+ T cells driven by allogeneic cells. These data suggest that ICOS favors differentiation of Th effector cells when cooperates with appropriate activation stimuli such as CD3+CD28 or CD3+IL-2, whereas it supports differentiation of regulatory T cells when costimulatory signals are insufficient.
Asunto(s)
Antígenos de Diferenciación de Linfocitos T/inmunología , Antígenos CD28/inmunología , Linfocitos T CD4-Positivos/inmunología , Citocinas/biosíntesis , Activación de Linfocitos/inmunología , Western Blotting , Linfocitos T CD4-Positivos/citología , Diferenciación Celular/inmunología , Técnica del Anticuerpo Fluorescente , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles , Interferón gamma/biosíntesis , Interleucina-2/biosíntesisRESUMEN
The Fas death receptor is expressed by activated lymphocytes and is involved in switching-off the immune response. Its inherited defects cause auto-immune lymphoproliferative syndrome. Impaired Fas function may also play a role in other auto-immune diseases, such as multiple sclerosis and type 1 diabetes mellitus. The aim of this work was to evaluate Fas function in T cells from patients with chronic inflammatory demyelinating polyneuropathy (CIDP). We evaluated Fas-induced apoptosis in T-cell lines from 27 patients with CIDP, 12 patients with acute inflammatory demyelinating polyneuropathy (AIDP), and 110 controls. CIDP patients displayed lower Fas function than both AIDP patients and controls, whereas no statistically significant difference was found between AIDP patients and controls. Moreover, Fas function was lower in CIDP patients with progressive course than in those with relapsing-remitting course and lower in CIDP patients with axonal damage than in those with pure demyelination. These data suggest that defective Fas function favours CIDP development and aggressive evolution.
Asunto(s)
Apoptosis/fisiología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/inmunología , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/fisiopatología , Receptores del Factor de Necrosis Tumoral/metabolismo , Linfocitos T/patología , Adulto , Anciano , Western Blotting , Caspasa 8 , Caspasa 9 , Caspasas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/metabolismo , Linfocitos T/inmunología , Receptor fasRESUMEN
P-selectin glycoprotein ligand-1 (PSGL-1) is an important adhesion molecule involved in lymphocyte recruitment into the brain, which represents a crucial step in the pathogenesis of multiple sclerosis (MS). Three hundred twenty-one MS patients and 342 controls were genotyped for the presence of a polymorphism in the PSGL-1 gene, consisting of a variable number of tandem repeats (VNTR) originating three possible alleles: A, B and C, in order to test whether they influence the susceptibility and the course of the disease. No significant differences among allelic frequencies of A, B and C alleles in MS as compared with controls were observed. Stratifying patients according to the course of the disease, a significantly increased frequency of the shortest C allele in PP-MS was found (7.1%), either in comparison with controls (P=0.011) or with all other MS patients, who had acute inflammatory attacks at onset and an initial RR form (P=0.036). Besides, none of SP-MS patients was a carrier of the C allele and B carriers converted later from RR to SP course as compared with A/A subjects (after 15.8 rather than 8.8 years, P=0.01). In conclusion, the C allele of the VNTR polymorphism in PSGL-1 is likely to be associated with PP-MS. As this allele has been demonstrated to have a very low efficiency in mediating lymphocyte binding to brain endothelium during attacks, its high frequency in PP-MS could be related to the absence of exacerbations in such patients.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Glicoproteínas de Membrana/genética , Repeticiones de Minisatélite/genética , Esclerosis Múltiple/genética , Polimorfismo Genético/genética , Adulto , Edad de Inicio , Adhesión Celular/genética , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Sistema Nervioso Central/fisiopatología , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes/genética , Pruebas Genéticas , Genotipo , Heterocigoto , Humanos , Activación de Linfocitos/genética , Masculino , Esclerosis Múltiple/metabolismoRESUMEN
Osteopontin (OPN) is an inflammatory cytokine highly expressed in multiple sclerosis (MS) plaques. In a previous work, we showed that four OPN polymorphisms form three haplotypes (A, B, and C) and that homozygotes for haplotype-A display lower OPN levels than non-AA subjects. In this work, we evaluated the distribution of these OPN haplotypes in 425 MS patients and 688 controls. Haplotype-A homozygotes had about 1.5 lower risk of developing MS than non-AA subjects. Clinical analysis of 288 patients showed that AA patients displayed slower switching from a relapsing remitting to a secondary progressive form and milder disease with slower evolution of disability. MS patients displayed increased OPN serum levels, which were partly due to the increased frequency of non-AA subjects. Moreover in AA patients, OPN levels were higher than in AA controls and similar to those found in both non-AA patients and controls, which suggests a role of the activated immune response. These data suggest that OPN genotypes may influence MS development and progression due to their influence on OPN levels.
Asunto(s)
Haplotipos/genética , Esclerosis Múltiple/genética , Sialoglicoproteínas/genética , Adulto , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática/estadística & datos numéricos , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/fisiopatología , Osteopontina , Estabilidad del ARN , ARN Mensajero/metabolismo , Índice de Severidad de la Enfermedad , Sialoglicoproteínas/sangre , Regulación hacia ArribaRESUMEN
The autoimmune/lymphoproliferative syndrome (ALPS) displays defective function of Fas, autoimmunities, lymphadenopathy/splenomegaly, and expansion of CD4/CD8 double-negative (DN) T cells. Dianzani autoimmune/lymphoproliferative disease (DALD) is an ALPS variant lacking DN cells. Both forms have been ascribed to inherited mutations hitting the Fas system but other factors may be involved. A pilot cDNA array analysis on a DALD patient detected overexpression of the cytokine osteopontin (OPN). This observation was confirmed by enzyme-linked immunosorbent assay (ELISA) detection of higher OPN serum levels in DALD patients (n = 25) than in controls (n = 50). Analysis of the OPN cDNA identified 4 polymorphisms forming 3 haplotypes (A, B, and C). Their overall distribution and genotypic combinations were different in patients (N = 26) and controls (N = 158) (P <.01). Subjects carrying haplotype B and/or C had an 8-fold higher risk of developing DALD than haplotype A homozygotes. Several data suggest that these haplotypes influence OPN levels: (1) in DALD families, high levels cosegregated with haplotype B or C; (2) in healthy controls, haplotype B or C carriers displayed higher levels than haplotype A homozygotes; and (3) in AB and AC heterozygotes, mRNA for haplotype B or C was more abundant than that for haplotype A. In vitro, exogenous OPN decreased activation-induced T-cell death, which suggests that high OPN levels are involved in the apoptosis defect.