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1.
Adv Exp Med Biol ; 1164: 225-233, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576552

RESUMO

Immune checkpoint blockade (ICB) has proved successful in the immunotherapeutic treatment of various human cancers. Despite its success, most patients are still not cured while immunogenic cold cancers are still poorly responsive. There is a need for novel clinical interventions in immunotherapy, either alone or in conjunction with ICB. Here, we outline our recent discovery that the intracellular signaling kinase glycogen synthase kinase-3 (GSK-3) is a central regulator of PD-1 in T-cells. We demonstrate the application of small molecule inhibitor (SMI) approaches to down-regulate PD-1 in tumor immunotherapy. GSK-3 SMIs were found as effective as anti-PD-1 in the elimination of melanoma in mouse models. We propose the development of novel SMIs to target co-receptors for the future of immunotherapy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase , Imunoterapia , Melanoma , Animais , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Humanos , Melanoma/terapia , Camundongos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T/fisiologia
3.
Nat Biotechnol ; 37(9): 1049-1058, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31332324

RESUMO

Chimeric antigen receptor (CAR)-T-cell therapy for solid tumors is limited due to heterogeneous target antigen expression and outgrowth of tumors lacking the antigen targeted by CAR-T cells directed against single antigens. Here, we developed a bicistronic construct to drive expression of a CAR specific for EGFRvIII, a glioblastoma-specific tumor antigen, and a bispecific T-cell engager (BiTE) against EGFR, an antigen frequently overexpressed in glioblastoma but also expressed in normal tissues. CART.BiTE cells secreted EGFR-specific BiTEs that redirect CAR-T cells and recruit untransduced bystander T cells against wild-type EGFR. EGFRvIII-specific CAR-T cells were unable to completely treat tumors with heterogenous EGFRvIII expression, leading to outgrowth of EGFRvIII-negative, EGFR-positive glioblastoma. However, CART.BiTE cells eliminated heterogenous tumors in mouse models of glioblastoma. BiTE-EGFR was locally effective but was not detected systemically after intracranial delivery of CART.BiTE cells. Unlike EGFR-specific CAR-T cells, CART.BiTE cells did not result in toxicity against human skin grafts in vivo.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Antígenos de Neoplasias/imunologia , Glioblastoma/terapia , Receptores de Antígenos Quiméricos , Animais , Antígenos de Neoplasias/metabolismo , Diferenciação Celular , Receptores ErbB , Glioblastoma/imunologia , Glioblastoma/metabolismo , Humanos , Camundongos , Neoplasias Experimentais , Linfócitos T/fisiologia
4.
Nat Biotechnol ; 37(9): 1034-1037, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31359007

RESUMO

Understanding of repair outcomes after Cas9-induced DNA cleavage is still limited, especially in primary human cells. We sequence repair outcomes at 1,656 on-target genomic sites in primary human T cells and use these data to train a machine learning model, which we have called CRISPR Repair Outcome (SPROUT). SPROUT accurately predicts the length, probability and sequence of nucleotide insertions and deletions, and will facilitate design of SpCas9 guide RNAs in therapeutically important primary human cells.


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , RNA Guia/genética , Linfócitos T/fisiologia , Linhagem Celular , Regulação da Expressão Gênica , Genoma , Genômica , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia
5.
Scand J Immunol ; 90(4): e12797, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31166602

RESUMO

Distinctive "two signal" paths in immunology, taken by researchers with different academic backgrounds, seem to have both contained facets of the truth. Having been influenced by education at a medical school where Almroth Wright's early contributions were not forgotten, the author's "path less followed" led to views that began to gain recognition late in the twentieth century when the intimate relationship between innate and acquired immunity became more apparent.


Assuntos
Modelos Imunológicos , Agregação de Receptores , Linfócitos T/fisiologia , Timo/imunologia , Imunidade Adaptativa , Animais , Autoantígenos/imunologia , Autoimunidade , Consenso , Quadruplex G , Humanos , Imunidade Inata , Ativação Linfocitária , Tolerância a Antígenos Próprios
6.
Nat Commun ; 10(1): 2864, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253807

RESUMO

The T cell immune synapse is a site of intense vesicular trafficking. Here we show that the golgin GMAP210, known to capture vesicles and organize membrane traffic at the Golgi, is involved in the vesicular transport of LAT to the immune synapse. Upon activation, more GMAP210 interact with LAT-containing vesicles and go together with LAT to the immune synapse. Regulating LAT recruitment and LAT-dependent signaling, GMAP210 controls T cell activation. Using a rerouting and capture assay, we show that GMAP210 captures VAMP7-decorated vesicles. Overexpressing different domains of GMAP210, we also show that GMAP210 allows their specific delivery to the immune synapse by tethering LAT-vesicles to the Golgi. Finally, in a model of ectopic expression of LAT in ciliated cells, we show that GMAP210 tethering activity controls the delivery of LAT to the cilium. Hence, our results reveal a function for the golgin GMAP210 conveying specific vesicles to the immune synapse.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Complexo de Golgi/fisiologia , Leucócitos Mononucleares/fisiologia , Proteínas de Membrana/metabolismo , Proteínas Nucleares/metabolismo , Vesículas Transportadoras/fisiologia , Linhagem Celular , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Proteínas Nucleares/genética , Proteínas R-SNARE/genética , Proteínas R-SNARE/metabolismo , Proteínas SNARE/genética , Proteínas SNARE/metabolismo , Transdução de Sinais , Linfócitos T/fisiologia
7.
Nat Rev Cancer ; 19(7): 392-404, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31209264

RESUMO

The potential of cancer immunotherapy relies on the mobilization of immune cells capable of producing antitumour cytokines and effectively killing tumour cells. These are major attributes of γδ T cells, a lymphoid lineage that is often underestimated despite its major role in tumour immune surveillance, which has been established in a variety of preclinical cancer models. This situation notwithstanding, in particular instances the tumour microenvironment seemingly mobilizes γδ T cells with immunosuppressive or tumour-promoting functions, thus emphasizing the importance of regulating γδ T cell responses in order to realize their translation into effective cancer immunotherapies. In this Review we outline both seminal work and recent advances in our understanding of how γδ T cells participate in tumour immunity and how their functions are regulated in experimental models of cancer. We also discuss the current strategies aimed at maximizing the therapeutic potential of human γδ T cells, on the eve of their exploration in cancer clinical trials that may position them as key players in cancer immunotherapy.


Assuntos
Imunoterapia , Neoplasias/terapia , Linfócitos T/fisiologia , Microambiente Tumoral/fisiologia , Humanos , Neoplasias/etiologia , Neoplasias/patologia
9.
Iran J Allergy Asthma Immunol ; 18(2): 143-152, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31066250

RESUMO

Assessment of the number of T-cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) copies has been recently described as biomarkers of newly formed T and B cells respectively. In this study, we aimed to explore the effects of demographic variables including age, gender, weight, height and ethnicity on these two episomal DNA molecules. Second, for the first time in our country, we determined the reference values of TREC and KREC copy numbers in different age groups of Iranian healthy individuals as a threshold for identifying T cell and B cell lymphopenia. The TREC and KREC copy numbers were evaluated in 251 dried blood spot (DBS) samples from healthy volunteers (age range: 0-60 years). Six primary immunodeficiency (PID) patients were included as disease controls. TREC and KREC copies were markedly reduced with increasing age. Although the levels of TREC and KREC were higher in females than males, this difference did not reach statistical significance. These findings suggest that demographic variables including age should be considered for interpretation results of the TREC/KREC assay.


Assuntos
Fatores Etários , Linfócitos B/fisiologia , Linfopenia/diagnóstico , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/fisiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Dosagem de Genes , Humanos , Lactente , Recém-Nascido , Irã (Geográfico) , Linfopenia/imunologia , Masculino , Pessoa de Meia-Idade , Padrões de Referência , Adulto Jovem
10.
Einstein (Sao Paulo) ; 17(2): eRB4733, 2019 May 02.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31066797

RESUMO

Healthy aging is partly related to appropriate function of the immune system. As already reported, some changes in this system are observed, including reduced number and repertoire of T cells due to thymic involution, accumulation of memory T cells by chronic infections, homeostatic proliferation compensating for the number of naïve T cells, decreased proliferation of T cells against a stimulus, telomere shortening, replicative senescence of the T cells, and inflammaging, besides the accumulation of myeloid-derived suppressor cells. The purpose of this article is to clarify each of these changes, aiming to minimize limitations of immunosenescence. If such associations can be established, these cells may be used as early and less invasive markers of aging-related diseases, as well as to indicate interventions, evaluate the efficacy of interventions and be a tool to achieve longevity with quality of life.


Assuntos
Envelhecimento/imunologia , Imunossenescência/imunologia , Células Supressoras Mieloides/fisiologia , Linfócitos T/fisiologia , Adaptação Fisiológica/imunologia , Proliferação de Células/fisiologia , Humanos
11.
Thorac Surg Clin ; 29(2): 123-131, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30927993

RESUMO

The thymus is a primary lymphoid organ essential for the development of T lymphocytes, which orchestrate adaptive immune responses. T-cell development in the thymus is spatially regulated; key checkpoints in T-cell maturation and selection occur in cortical and medullary regions to eliminate self-reactive T cells, establish central tolerance, and export naïve T cells to the periphery with the potential to recognize diverse pathogens. Thymic output is also temporally regulated due to age-related involution of the thymus accompanied by loss of epithelial cells. This review discusses the structural and age-related control of thymus function in humans.


Assuntos
Timo/imunologia , Timo/fisiologia , Envelhecimento/imunologia , Envelhecimento/fisiologia , Homeostase/fisiologia , Humanos , Sistema Imunitário/fisiologia , Linfócitos T/fisiologia , Timo/embriologia
12.
Allergol. immunopatol ; 47(2): 141-151, mar.-abr. 2019. tab
Artigo em Inglês | IBECS | ID: ibc-180802

RESUMO

Background: The del22q11 syndrome patients present immunological abnormalities associated to thymus alterations. Up to 75% of them present cardiopathies and thymus is frequently removed during surgery. The thymectomy per se has a deleterious effect concerning lymphocyte subpopulations, and T cell function. When compared to healthy controls, these patients have higher infections propensity of variable severity. The factors behind these variations are unknown. We compared immunological profiles of del22q11.2 Syndrome patients with and without thymectomy to establish its effect in the immune profile. Methods: Forty-six del22q11.2 syndrome patients from 1 to 16 years old, 19 of them with partial or total thymectomy were included. Heart disease type, heart surgery, infections events and thymus resection were identified. Immunoglobulin levels, flow cytometry for lymphocytes subpopulations and TREC levels were determined, and statistical analyses were performed. Results: The thymectomy group had a lower lymphocyte index, both regarding total cell count and when comparing age-adjusted Z scores. Also, CD3+, CD4+ and CD8+ lower levels were observed in this group, the lowest count in those patients who had undergone thymus resection during the first year of life. Their TREC level median was 23.6/μL vs 16.1 miL in the non-thymus group (p = 0.22). No differences were identified regarding immunoglobulin levels or infection events frequencies over the previous year. Conclusion: Patients with del22q11.2 syndrome subjected to thymus resection present lower lymphocyte and TREC indexes when compared to patients without thymectomy. This situation may be influenced by the age at the surgery and the time elapsed since the procedure


No disponible


Assuntos
Humanos , Masculino , Feminino , Lactente , Pré-Escolar , Criança , Adolescente , Linfócitos T/fisiologia , Subpopulações de Linfócitos T/fisiologia , Timectomia/métodos , Timo/cirurgia , Cromossomos Humanos Par 22/imunologia , Deleção Cromossômica , Citometria de Fluxo , Receptores de Antígenos de Linfócitos T/genética
13.
Proc Natl Acad Sci U S A ; 116(13): 5914-5919, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30850527

RESUMO

An essential feature of the adaptive immune system is the proliferation of antigen-specific lymphocytes during an immune reaction to form a large pool of effector cells. This proliferation must be regulated to ensure an effective response to infection while avoiding immunopathology. Recent experiments in mice have demonstrated that the expansion of a specific clone of T cells in response to cognate antigen obeys a striking inverse power law with respect to the initial number of T cells. Here, we show that such a relationship arises naturally from a model in which T cell expansion is limited by decaying levels of presented antigen. The same model also accounts for the observed dependence of T cell expansion on affinity for antigen and on the kinetics of antigen administration. Extending the model to address expansion of multiple T cell clones competing for antigen, we find that higher-affinity clones can suppress the proliferation of lower-affinity clones, thereby promoting the specificity of the response. Using the model to derive optimal vaccination protocols, we find that exponentially increasing antigen doses can achieve a nearly optimized response. We thus conclude that the dynamics of presented antigen is a key regulator of both the size and specificity of the adaptive immune response.


Assuntos
Apresentação do Antígeno/fisiologia , Linfócitos T/fisiologia , Animais , Imunidade Celular , Ativação Linfocitária/imunologia , Ativação Linfocitária/fisiologia , Camundongos , Camundongos Transgênicos , Modelos Imunológicos , Modelos Teóricos , Vacinação/métodos
14.
Int Immunopharmacol ; 70: 498-503, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30875561

RESUMO

Chimeric antigen receptor T (CAR-T) cell therapy provides possibility for the treatment of malignancies since clinical trials have shown that CAR-T therapy has a significant anti-tumor effect. Although many efforts have been made to improve the efficacy and reduce the side effects of CAR-T therapy, there are still many problems to solve. With the rapid development of this field, combination immunotherapy has been proved to improve the efficacy of CAR-T therapy. Studies have shown that radiotherapy, chemotherapy, oncolytic virotherapy, BTK inhibitors and immune checkpoint blockade-based therapy may further enhance the efficacy of CAR-T therapy while CRISPR/Cas9 technology and IL-1 blockade may improve the safety. In this review, we summarized the advantages and the mechanisms of the combination immunotherapy based on CAR-T cell therapy.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia/métodos , Neoplasias/terapia , Receptores de Antígenos Quiméricos/genética , Linfócitos T/fisiologia , Animais , Anticorpos Monoclonais/uso terapêutico , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Terapia Combinada , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Humanos , Interleucina-1/antagonistas & inibidores , Neoplasias/imunologia , Terapia Viral Oncolítica , Inibidores de Proteínas Quinases/uso terapêutico , Radioimunoterapia , Linfócitos T/transplante
15.
PLoS Pathog ; 15(2): e1007589, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30818370

RESUMO

Human T Lymphotropic virus (HTLV) infection can persist in individuals resulting, at least in part, from viral escape of the innate immunity, including inhibition of type I interferon response in infected T-cells. Plasmacytoid dendritic cells (pDCs) are known to bypass viral escape by their robust type I interferon production. Here, we demonstrated that pDCs produce type I interferons upon physical cell contact with HTLV-infected cells, yet pDC activation inversely correlates with the ability of the HTLV-producing cells to transmit infection. We show that pDCs sense surface associated-HTLV present with glycan-rich structure referred to as biofilm-like structure, which thus represents a newly described viral structure triggering the antiviral response by pDCs. Consistently, heparan sulfate proteoglycans and especially the cell surface pattern of terminal ß-galactoside glycosylation, modulate the transmission of the immunostimulatory RNA to pDCs. Altogether, our results uncover a function of virus-containing cell surface-associated glycosylated structures in the activation of innate immunity.


Assuntos
Células Dendríticas/fisiologia , Infecções por HTLV-I/metabolismo , Citocinas , Galactosídeos/metabolismo , Glicosilação , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Vírus Linfotrópico T Tipo 2 Humano/imunologia , Vírus Linfotrópico T Tipo 2 Humano/patogenicidade , Humanos , Imunidade Inata/fisiologia , Interferon Tipo I/imunologia , Interferon-alfa/imunologia , Interferon-alfa/metabolismo , Células Jurkat , Linfócitos T/imunologia , Linfócitos T/fisiologia
16.
Crit Rev Oncol Hematol ; 136: 1-12, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30878123

RESUMO

Adoptive cellular therapy (ACT) is an immunotherapy which involves the passive transfer of lymphocytes into a lymphodepleted host after ex vivo stimulation and expansion. Tumor-infiltrating lymphocytes (TILs) have shown objective tumor responses mainly restricted to melanoma and rely on a laborious manufacturing process. These limitations led to emergence of engineered cells, where normal peripheral blood lymphocytes are modified to express T cell receptors (TCRs) or chimeric antigen receptors (CARs) specific for tumor-associated antigens (TAAs). To date, CD19-targeted chimeric antigen receptor T (CAR T) cells have been the most extensively studied, showing complete and durable responses in B-cell malignancies. Antitumor responses with engineered T cells have often been accompanied by undesired toxicities in clinical trials including cytokine release syndrome (CRS) and neurotoxicity. In this review, we provide an overview of adoptive cellular strategies, early and ongoing clinical trials, adverse events and strategies to mitigate side effects and overcome limitations.


Assuntos
Imunoterapia Adotiva/métodos , Linfócitos T/transplante , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto/métodos , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/transplante , Melanoma/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/fisiologia
17.
Clin Lab Med ; 39(1): 107-123, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30709500

RESUMO

There is growing evidence supporting the genetic variability outside of HLA system that is contributing to the variation in transplant outcomes. Determining novel predictors could help to identify patients at risk and tailor their immunosuppressive regimens. This article discusses the various single nucleotide polymorphisms in costimulatory molecules and cytokines that have been evaluated for their effect on transplantation. An overview of how gene polymorphism studies are conducted and factors to consider in the experimental design to ensure meaningful data can be concluded are discussed.


Assuntos
Antígenos B7/genética , Citocinas/genética , Rejeição de Enxerto/imunologia , Polimorfismo de Nucleotídeo Único , Transplante , Antígenos B7/metabolismo , Antígenos B7/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Receptores do Fator de Necrose Tumoral/genética , Linfócitos T/imunologia , Linfócitos T/fisiologia , Resultado do Tratamento , Fator de Necrose Tumoral alfa/genética
18.
Clin Lab Med ; 39(1): 157-169, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30709504

RESUMO

It is increasingly recognized that calcineurin inhibitors (CNI) such as cyclosporine and tacrolimus are not ideal immunosuppressive agents. Side effects, including increased rates of infection, hypertension, and malignancy, can be severe. Thus, in the past decade, there has been much focus on the development of novel therapeutic agents and strategies designed to replace or minimize CNI exposure in transplant patients. This article reviews potential novel targets in T cells, alloantibody-producing B cells, plasma cells, and complement in transplantation.


Assuntos
Imunossupressão/métodos , Transplante , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Fatores Imunológicos/uso terapêutico , Modelos Imunológicos , Linfócitos T/fisiologia , Condicionamento Pré-Transplante/métodos
19.
Clin Lab Med ; 39(1): 87-106, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30709511

RESUMO

Costimulation is a critical step in T-cell activation, and costimulatory blockade at the time of T cell activation leads to T-cell anergy and allograft tolerance in animal models of transplantation. CD28:B7 is the most important costimulatory pathway and the balance of signals between CD28 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) is a central determinant of transplant outcome. Form a clinical standpoint, CTLA-4 Ig is the only approved agent for costimulation blockade in transplantation. Advantages and disadvantages of its use are discussed. Progress in developing novel agents to target other pathways, including the promising CD40:CD154 pathway, is also discussed.


Assuntos
Rejeição de Enxerto , Linfócitos T/fisiologia , Tolerância ao Transplante , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/fisiologia , Humanos , Transdução de Sinais , Linfócitos T/metabolismo
20.
Methods Mol Biol ; 1930: 1-9, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30610592

RESUMO

The inherent ability of T-cells to migrate is critical for a fully functional immune system, both in normal immune surveillance and for mounting an adaptive immune response. At the same time, inappropriate trafficking of T-cells can be a pathological factor for immune-mediated or chronic inflammatory diseases. T-cell motility is critically dependent on a series of ligand-receptor interactions, a precisely regulated intracellular signaling, an involvement of adaptor proteins, and dynamic remodeling of the cytoskeletal systems. The leukocyte integrin LFA-1 receptor present on T-cells binds to the ligand intercellular adhesion molecule 1 (ICAM-1) and this LFA-1/ICAM-1 contact acts as a trigger for T-cell motility. In this book, we present a collection of methods and protocols that are frequently used by researchers to better understand T-cell motility in health and diseases.


Assuntos
Molécula 1 de Adesão Intercelular/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Domínios e Motivos de Interação entre Proteínas , Linfócitos T/citologia , Movimento Celular , Células Cultivadas , Humanos , Transdução de Sinais , Linfócitos T/metabolismo , Linfócitos T/fisiologia
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