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1.
Cells ; 10(11)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34831116

RESUMO

The metabolic changes that occur in tumor microenvironment (TME) can influence not only the biological activity of tumor cells, which become more aggressive and auto sustained, but also the immune response against tumor cells, either producing ineffective responses or polarizing the response toward protumor activity. γδ T cells are a subset of T cells characterized by a plasticity that confers them the ability to differentiate towards different cell subsets according to the microenvironment conditions. On this basis, we here review the more recent studies focused on altered tumor metabolism and γδ T cells, considering their already known antitumor role and the possibility of manipulating their effector functions by in vitro and in vivo approaches. γδ T cells, thanks to their unique features, are themselves a valid alternative to overcome the limits associated with the use of conventional T cells, such as major histocompatibility complex (MHC) restriction, costimulatory signal and specific tumor-associated antigen recognition. Lipids, amino acids, hypoxia, prostaglandins and other metabolic changes inside the tumor microenvironment could reduce the efficacy of this important immune population and polarize γδ T cells toward IL17 producing cells that play a pro tumoral role. A deeper knowledge of this phenomenon could be helpful to formulate new immunotherapeutic approaches that target tumor metabolisms.

2.
Vaccines (Basel) ; 9(6)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071430

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection dysregulates the immune system by lymphopenia of B cells, monocytes, eosinophils, basophils, and cytotoxic cells such as CD8, γδ T cells, and natural killer (NK) cells. Despite many studies being conducted to better understand the effects of SARS-CoV-2 on the immune system, many mechanisms still remain unclear, hindering the development of novel therapeutic approaches and strategies to improve the host's immune defense. This mini-review summarizes the findings on the role of γδ T cells in coronavirus disease 2019 (COVID-19), providing an overview of the excellent anti-viral therapeutic potential of γδ T cells, that had not yet been exploited in depth.

4.
Immunol Rev ; 298(1): 153-164, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32691450

RESUMO

The finding that γδ T cells are present among tumor-infiltrating lymphocytes in humans suggests they participate in tumor immune surveillance, but their relevance is unclear because the relative abundance of tumor-infiltrating γδ T cells correlates with positive or negative, or even do not correlate with prognosis. This likely depends on the fact that tumor-infiltrating γδ T cells may play substantially different effector or regulatory functions, and correlation with patient's prognosis relies on distinct γδ T cell subsets in the context of the tumor. There is interest to exploit γδ T cells in tumor immunotherapy, but to make this approach successful there is urgent need to fully understand the biological functions of γδ T cells and of how they can be manipulated in vivo and ex vivo to safely provide benefit to the host. This review focuses on our previous and ongoing studies of tumor-infiltrating γδ T lymphocytes in different types of human cancer. Moreover, we discuss the interaction of tumor-infiltrating γδ T cells with other cells and molecules present in the tumor microenvironment, and their clinical relevance on the ground, that deep knowledge in this field can be used further for better immunotherapeutic intervention in cancer.

5.
J Leukoc Biol ; 108(2): 749-760, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32202356

RESUMO

Inflammatory bowel disease (IBD) remains a global health problem with a significant percentage of patients progressing to chronic inflammation and colitis-associated cancer (CAC). Whether or not γδ T cells contribute to initiation and maintenance of inflammation in IBD and in the development of CAC is not known. We have evaluated the frequency, phenotype, and functions of γδ T cells among tissue-infiltrating lymphocytes in healthy donors and IBD and CAC patients. Results show that Vδ1 T cells are the dominant γδ T-cell population in healthy tissue, whereas Vδ2 T significantly abound in chronic IBD. Vδ2 T cells produce more IFN-γ, TNF-α, and IL-17 than Vδ1 T cells in chronic inflamed IBD. In CAC patients no significant cytokine production was detected in tissue-resident Vδ1 T cells, but Vδ2 T cells produced remarkable amounts of IFN-γ and TNF-α; these data were confirmed by the analysis of an independent cohort of IBD transcriptomes. Moreover, transcriptomes of IBD patients revealed a clear-cut clusterization of genes related with the maintenance of the inflammatory status. In conclusion, our results demonstrating that Vδ2 T cells have a proinflammatory profile in chronic IBD are suggestive of their participation in IBD and CAC pathogenesis.


Assuntos
Colite/complicações , Colite/imunologia , Neoplasias do Colo/etiologia , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto , Idoso , Biomarcadores , Doença Crônica , Colite/patologia , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Citocinas/metabolismo , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Doenças Inflamatórias Intestinais/patologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade
6.
JCI Insight ; 4(24)2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31689241

RESUMO

γδ T cells account for a large fraction of human intestinal intraepithelial lymphocytes (IELs) endowed with potent antitumor activities. However, little is known about their origin, phenotype, and clinical relevance in colorectal cancer (CRC). To determine γδ IEL gut specificity, homing, and functions, γδ T cells were purified from human healthy blood, lymph nodes, liver, skin, and intestine, either disease-free, affected by CRC, or generated from thymic precursors. The constitutive expression of NKp46 specifically identifies a subset of cytotoxic Vδ1 T cells representing the largest fraction of gut-resident IELs. The ontogeny and gut-tropism of NKp46+/Vδ1 IELs depends both on distinctive features of Vδ1 thymic precursors and gut-environmental factors. Either the constitutive presence of NKp46 on tissue-resident Vδ1 intestinal IELs or its induced expression on IL-2/IL-15-activated Vδ1 thymocytes are associated with antitumor functions. Higher frequencies of NKp46+/Vδ1 IELs in tumor-free specimens from CRC patients correlate with a lower risk of developing metastatic III/IV disease stages. Additionally, our in vitro settings reproducing CRC tumor microenvironment inhibited the expansion of NKp46+/Vδ1 cells from activated thymic precursors. These results parallel the very low frequencies of NKp46+/Vδ1 IELs able to infiltrate CRC, thus providing insights to either follow-up cancer progression or to develop adoptive cellular therapies.


Assuntos
Neoplasias Colorretais/imunologia , Mucosa Intestinal/citologia , Linfócitos Intraepiteliais/imunologia , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Linfócitos T Citotóxicos/imunologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Animais , Antígenos Ly/metabolismo , Colo/citologia , Colo/imunologia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Progressão da Doença , Feminino , Humanos , Íleo/citologia , Íleo/imunologia , Imunoterapia Adotiva/métodos , Mucosa Intestinal/imunologia , Linfócitos Intraepiteliais/metabolismo , Linfócitos Intraepiteliais/transplante , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Globulina de Ligação a Hormônio Sexual , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/transplante , Adulto Jovem
7.
Expert Opin Biol Ther ; 19(9): 887-895, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31220420

RESUMO

Introduction: Cancer immunotherapy relies on the development of an efficient and long-lasting anti-tumor response, generally mediated by cytotoxic T cells. γδ T cells possess distinctive features that justify their use in cancer immunotherapy. Areas covered: Here we will review our current knowledge on the functions of human γδ T cells that may be relevant in tumor immunity and the most recent advances in our understanding of how these functions are regulated in the tumor microenvironment. We will also discuss the major achievements and limitations of γδ T cell-based immunotherapy of cancer. Expert opinion: Several small-scale clinical trials have been conducted in cancer patients using either in vivo activation of γδ T cells or adoptive transfer of ex vivo-expanded γδ T cells. Both strategies are safe and give some clinical benefit to patients, thus providing a proof of principle for their utilization in addition to conventional therapies. However, low objective response rates have been obtained in both settings and therefore larger and well-controlled trials are needed. Discovering the factors which influence the success of γδ T cell-based immunotherapy will lead to a better understanding of their mechanism of action and to harness these cells for effective and durable anti-tumor responses.


Assuntos
Imunoterapia Adotiva , Linfócitos Intraepiteliais/imunologia , Neoplasias/terapia , Animais , Humanos , Linfócitos Intraepiteliais/transplante , Neoplasias/imunologia , Microambiente Tumoral
8.
Investig Clin Urol ; 60(2): 91-98, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30838341

RESUMO

Purpose: The aim of our study was to prospectively evaluate the distribution of gamma-delta (γδ)1 and γδ2 T cells and their phenotypes in peripheral blood and prostate samples of patients diagnosed with or without prostate cancer (PCa) at prostate biopsy. Materials and Methods: A consecutive series of 43 outpatients underwent trans-rectal echo-guided prostate biopsy for suspected PCa. Flow cytometry analysis was used to identify and characterize the γδ T cells populations in peripheral blood and tissue samples. Patients were stratified according to the presence or not of PCa, and its International Society of Urological Pathology (ISUP) grade (1 vs. ≥2). Results: The distribution of γδ T cells in peripheral blood and prostate tissue showed wide variability and non-significant differences. A slightly higher percentage of δ2 T cells and a slightly lower percentage of δ1 T cells were found in peripheral blood of cancer patients. A non-significantly higher percentage of both Vδ1 and Vδ2 was expressed in cancer tissues, but a trend for lower distribution of δ1 and δ2 T cells was observed in ISUP grade ≥2. The "central memory" and "effector memory" were the most expressed T cells phenotype in peripheral blood and tissue samples. However no substantial differences in T cells subtypes distribution between cancer and healthy tissue were observed. Conclusions: No substantially different percentages of γδ T cells were found in peripheral blood and biopsy samples of healthy and PCa patients. However a non-significant trend for lower infiltrate in higher ISUP grade cancer tissue was observed, suggesting a possible role for the immunosurveillance of PCa.


Assuntos
Linfócitos Intraepiteliais/patologia , Linfócitos do Interstício Tumoral/patologia , Células Neoplásicas Circulantes/patologia , Neoplasias da Próstata/patologia , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
9.
J Crohns Colitis ; 13(7): 873-883, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-30689780

RESUMO

BACKGROUND AND AIMS: Inflammatory bowel disease [IBD] is a complex chronic inflammatory disease of the human gut with no clear aetiology. Traditionally, dysregulated adaptive immune responses play an important role even though accumulating evidence suggests a role also for innate immunity. Because of the well-known plasticity of γδ T cells, we investigated their percentage occurrence, phenotypic features and effector functions in the intestinal mucosa of early-onset and long-standing IBD patients, as compared to healthy subjects. METHODS: Fresh biopsies from 30 Crohn's disease and ulcerative colitis patients were obtained and digested, and cells were analysed by flow cytometry. RESULTS: We found a reduced frequency of Vδ1 T cells in tissue from early and late IBD patients (2.24% and 1.95%, respectively, vs 5.44% in healthy tissue) but an increased frequency of Vδ2 T cells in the gut of late IBD patients (3.19% in late patients vs 1.5% in early patients and 1.65% in healthy tissue). The infiltrating Vδ2 T cells had predominant effector memory and terminally differentiated phenotypes and produced elevated levels of tumour necrosis factor-α [TNF-α] and interleukin-17 [IL-17]. The frequency of tissue Vδ2 T cells correlated with the extent of the inflammatory response and the severity of IBD. CONCLUSION: Our study shows that tissue Vδ1 T cells are decreased in IBD patients while Vδ2 T cells are increased in the gut of IBD patients and contribute to TNF-α production. Moreover, we identify an as yet unappreciated role of Vδ2 T cells in IL-17 production in the gut of long-standing IBD patients, suggesting that they also participate in the chronic inflammatory process.


Assuntos
Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Biópsia , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo
10.
Front Immunol ; 9: 1395, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29963061

RESUMO

γδ T cells possess cytotoxic antitumor activity mediated by production of proinflammatory cytokines, direct cytotoxic activity, and regulation of the biological functions of other cell types. Hence, these features have prompted the development of therapeutic strategies in which γδ T cells agonists or ex vivo-expanded γδ T cells are administered to tumor patients. Several studies have shown that γδ T cells are an important component of tumor-infiltrating lymphocytes in patients affected by different types of cancer and a recent analysis of ~18,000 transcriptomes from 39 human tumors identified tumor-infiltrating γδ T cells as the most significant favorable cancer-wide prognostic signature. However, the complex and intricate interactions between tumor cells, tumor microenvironment (TME), and tumor-infiltrating immune cells results in a balance between tumor-promoting and tumor-controlling effects, and γδ T cells functions are often diverted or impaired by immunosuppressive signals originating from the TME. This review focuses on the dangerous liason between γδ T cells and tumoral microenvironment and raises the possibility that strategies capable to reduce the immunosuppressive environment and increase the cytotoxic ability of γδ T cells may be the key factor to improve their utilization in tumor immunotherapy.

11.
Front Immunol ; 9: 1119, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29875774

RESUMO

T-cell-mediated immune responses play a fundamental role in controlling Mycobacterium tuberculosis (M. tuberculosis) infection, and traditionally, this response is thought to be mediated by Th1-type CD4+ T-cells secreting IFN-γ. While studying the function and specificity of M. tuberculosis-reactive CD4+ T-cells in more detail at the single cell level; however, we found a human CD4+ T-cell population with a naive phenotype that interestingly was capable of producing multiple cytokines (TCNP cells). CD4+ TCNP cells phenotyped as CD95lo CD28int CD49dhi CXCR3hi and showed a broad distribution of T cell receptor Vß segments. They rapidly secreted multiple cytokines in response to different M. tuberculosis antigens, their frequency was increased during active disease, but was comparable to latent tuberculosis infection in treated TB patients. These results identify a novel human CD4+ T-cell subset involved in the human immune response to mycobacteria, which is present in active TB patients' blood. These results significantly expand our understanding of the immune response in infectious diseases.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Citocinas/metabolismo , Imunofenotipagem , Mycobacterium tuberculosis/imunologia , Tuberculose/imunologia , Tuberculose/metabolismo , Adulto , Antígenos de Bactérias/imunologia , Contagem de Linfócito CD4 , Progressão da Doença , Feminino , Humanos , Masculino , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Tuberculose/microbiologia , Adulto Jovem
12.
J Leukoc Biol ; 103(3): 485-492, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29345336

RESUMO

γδ T cells are a subset of T lymphocytes that have been implicated in immunosurveillance against infections and tumors. γδ T cells are endowed with antitumor activities, and hence several γδ T cell-based small-scale clinical trials have been conducted either by in vivo activation by intravenous administration of aminobiphosphonates or by adoptive transfer of in vitro expanded γδ T cells. Although both these strategies have yielded promising results, there are a number of limitations associated with each of them which, if overcome may help to further improve efficacy. One of the most important limits is the possible polarization of tumor-infiltrating γδ T cells toward different γδ T cells population with functional activities that help the progression and spread of the tumor. Here, we review the modalities and the possible mechanisms involved in the polarization of tumor-infiltrating γδ T cells upon interaction with several components of the tumor microenvironment and discuss their implications for the manipulation of γδ T cells in cancer immunotherapy.


Assuntos
Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo
13.
Front Immunol ; 8: 1401, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29163482

RESUMO

γδ T cells are a minor population (~5%) of CD3 T cells in the peripheral blood, but abound in other anatomic sites such as the intestine or the skin. There are two major subsets of γδ T cells: those that express Vδ1 gene, paired with different Vγ elements, abound in the intestine and the skin, and recognize the major histocompatibility complex (MHC) class I-related molecules such as MHC class I-related molecule A, MHC class I-related molecule B, and UL16-binding protein expressed on many stressed and tumor cells. Conversely, γδ T cells expressing the Vδ2 gene paired with the Vγ9 chain are the predominant (50-90%) γδ T cell population in the peripheral blood and recognize phosphoantigens (PAgs) derived from the mevalonate pathway of mammalian cells, which is highly active upon infection or tumor transformation. Aminobisphosphonates (n-BPs), which inhibit farnesyl pyrophosphate synthase, a downstream enzyme of the mevalonate pathway, cause accumulation of upstream PAgs and therefore promote γδ T cell activation. γδ T cells have distinctive features that justify their utilization in antitumor immunotherapy: they do not require MHC restriction and are less dependent that αß T cells on co-stimulatory signals, produce cytokines with known antitumor effects as interferon-γ and tumor necrosis factor-α and display cytotoxic and antitumor activities in vitro and in mouse models in vivo. Thus, there is interest in the potential application of γδ T cells in tumor immunotherapy, and several small-sized clinical trials have been conducted of γδ T cell-based immunotherapy in different types of cancer after the application of PAgs or n-BPs plus interleukin-2 in vivo or after adoptive transfer of ex vivo-expanded γδ T cells, particularly the Vγ9Vδ2 subset. Results from clinical trials testing the efficacy of any of these two strategies have shown that γδ T cell-based therapy is safe, but long-term clinical results to date are inconsistent. In this review, we will discuss the major achievements and pitfalls of the γδ T cell-based immunotherapy of cancer.

14.
Cancer Res ; 77(12): 3268-3279, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28400477

RESUMO

The tumor microenvironment supplies proinflammatory cytokines favoring a permissive milieu for cancer cell growth and invasive behavior. Here we show how breast cancer progression is facilitated by IL4 secreted by adipose tissue and estrogen receptor-positive and triple-negative breast cancer cell types. Blocking autocrine and paracrine IL4 signaling with the IL4Rα antagonist IL4DM compromised breast cancer cell proliferation, invasion, and tumor growth by downregulating MAPK pathway activity. IL4DM reduced numbers of CD44+/CD24- cancer stem-like cells and elevated expression of the dual specificity phosphatase DUSP4 by inhibiting NF-κB. Enforced expression of DUSP4 drove conversion of metastatic cells to nonmetastatic cells. Mechanistically, RNAi-mediated attenuation of DUSP4 activated the ERK and p38 MAPK pathways, increased stem-like properties, and spawned metastatic capacity. Targeting IL4 signaling sensitized breast cancer cells to anticancer therapy and strengthened immune responses by enhancing the number of IFNγ-positive CTLs. Our results showed the role of IL4 in promoting breast cancer aggressiveness and how its targeting may improve the efficacy of current therapies. Cancer Res; 77(12); 3268-79. ©2017 AACR.


Assuntos
Neoplasias da Mama/patologia , Fosfatases de Especificidade Dupla/metabolismo , Interleucina-4/metabolismo , Fosfatases da Proteína Quinase Ativada por Mitógeno/metabolismo , Microambiente Tumoral , Western Blotting , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Citometria de Fluxo , Xenoenxertos , Humanos
15.
Cancer Immunol Res ; 5(5): 397-407, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28351891

RESUMO

The identification of reciprocal interactions between tumor-infiltrating immune cells and the microenviroment may help us understand mechanisms of tumor growth inhibition or progression. We have assessed the frequencies of tumor-infiltrating and circulating γδ T cells and regulatory T cells (Treg) from 47 patients with squamous cell carcinoma (SCC), to determine if they correlated with progression or survival. Vδ1 T cells infiltrated SSC tissue to a greater extent than normal skin, but SCC patients and healthy subjects had similar amounts circulating. However, Vδ2 T cells were present at higher frequencies in circulation than in the tissue of either cancer patients or healthy donors. Tregs were decreased in the peripheral blood of SCC patients, but were significantly increased in the tumor compartment of these patients. Tumor-infiltrating γδ T cells preferentially showed an effector memory phenotype and made either IL17 or IFNγ depending on the tumor stage, whereas circulating γδ T cells of SCC patients preferentially made IFNγ. Different cell types in the tumor microenvironment produced chemokines that could recruit circulating γδ T cells to the tumor site and other cytokines that could reprogram γδ T cells to produce IL17. These findings suggest the possibility that γδ T cells in SCC are recruited from the periphery and their features are then affected by the tumor microenvironment. Elevated frequencies of infiltrating Vδ2 T cells and Tregs differently correlated with early and advanced tumor stages, respectively. Our results provide insights into the functions of tumor-infiltrating γδ T cells and define potential tools for tumor immunotherapy. Cancer Immunol Res; 5(5); 397-407. ©2017 AACR.


Assuntos
Carcinoma de Células Escamosas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Cutâneas/imunologia , Subpopulações de Linfócitos T/imunologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/patologia , Citocinas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Cutâneas/patologia , Microambiente Tumoral
16.
Oncotarget ; 7(38): 60896-60905, 2016 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-27590513

RESUMO

Vγ9Vδ2 T cells and plasmacytoid dendritic cells (pDCs) are two distinct cell types of innate immunity that participate in early phases of immune response. We investigated whether a close functional relationship exists between these two cell populations using an in vitro co-culture in a human system.pDCs that had been activated by IL-3 and the TLR9 ligand CpG induced substantial activation of Vγ9Vδ2 T cells upon co-culture, which was cell-to-cell contact dependent, as demonstrated in transwell experiments, but that did not involve any of the costimulatory molecules potentially expressed by pDCs or Vγ9V2 T cells, such as ICOS-L, OX40 and CD40L. Activated pDCs selectively induced IL-17, but not IFN-γ, responses of Vγ9Vδ2T cells, which was dominant over the antigen-induced response, and this was associated with the expansion of memory (both central and effector memory) subsets of Vγ9Vδ2 T cells.Overall, our results provide a further piece of information on the complex relationship between these two populations of cells with innate immunity features during inflammatory responses.


Assuntos
Células Dendríticas/imunologia , Interleucina-17/metabolismo , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Apresentação do Antígeno , Ligante de CD40/metabolismo , Comunicação Celular , Proliferação de Células , Técnicas de Cocultura , Ilhas de CpG , Humanos , Imunidade Inata , Memória Imunológica , Ligante Coestimulador de Linfócitos T Induzíveis/metabolismo , Interferon gama/metabolismo , Leucócitos Mononucleares/citologia , Ligantes , Fenótipo , Receptores OX40/metabolismo
17.
Clin Transl Gastroenterol ; 7(7): e178, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27388423

RESUMO

OBJECTIVES: Non-celiac wheat sensitivity (NCWS) is defined as a reaction to ingested wheat after exclusion of celiac disease and wheat allergy. As its pathogenesis is incompletely understood, we evaluated the inflammatory response in the rectal mucosa of patients with well-defined NCWS. METHODS: The prospective study included 22 patients with irritable bowel syndrome (IBS)-like clinical presentation, diagnosed with NCWS by double-blind placebo-controlled challenge. Eight IBS patients not improving on wheat-free diet were used as controls. Two weeks after oral challenge was performed with 80 grams of wheat daily, cells were isolated from rectal biopsies and thoroughly characterized by fluorescence-activated cell sorting analysis for intracellular cytokines and surface markers. RESULTS: Rectal biopsies from wheat-challenged NCWS patients showed that a significant mucosal CD45(+) infiltrate consisted of CD3(+) and CD3(-) lymphocytes, with the latter spontaneously producing more interferon (IFN)-γ than IBS controls. About 30% of IFN-γ-producing CD45(+) cells were T-bet(+), CD56(-), NKP44(-), and CD117(-), defining them as a type-1 innate lymphoid cells (ILC1). IFN-γ-producing ILC1 cells significantly decreased in 10 patients analyzed 2 weeks after they resumed a wheat-free diet. CONCLUSIONS: These data indicate that, in patients with active NCWS, IFN-γ-producing ILC1 cells infiltrate rectal mucosa and support a role for this innate lymphoid cell population in the pathogenesis of NCWS.

19.
Front Immunol ; 5: 607, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25505472

RESUMO

There is increasing clinical evidence indicating that the immune system may either promote or inhibit tumor progression. Several studies have demonstrated that tumors undergoing remission are largely infiltrated by T lymphocytes [tumor-infiltrating lymphocytes (TILs)], but on the other hand, several studies have shown that tumors may be infiltrated by TILs endowed with suppressive features, suggesting that TILs are rather associated with tumor progression and unfavorable prognosis. γδ T lymphocytes are an important component of TILs that may contribute to tumor immunosurveillance, as also suggested by promising reports from several small phase-I clinical trials. Typically, γδ T lymphocytes perform effector functions involved in anti-tumor immune responses (cytotoxicity, production of IFN-γ and TNF-α, and dendritic cell maturation), but under appropriate conditions they may divert from the typical Th1-like phenotype and polarize to Th2, Th17, and Treg cells thus acquiring the capability to inhibit anti-tumor immune responses and promote tumor growth. Recent studies have shown a high frequency of γδ T lymphocytes infiltrating different types of cancer, but the nature of this association and the exact mechanisms underlying it remain uncertain and whether or not the presence of tumor-infiltrating γδ T lymphocytes is a definite prognostic factor remains controversial. In this paper, we will review studies of tumor-infiltrating γδ T lymphocytes from patients with different types of cancer, and we will discuss their clinical relevance. Moreover, we will also discuss on the complex interplay between cancer, tumor stroma, and γδ T lymphocytes as a major determinant of the final outcome of the γδ T lymphocyte response. Finally, we propose that targeting γδ T lymphocyte polarization and skewing their phenotype to adapt to the microenvironment might hold great promise for the treatment of cancer.

20.
Respir Med ; 101(3): 531-8, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16893638

RESUMO

AIM: To study the relationship between respiratory/allergic disorders and chronic environmental tobacco smoke (ETS) exposure to husband or at workplace among non-smoking women of a general population in Italy. METHODS: Analyses regard 2195 married or employed women. Information was collected through a self-administered questionnaire. ETS exposure was validated by salivary cotinine. RESULTS: Exposure both to husband and at work resulted a significant risk factor for current dyspnoea (odds ratio (OR) 1.61, 95% confidence interval (CI) 1.20-2.16), any shortness of breath at rest (OR 2.81, 95% CI 1.83-4.30), recent wheeze (OR 1.71, 95% CI 1.04-2.82), recent attacks of shortness of breath with wheeze (OR 1.85, 95% CI 1.05-3.26), asthma diagnosis/symptoms (OR 1.50, 95% CI 1.09-2.08), diagnosis of asthma or bronchitis/emphysema (obstructive lung diseases (OLD)) (OR 2.24, 95% CI 1.40-3.58), current cough/phlegm (OR 1.52, 95% CI 1.07-2.15), and rhino-conjunctivitis (OR 1.48, 95% CI 1.13-1.94). Exposure only at work yielded higher adjusted odds ratios for all health conditions, except for rhino-conjunctivitis. Overall, about 24% of shortness of breath at rest, 16% of dyspnoea, 17% of rhino-conjunctivitis, 12% of OLD, and 10% of asthma diagnosis/symptoms are attributable to the effect of exposures to both husband and at work. Twelve percent of shortness of breath at rest and 10% of rhino-conjunctivitis cases might be avoided by eliminating exposure only at work and only to husband, respectively. CONCLUSIONS: Lifetime ETS exposure, especially at work, is associated with respiratory symptoms/diseases, and it accounts for a sizeable proportion of such disorders. The combined effect of both exposures is higher than the separate effects.


Assuntos
Pneumopatias/etiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/epidemiologia , Asma/etiologia , Bronquite/epidemiologia , Bronquite/etiologia , Conjuntivite/epidemiologia , Conjuntivite/etiologia , Dispneia/epidemiologia , Dispneia/etiologia , Exposição Ambiental/efeitos adversos , Feminino , Humanos , Itália/epidemiologia , Pneumopatias/epidemiologia , Pessoa de Meia-Idade , Exposição Ocupacional/efeitos adversos , Razão de Chances , Vigilância da População/métodos , Prevalência , Enfisema Pulmonar/epidemiologia , Enfisema Pulmonar/etiologia , Sons Respiratórios/etiologia , Rinite/epidemiologia , Rinite/etiologia , Fatores Socioeconômicos , Cônjuges
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