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1.
Brain ; 146(9): 3747-3759, 2023 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-37208310

RESUMO

Molecular biomarkers for neurodegenerative diseases are critical for advancing diagnosis and therapy. Normal pressure hydrocephalus (NPH) is a neurological disorder characterized by progressive neurodegeneration, gait impairment, urinary incontinence and cognitive decline. In contrast to most other neurodegenerative disorders, NPH symptoms can be improved by the placement of a ventricular shunt that drains excess CSF. A major challenge in NPH management is the identification of patients who benefit from shunt surgery. Here, we perform genome-wide RNA sequencing of extracellular vesicles in CSF of 42 NPH patients, and we identify genes and pathways whose expression levels correlate with gait, urinary or cognitive symptom improvement after shunt surgery. We describe a machine learning algorithm trained on these gene expression profiles to predict shunt surgery response with high accuracy. The transcriptomic signatures we identified may have important implications for improving NPH diagnosis and treatment and for understanding disease aetiology.

2.
J Immunol ; 196(2): 678-90, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26643476

RESUMO

Embryos and tumors are both masses of dividing cells expressing foreign Ags, but they are not rejected by the immune system. We hypothesized that similar tolerogenic mechanisms prevent their rejection. Global comparison of fetal and tumor microenvironments through transcriptomics in mice revealed strikingly similar and dramatic decreases in expression of numerous immune-related pathways, including Ag presentation and T cell signaling. Unsupervised analyses highlighted the parallel kinetics and similarities of immune signature downregulation, from the very first days after tumor or embryo implantation. Besides upregulated signatures related to cell proliferation, the only significant signatures shared by the two conditions across all biological processes and all time points studied were downmodulated immune response signatures. Regulatory T cell depletion completely reverses this immune downmodulation to an immune upregulation that leads to fetal or tumor immune rejection. We propose that evolutionarily selected mechanisms that protect mammalian fetuses from immune attack are hijacked to license tumor development.


Assuntos
Desenvolvimento Fetal/imunologia , Tolerância Imunológica/imunologia , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Evasão Tumoral/imunologia , Animais , Feminino , Feto/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Transcriptoma
3.
Immunology ; 146(4): 657-70, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26370005

RESUMO

To further investigate the contribution of intercellular adhesion molecule-1 (ICAM-1) to adaptive immune responses, we analysed T-cell development and function in mice lacking full-length ICAM-1 (ICAM-1(tm1Jcgr) ). Compared with wild-type (ICAM-1(WT) ) mice, ICAM-1(tm1Jcgr) mice have impaired thymocyte development. Proportions and numbers of double negative, double positive, mature CD4(+) and CD8(+) thymocytes, as well as of regulatory T (Treg) cells were also significantly decreased. In the periphery, ICAM-1(tm1Jcgr) mice had significantly decreased proportions and numbers of naive and activated/memory CD4(+) and CD8(+) T cells, as well as of Treg cells, in lymph nodes but not in the spleen. In vitro activation of CD4(+) and CD8(+) T cells from ICAM-1(tm1Jcgr) mice with anti-CD3 antibodies and antigen-presenting cells (APCs) resulted in a significantly weaker proliferation, whereas proliferation induced with anti-CD3 and anti-CD28 antibody-coated beads was normal. In vivo immunization of ICAM-1(tm1Jcgr) mice resulted in normal generation of specific effector and memory immune responses that protect against a viral challenge. However, contrary to ICAM-1(WT) mice, immunization-induced specific effectors could not eradicate immunogen-expressing tumours. Treg cells from ICAM-1(tm1Jcgr) mice have abnormal activation and proliferation induced by anti-CD3 antibody and APCs, and have markedly decreased suppressive activity in vitro. In contrast to ICAM-1(WT) mice, they were unable to control experimentally induced colitis in vivo. Hence, our results further highlight the pleiotropic role of ICAM-1 in T-cell-dependent immune responses, with a major role in Treg cell development and suppressive function.


Assuntos
Membrana Celular/metabolismo , Expressão Gênica , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Cálcio/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Colite/genética , Colite/imunologia , Colite/metabolismo , Modelos Animais de Doenças , Feminino , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Timócitos/citologia , Timócitos/metabolismo
4.
J Immunol ; 191(5): 2273-81, 2013 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-23913969

RESUMO

Regulatory T cells (Tregs) play crucial roles in both fetal and tumor development. We recently showed that immunosurveillance by pre-existing CD44(high)CD62L(low) activated/memory Tregs (amTregs) specific for self-Ags protects emergent tumor cells in mice. This Treg response of a memory type is more rapid than and dominates the antitumor response of tumor-specific effector T cells. In this study, we report striking similarities between the early Treg responses to embryo and tumor implantation. Tregs are rapidly recruited to uterus-draining lymph nodes and activated in the first days after embryo implantation in both syngeneic and allogeneic matings; express the markers of the amTreg subset; and are at least in part self-Ag specific, as seen in tumor emergence. Unlike in the tumor emergence setting, however, for which preimmunization against tumor Ags is sufficient for complete tumor eradication even in the presence of Tregs, Treg depletion is additionally required for high frequencies of fetus loss after preimmunization against paternal tissue Ags. Thus, amTregs play a major role in protecting embryos in both naive and preimmune settings. This role and the ensuing therapeutic potential are further highlighted by showing that Treg stimulation, directly by low-dose IL-2 or indirectly by Fms-related tyrosine kinase 3 ligand, led to normal pregnancy rates in a spontaneous abortion-prone model.


Assuntos
Implantação do Embrião/imunologia , Embrião de Mamíferos/imunologia , Tolerância Imunológica/imunologia , Memória Imunológica/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Feminino , Citometria de Fluxo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/imunologia , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
Nature ; 459(7249): 1000-4, 2009 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-19536265

RESUMO

T-cell acute lymphoblastic leukaemia (T-ALL) is a blood malignancy afflicting mainly children and adolescents. T-ALL patients present at diagnosis with increased white cell counts and hepatosplenomegaly, and are at an increased risk of central nervous system (CNS) relapse. For that reason, T-ALL patients usually receive cranial irradiation in addition to intensified intrathecal chemotherapy. The marked increase in survival is thought to be worth the considerable side-effects associated with this therapy. Such complications include secondary tumours, neurocognitive deficits, endocrine disorders and growth impairment. Little is known about the mechanism of leukaemic cell infiltration of the CNS, despite its clinical importance. Here we show, using T-ALL animal modelling and gene-expression profiling, that the chemokine receptor CCR7 (ref. 5) is the essential adhesion signal required for the targeting of leukaemic T-cells into the CNS. Ccr7 gene expression is controlled by the activity of the T-ALL oncogene Notch1 and is expressed in human tumours carrying Notch1-activating mutations. Silencing of either CCR7 or its chemokine ligand CCL19 (ref. 6) in an animal model of T-ALL specifically inhibits CNS infiltration. Furthermore, murine CNS-targeting by human T-ALL cells depends on their ability to express CCR7. These studies identify a single chemokine-receptor interaction as a CNS 'entry' signal, and open the way for future pharmacological targeting. Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS-targeted therapy, thus reducing its associated short- and long-term complications.


Assuntos
Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Leucemia de Células T/metabolismo , Leucemia de Células T/patologia , Receptores CCR7/metabolismo , Transdução de Sinais , Animais , Adesão Celular , Linhagem Celular Tumoral , Quimiocina CCL19/deficiência , Quimiocina CCL19/metabolismo , Quimiocina CCL21/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptores CCR7/deficiência
6.
J Exp Med ; 201(10): 1677-87, 2005 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-15897281

RESUMO

Transcription factor, nuclear factor kappaB (NF-kappaB), is required for osteoclast formation in vivo and mice lacking both of the NF-kappaB p50 and p52 proteins are osteopetrotic. Here we address the relative roles of the two catalytic subunits of the IkappaB kinase (IKK) complex that mediate NF-kappaB activation, IKKalpha and IKKbeta, in osteoclast formation and inflammation-induced bone loss. Our findings point out the importance of the IKKbeta subunit as a transducer of signals from receptor activator of NF-kappaB (RANK) to NF-kappaB. Although IKKalpha is required for RANK ligand-induced osteoclast formation in vitro, it is not needed in vivo. However, IKKbeta is required for osteoclastogenesis in vitro and in vivo. IKKbeta also protects osteoclasts and their progenitors from tumor necrosis factor alpha-induced apoptosis, and its loss in hematopoietic cells prevents inflammation-induced bone loss.


Assuntos
Reabsorção Óssea/metabolismo , NF-kappa B/metabolismo , Osteoclastos/metabolismo , Precursores de Proteínas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Apoptose , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Proteínas de Transporte/metabolismo , Diferenciação Celular , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Quinase I-kappa B , Inflamação/genética , Inflamação/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Células Progenitoras Mieloides/metabolismo , NF-kappa B/genética , Subunidade p50 de NF-kappa B , Subunidade p52 de NF-kappa B , Precursores de Proteínas/genética , Proteínas Serina-Treonina Quinases/genética , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
7.
Cell Death Differ ; 25(6): 1094-1106, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29445126

RESUMO

Mice deficient in epidermal growth factor receptor (Egfr-/- mice) are growth retarded and exhibit severe bone defects that are poorly understood. Here we show that EGFR-deficient mice are osteopenic and display impaired endochondral and intramembranous ossification resulting in irregular mineralization of their bones. This phenotype is recapitulated in mice lacking EGFR exclusively in osteoblasts, but not in mice lacking EGFR in osteoclasts indicating that osteoblasts are responsible for the bone phenotype. Experiments are presented demonstrating that signaling via EGFR stimulates osteoblast proliferation and inhibits their differentiation by suppression of the IGF-1R/mTOR-pathway via ERK1/2-dependent up-regulation of IGFBP-3. Osteoblasts from Egfr-/- mice show increased levels of IGF-1R and hyperactivation of mTOR-pathway proteins, including enhanced phosphorylation of 4E-BP1 and S6. The same changes are also seen in Egfr-/- bones. Importantly, pharmacological inhibition of mTOR with rapamycin decreases osteoblasts differentiation as well as rescues the low bone mass phenotype of Egfr-/- fetuses. Our results demonstrate that suppression of the IGF-1R/mTOR-pathway by EGFR/ERK/IGFBP-3 signaling is necessary for balanced osteoblast maturation providing a mechanism for the skeletal phenotype observed in EGFR-deficient mice.


Assuntos
Desenvolvimento Ósseo , Proliferação de Células , Receptores ErbB/metabolismo , Osteoblastos/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Animais , Receptores ErbB/genética , Camundongos , Camundongos Knockout , Osteoblastos/citologia , Serina-Treonina Quinases TOR/genética
8.
Adv Exp Med Biol ; 602: 125-34, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17966397

RESUMO

Transcription factor NF-kappaB has been well recognized as a pivotal player in osteclastogenesis and inflammation-induced bone loss. Here, we discuss our recent results obtained using a genetic approach in mice that indicate the importance of IKKbeta, and not IKKalpha, as a transducer of signals from receptor activator of NF-kappaB (RANK) to NF-kappaB. Ablation of IKKbeta results in lack of osteoclastogenesis and unresponsiveness of IKKbeta-deficient mice to inflammation-induced bone loss. In the need of a more effective therapy for the treatment of inflammatory diseases causing bone resorption, specific inhibition of IKKbeta represents a logical alternative strategy to the current therapies.


Assuntos
Artrite Reumatoide/metabolismo , Quinase I-kappa B/metabolismo , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Animais , Apoptose , Artrite Reumatoide/tratamento farmacológico , Remodelação Óssea , Reabsorção Óssea , Quinase I-kappa B/antagonistas & inibidores , Camundongos , NF-kappa B/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
9.
Front Immunol ; 5: 389, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25191324

RESUMO

In this review, we first revisit the original concept of "suppressor T-cells" in pregnancy, put it in a historical perspective, and then highlight the main data that licensed its resurrection and revision into the concept of "regulatory T-cells" (Tregs) in pregnancy. We review the evidence for a major role of Tregs in murine and human pregnancy and discuss Treg interactions with dendritic and uterine natural killer cells, other players of maternal-fetal tolerance. Finally, we highlight what we consider as the most important questions in the field.

10.
J Clin Invest ; 122(10): 3718-30, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22945631

RESUMO

A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4). However, the determinants of response to anti-CTLA-4 mAb treatment remain incompletely understood. In murine models, anti-CTLA-4 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions, including local ionizing radiation (IR) therapy. We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor-infiltrating CD8+ T lymphocytes (TILs) following treatment with the anti-CTLA-4 mAb 9H10. Alone, 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo. In contrast, the combination of 9H10 and IR restored MHC class I-dependent arrest. After implantation, the carcinoma cells had reduced expression of retinoic acid early inducible-1 (RAE-1), a ligand for natural killer cell group 2D (NKG2D) receptor. We found that RAE-1 expression was induced by IR in vivo and that anti-NKG2D mAb blocked the TIL arrest induced by IR/9H10 combination therapy. These results demonstrate that anti-CTLA-4 mAb therapy induces motility of TIL and that NKG2D ligation offsets this effect to enhance TILs arrest and antitumor activity.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfócitos T CD8-Positivos/efeitos dos fármacos , Antígeno CTLA-4/antagonistas & inibidores , Imunoterapia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Neoplasias Mamárias Experimentais/terapia , Animais , Anticorpos Monoclonais/farmacologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos da radiação , Linhagem Celular Tumoral/imunologia , Linhagem Celular Tumoral/transplante , Movimento Celular , Terapia Combinada , Citotoxicidade Imunológica/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos da radiação , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos da radiação , Antígenos H-2/imunologia , Molécula 1 de Adesão Intercelular/biossíntese , Molécula 1 de Adesão Intercelular/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/efeitos da radiação , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/radioterapia , Neoplasias Mamárias Experimentais/secundário , Camundongos , Camundongos Endogâmicos BALB C , Subfamília K de Receptores Semelhantes a Lectina de Células NK/antagonistas & inibidores , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas Associadas à Matriz Nuclear/biossíntese , Proteínas Associadas à Matriz Nuclear/genética , Proteínas de Transporte Nucleocitoplasmático/biossíntese , Proteínas de Transporte Nucleocitoplasmático/genética , Receptores CXCR/genética , Receptores CXCR6 , Microambiente Tumoral/imunologia
11.
J Exp Med ; 209(10): 1723-42, S1, 2012 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-22966001

RESUMO

Foxp3 activity is essential for the normal function of the immune system. Two types of regulatory T (T reg) cells express Foxp3, thymus-generated natural T reg (nT reg) cells, and peripherally generated adaptive T reg (iT reg) cells. These cell types have complementary functions. Until now, it has not been possible to distinguish iT reg from nT reg cells in vivo based solely on surface markers. We report here that Neuropilin 1 (Nrp1) is expressed at high levels by most nT reg cells; in contrast, mucosa-generated iT reg and other noninflammatory iT reg cells express low levels of Nrp1. We found that Nrp1 expression is under the control of TGF-ß. By tracing nT reg and iT reg cells, we could establish that some tumors have a very large proportion of infiltrating iT reg cells. iT reg cells obtained from highly inflammatory environments, such as the spinal cords of mice with spontaneous autoimmune encephalomyelitis (EAE) and the lungs of mice with chronic asthma, express Nrp1. In the same animals, iT reg cells in secondary lymphoid organs remain Nrp1(low). We also determined that, in spontaneous EAE, iT reg cells help to establish a chronic phase of the disease.


Assuntos
Mucosa/imunologia , Neuropilina-1/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Timo/imunologia , Animais , Linhagem da Célula , Membrana Celular/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/imunologia , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Intestinos/microbiologia , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Metagenoma/imunologia , Camundongos , Camundongos Transgênicos , Mucosa/metabolismo , Neuropilina-1/genética , Timo/metabolismo , Fator de Crescimento Transformador beta/farmacologia
12.
Genes Dev ; 18(5): 584-94, 2004 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-15037551

RESUMO

The molecular circuitry underlying innate immunity is constructed of multiple, evolutionarily conserved signaling modules with distinct regulatory targets. The MAP kinases and the IKK-NF-kappa B molecules play important roles in the initiation of immune effector responses. We have found that the Drosophila NF-kappa B protein Relish plays a crucial role in limiting the duration of JNK activation and output in response to Gram-negative infections. Relish activation is linked to proteasomal degradation of TAK1, the upstream MAP kinase kinase kinase required for JNK activation. Degradation of TAK1 leads to a rapid termination of JNK signaling, resulting in a transient JNK-dependent response that precedes the sustained induction of Relish-dependent innate immune loci. Because the IKK-NF-kappa B module also negatively regulates JNK activation in mammals, thereby controlling inflammation-induced apoptosis, the regulatory cross-talk between the JNK and NF-kappa B pathways appears to be broadly conserved.


Assuntos
Proteínas de Drosophila/imunologia , Imunidade/genética , MAP Quinase Quinase Quinases/imunologia , Proteínas Quinases Ativadas por Mitógeno/imunologia , Fatores de Transcrição/imunologia , Animais , Linhagem Celular , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/imunologia , Endopeptidases/metabolismo , Retroalimentação Fisiológica , Regulação da Expressão Gênica/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno , Lipopolissacarídeos/farmacologia , MAP Quinase Quinase Quinases/genética , Proteínas Quinases Ativadas por Mitógeno/genética , NF-kappa B , Receptor Cross-Talk/imunologia , Transdução de Sinais/imunologia , Fatores de Transcrição/genética , Transcrição Gênica/imunologia
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