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1.
Oxid Med Cell Longev ; 2019: 7471890, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31281590

RESUMO

Hyperthyroidism is an endocrine disorder characterized by excessive secretion of thyroid hormones T3 and T4. Thyroid hormones exert pleiotropic actions on numerous tissues and induce an overall increase in metabolism, with an increase in energy demand and oxygen consumption. Therefore, the purpose of this study was to investigate the effects of hyperthyroidism on the production of reactive oxygen species (ROS) in lymph node and spleen cells of euthyroid and hyperthyroid mice, analyzing antioxidant mechanisms involved in the restitution of the cellular redox state. For this, thirty female Balb/c (H-2d) mice were randomly divided into two groups: euthyroid (by treatment with placebo) and hyperthyroid (by treatment with 12 mg/l of T4 in drinking water for 30 days). We found a significant increase in ROS and an increase in the genomic and protein expression of the antioxidant enzymes catalase (CAT) and glutathione peroxidase-1 (GPx-1) in lymph node and spleen cells of hyperthyroid mice. In vitro treatment with H2O2 (250 µM) of the lymphoid cells of euthyroid mice increased the expression levels of CAT and GPx-1. The hyperthyroidism increased the phosphorylation levels of Nrf2 (nuclear factor erythroid 2-related factor) and the kinase activity of protein kinase C (PKC) and extracellular signal-regulated kinase (ERK). Additionally, we found an increase in the expression of the classic isoenzymes of PKCα, ß and γ. In conclusion, these results indicated that the increase in ROS found in the hyperthyroid state induces the antioxidant enzyme transcription through the activation of the Nrf-2 factor in lymphoid tissues. This shows the influence of hyperthyroidism on the regulation of the cellular antioxidant system.


Assuntos
Catalase/genética , Glutationa Peroxidase/genética , Hipertireoidismo/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/fisiologia , Superóxido Dismutase-1/genética , Animais , Catalase/biossíntese , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Glutationa Peroxidase/biossíntese , Hipertireoidismo/sangue , Hipertireoidismo/enzimologia , Hipertireoidismo/genética , Tecido Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/genética , Proteína Quinase C/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase-1/biossíntese , Tireotropina/sangue , Tiroxina/administração & dosagem , Tiroxina/sangue , Ativação Transcricional , Tri-Iodotironina/sangue
2.
Anat Histol Embryol ; 48(5): 476-485, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31305954

RESUMO

The proximal caecum in quails consists of lymphoid and non-lymphoid structures. The caecal tonsils in the proximal part of the caecum are units of gut-associated lymphoid tissue in poultry. This study aimed to examine the histological characteristics of the proximal caecum, as well as compositions of dendritic cells (DCs) and antigen-presenting cells (APCs) in the caecal tonsil of quails. Tissue sections were stained with Crossman's triple, periodic acid-Schiff, Gordon and Sweet's silver, Congo red and methyl green-pyronin dyes, as well as immunohistochemically by the streptavidin-biotin-peroxidase complex method. Caecal lymphoid tissue was located in the lamina propria and submucosa. Germinative centres were observed within the lymphoid tissue. Reticular fibres were mainly distributed in the border area of the germinal centre with only a few fibres scattered in the centre. Plasma cells were observed in the subepithelial region and germinal centres. Eosinophil granulocytes were prevalent in the lymphoid tissue. Additionally, CD83-immunoreactive DCs and MHC class II immunoreactive APCs were present in the subepithelial area and diffuse lymphoid tissue. While DCs were seen in the germinal centres of tonsillar units, APCs were rarely present in the germinal centres, but they were noticed around the germinal centres. In conclusion, the histological structure of the proximal caecum in quails and the distributions of some immunological cells in the caecal tonsils were revealed. Therefore, the defensive role of the caecal tonsils in the digestive system may be better understood, and comparative studies may be carried out.


Assuntos
Ceco , Tecido Linfoide/citologia , Tonsila Palatina , Animais , Células Apresentadoras de Antígenos/metabolismo , Biomarcadores , Ceco/anatomia & histologia , Ceco/citologia , Ceco/imunologia , Coturnix , Células Dendríticas/metabolismo , Tecido Linfoide/metabolismo , Tonsila Palatina/anatomia & histologia , Tonsila Palatina/citologia , Tonsila Palatina/imunologia
3.
Int J Mol Sci ; 20(9)2019 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-31035605

RESUMO

Dual specificity phosphatases (DUSPs) have a well-known role as regulators of the immune response through the modulation of mitogen-activated protein kinases (MAPKs). Yet the precise interplay between the various members of the DUSP family with protein kinases is not well understood. Recent multi-omics studies characterizing the transcriptomes and proteomes of immune cells have provided snapshots of molecular mechanisms underlying innate immune response in unprecedented detail. In this study, we focus on deciphering the interplay between members of the DUSP family with protein kinases in immune cells using publicly available omics datasets. Our analysis resulted in the identification of potential DUSP-mediated hub proteins including MAPK7, MAPK8, AURKA, and IGF1R. Furthermore, we analyzed the association of DUSP expression with TLR4 signaling and identified VEGF, FGFR, and SCF-KIT pathway modules to be regulated by the activation of TLR4 signaling. Finally, we identified several important kinases including LRRK2, MAPK8, and cyclin-dependent kinases as potential DUSP-mediated hubs in TLR4 signaling. The findings from this study have the potential to aid in the understanding of DUSP signaling in the context of innate immunity. Further, this will promote the development of therapeutic modalities for disorders with aberrant DUSP signaling.


Assuntos
Fosfatases de Especificidade Dupla/metabolismo , Imunomodulação , Proteínas Quinases/metabolismo , Transdução de Sinais , Animais , Evolução Biológica , Células Sanguíneas/metabolismo , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos , Mapeamento de Interação de Proteínas , Mapas de Interação de Proteínas , Proteoma , Proteômica/métodos
4.
Cancer Sci ; 110(6): 1853-1862, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30997706

RESUMO

The efficacy of preoperative neoadjuvant chemoradiotherapy (NAC) in cases of pancreatic cancer with extremely poor prognoses has been reported. In this study, we aimed to identify novel biomarkers that reflect prognoses following chemoradiotherapy using tertiary lymphoid organs (TLO) expressed in the tumor microenvironment. Resected tumor specimens were obtained from 140 pancreatic cancer patients. We retrospectively investigated the clinical relevance of TLO by categorizing patients into those who underwent upfront surgery (surgery first [SF]) and those who received NAC. The immunological elements within TLO were analyzed by immunohistochemistry (IHC). In the IHC analysis, the proportions of CD8+ T lymphocytes, PNAd+ high endothelial venules, CD163+ macrophages and Ki-67+ cells within the TLO were higher in the NAC group than in the SF group. In contrast, the proportion of programmed cell death-1+ immunosuppressive lymphocytes within TLO was lower in the NAC group than in the SF group. The NAC group demonstrated favorable prognoses compared with the SF group. In the multivariate analysis, the TLO/tumor ratio was determined as an independent predictive prognostic factor. In conclusion, the administration of preoperative chemoradiotherapy may influence the immunological elements in the tumor microenvironment and result in favorable prognoses in pancreatic ductal adenocarcinoma patients.


Assuntos
Carcinoma Ductal Pancreático/imunologia , Tecido Linfoide/imunologia , Neoplasias Pancreáticas/imunologia , Microambiente Tumoral/imunologia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Ductal Pancreático/cirurgia , Carcinoma Ductal Pancreático/terapia , Quimiorradioterapia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Tecido Linfoide/metabolismo , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/terapia , Prognóstico , Estudos Retrospectivos
5.
Immunol Lett ; 210: 29-32, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31004681

RESUMO

The maintenance and dynamics of memory T-cells in the bone marrow are a matter of ongoing debate. It has been suggested that memory T-cells in the bone marrow are maintained as long-lived, quiescent cells. We have recently shown that memory T-cells isolated from goat bone marrow undergo self-renewal and recirculate via the blood and lymph. Using the well-established memory T-cell markers CD44 and CD62L we here show very similar results in mice. This provides further support for the concept that memory T-cells are continuously self-renewing and recirculating between blood, bone marrow, spleen and lymph nodes.


Assuntos
Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Deutério , Memória Imunológica , Marcação por Isótopo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Biomarcadores , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos , Modelos Biológicos
6.
Nutrients ; 11(4)2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987366

RESUMO

Intensive exercise can lead to oxidative stress, which can be particularly deleterious for lymphoid tissues. Hesperidin has demonstrated its antioxidant activity, but few studies focus on its influence on intensive training. The aim of this study was to assess the impact of hesperidin on the oxidant/antioxidant status of lymphoid tissues after an intensive training program. Wistar rats were trained for five weeks (five days per week), including two exhaustion tests plus three trainings per week. During this period, animals were orally administrated with 200 mg/kg of hesperidin or vehicle (three days per week). The oxidative status was determined before, immediately after and 24 h after an additional exhaustion test. The production of reactive oxygen species (ROS) by peritoneal macrophages, superoxide dismutase (SOD) and catalase activities in spleen, thymus and liver, and hepatic glutathione peroxidase activity (GPx) were assessed. Hesperidin prevented an increase in ROS production induced by the additional exhaustion test. Likewise, hesperidin avoided a decrease in SOD and catalase activities in the thymus and spleen that was found after the additional exhaustion test. The antioxidant effects of hesperidin were associated with a higher performance in the assessed training model. These results suggest that hesperidin, acting as an antioxidant, can prevent oxidative stress induced by exercise and improve exercise performance.


Assuntos
Antioxidantes/farmacologia , Tolerância ao Exercício/efeitos dos fármacos , Hesperidina/farmacologia , Tecido Linfoide/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Condicionamento Físico Animal , Esforço Físico , Animais , Catalase/metabolismo , Células Cultivadas , Feminino , Glutationa Peroxidase/metabolismo , Tecido Linfoide/metabolismo , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Fatores de Tempo
7.
Ther Deliv ; 10(1): 63-80, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30730825

RESUMO

Under many circumstances, prophylactic immunizations are considered as the only possible strategy to control infectious diseases. Considerable efforts are typically invested in immunogen selection but, erroneously, the route of administration is not usually a major concern despite the fact that it can strongly influence efficacy. The skin is now considered a key component of the lymphatic system with tremendous potential as a target for vaccination. The purpose of this review is to present the immunological basis of the skin-associated lymphoid tissue, so as to provide understanding of the skin vaccination strategies. Several strategies are currently being developed for the transcutaneous delivery of antigens. The classical, mechanical or chemical disruptions versus the newest approaches based on microneedles for antigen delivery through the skin are discussed herein.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Absorção Cutânea , Pele/metabolismo , Vacinação/métodos , Vacinas/administração & dosagem , Administração Cutânea , Ensaios Clínicos como Assunto , Humanos , Tecido Linfoide/metabolismo , Agulhas/efeitos adversos
8.
Immunity ; 50(2): 493-504.e7, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30737144

RESUMO

Non-lymphoid tissues (NLTs) harbor a pool of adaptive immune cells with largely unexplored phenotype and development. We used single-cell RNA-seq to characterize 35,000 CD4+ regulatory (Treg) and memory (Tmem) T cells in mouse skin and colon, their respective draining lymph nodes (LNs) and spleen. In these tissues, we identified Treg cell subpopulations with distinct degrees of NLT phenotype. Subpopulation pseudotime ordering and gene kinetics were consistent in recruitment to skin and colon, yet the initial NLT-priming in LNs and the final stages of NLT functional adaptation reflected tissue-specific differences. Predicted kinetics were recapitulated using an in vivo melanoma-induction model, validating key regulators and receptors. Finally, we profiled human blood and NLT Treg and Tmem cells, and identified cross-mammalian conserved tissue signatures. In summary, we describe the relationship between Treg cell heterogeneity and recruitment to NLTs through the combined use of computational prediction and in vivo validation.


Assuntos
Adaptação Fisiológica/imunologia , Análise de Célula Única/métodos , Linfócitos T Reguladores/imunologia , Transcriptoma/imunologia , Adaptação Fisiológica/genética , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/imunologia , Colo/imunologia , Colo/metabolismo , Humanos , Memória Imunológica/genética , Memória Imunológica/imunologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Pele/imunologia , Pele/metabolismo , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/metabolismo
9.
Nutrients ; 11(2)2019 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-30717392

RESUMO

Hesperidin, found in citrus fruits, has shown a wide range of biological properties. Nonetheless, a more in-depth investigation is required on the effects on the immune system, and in particular, on the gut-associated lymphoid tissue, together with its relationship with the gut microbiota. Therefore, we aimed to establish the influence of oral hesperidin administration on the intestinal lymphoid tissue and on the gut microbiota composition in healthy animals. Lewis rats were orally administrated 100 or 200 mg/kg hesperidin three times per week for four weeks. Microbiota composition and IgA-coated bacteria were determined in caecal content. Mesenteric lymph node lymphocyte (MLNL) composition and functionality were assessed. IgA, cytokines, and gene expression in the small intestine were quantified. Hesperidin administration resulted in a higher number of bacteria and IgA-coated bacteria, with changes in microbiota composition such as higher Lactobacillus proportion. Hesperidin was also able to increase the small intestine IgA content. These changes in the small intestine were accompanied by a decrease in interferon-γ and monocyte chemotactic protein-1 concentration. In addition, hesperidin increased the relative proportion of TCRαß+ lymphocytes in MLNL. These results show the immunomodulatory actions of hesperidin on the gut-associated lymphoid tissue and reinforce its role as a prebiotic.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Hesperidina/farmacologia , Imunidade nas Mucosas/efeitos dos fármacos , Imunoglobulina A/metabolismo , Intestino Delgado/efeitos dos fármacos , Tecido Linfoide/efeitos dos fármacos , Prebióticos , Animais , Ceco/metabolismo , Ceco/microbiologia , Quimiocina CCL2/metabolismo , Citrus/química , Fatores Imunológicos/farmacologia , Interferon gama/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Intestino Delgado/microbiologia , Lactobacillus , Linfócitos/metabolismo , Tecido Linfoide/metabolismo , Masculino , Proteína Cofatora de Membrana , Mesentério , Extratos Vegetais/farmacologia , Ratos Endogâmicos Lew , Receptores de Antígenos de Linfócitos T alfa-beta
10.
Behav Brain Res ; 362: 152-159, 2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-30641160

RESUMO

Inadequate sleep is a major health concern of modern societies in view of the increased morbidity and mortality rates from physiological disturbances, including compromised adaptive immune responses. Many studies investigated the effect sleep restriction (SR) on the normal immune response in terms of leukocyte number and circulating cytokine and T helper cell (Th) profiles, but none considered the major histocompatibility complex (MHC), namely class II molecules. As no information exists about the normal temporal expression of MHC class II, the present study aimed at understanding how SR affects the adaptive immune response via altering the 1) normal daily expression profile and 2) overall constitutive levels of murine MHC class II by leukocytes' isolates from spleen and axillary lymph nodes. Male C57BL/6 mice were acclimatized to 12:12 light/dark cycle (lights on at 0700, corresponding to Zeitgeber time (ZT) 0) for a week before splitting into 2 groups: control (C) and SR (exposed to a 12 and 18 h of activity, respectively). SR was carried for one week before lymphoid tissues from both C and SR mice were sampled at the following time points: ZT0, ZT5, ZT10, ZT13, and ZT18. Spleen and lymph node cells were assessed for leukocyte number and MHC class II expression at the preselected time points using flow cytometry. SR resulted in a 21% decrease in granulocyte and 24% increase in agranulocyte numbers. MHC class II expression in both lymphoid tissues of C mice varied synchronously across the preselected times of day; they were relatively high just prior to activity onset and later in this period. Comparatively, the diurnal protein profile was altered in both lymphoid tissues of SR: 1) the rise of MHC class II expression during the rest period occurred 4-5 hours earlier and 2) the cyclical pattern during the activity period was blunted and protein expression was maintained at relatively high levels. MHC class II expression was higher in the lymph nodes and lower in the spleen of SR than C, though these differences did not reach statistical significance. In SR; however, the average protein level was significantly higher in lymph nodes than spleen (376.0 + 184.9 vs 188.6 + 42.2, respectively; p = .002) and higher in the granulocytes relative to agranulocytes. Our findings provide empirical evidence of a constitutive diurnal expression pattern for MHC class II molecules that is prone to upregulation upon SR, namely in lymph nodes, and specifically expressed by granulocytes. We speculate that, in mice, chronic sleep deprivation would further dysregulate MHC class II expression that might result in aberrant T cell activation with probable immune-associated pathological diseases such as allergies, autoimmunity, and tumors.


Assuntos
Antígenos de Histocompatibilidade Classe II/metabolismo , Tecido Linfoide/metabolismo , Sono/fisiologia , Baço/metabolismo , Animais , Interferon gama/metabolismo , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
Gen Physiol Biophys ; 38(1): 91-100, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30657461

RESUMO

Pregnant Wistar rats were exposed to ethanol under chronic conditions using the gavage method to assess the complement activation and effects of oxidative stress on fetus lymphoid organs and liver. The effects were monitored on both the 10th (G10) and the 30th (G30) day of the offspring of alcoholic mother rats. Maternal ethanol caused a significant decrease in the glutathione level, whereas malondialdehyde and carbonyl levels increased in the liver and lymphoid tissues. Na+,K+-ATPase, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase activities in these organs also decreased. Furthermore, complement C3 and C5 activities of G10 and G30 groups were significantly higher compared with those of the control group. In conclusion, the results demonstrated that alcohol was capable of triggering damage to the membranes of the liver and lymphoid tissues of G10 and G30 groups, and C3 and C5 contributed to the development of alcohol-induced fetal tissue injury.


Assuntos
Animais Recém-Nascidos/imunologia , Animais Recém-Nascidos/metabolismo , Ativação do Complemento/efeitos dos fármacos , Etanol/farmacologia , Tecido Linfoide/efeitos dos fármacos , Tecido Linfoide/metabolismo , Mães , Estresse Oxidativo , Animais , Antioxidantes , Etanol/efeitos adversos , Feminino , Doenças Fetais/induzido quimicamente , Doenças Fetais/imunologia , Doenças Fetais/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Tecido Linfoide/imunologia , Gravidez , Ratos , Ratos Wistar
12.
Immunol Cell Biol ; 97(1): 29-38, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30107066

RESUMO

BPSM1 (Bone phenotype spontaneous mutant 1) mice develop severe polyarthritis and heart valve disease as a result of a spontaneous mutation in the Tnf gene. In these mice, the insertion of a retrotransposon in the 3' untranslated region of Tnf causes a large increase in the expression of the cytokine. We have found that these mice also develop inducible bronchus-associated lymphoid tissue (iBALT), as well as nodular lymphoid hyperplasia (NLH) in the bone marrow. Loss of TNFR1 prevents the development of both types of follicles, but deficiency of TNFR1 in the hematopoietic compartment only prevents the iBALT and not the NLH phenotype. We show that the development of arthritis and heart valve disease does not depend on the presence of the tertiary lymphoid tissues. Interestingly, while loss of IL-17 or IL-23 limits iBALT and NLH development to some extent, it has no effect on polyarthritis or heart valve disease in BPSM1 mice.


Assuntos
Tecido Linfoide/patologia , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Fator de Necrose Tumoral alfa/biossíntese , Animais , Medula Óssea/patologia , Hiperplasia , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-23/genética , Interleucina-23/metabolismo , Tecido Linfoide/metabolismo , Camundongos , Fator de Necrose Tumoral alfa/genética
13.
Leukemia ; 33(3): 625-637, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30267008

RESUMO

Chronic lymphocytic leukemia (CLL) is associated with substantial alterations in T-cell composition and function. However, the role of T-cells in CLL remains largely controversial. Here, we utilized the Eµ-TCL1 mouse model of CLL as well as blood and lymph node samples of CLL patients to investigate the existence of anti-tumoral immune responses in CLL, and to characterize involved immune cell populations. Thereby, we identified an oligoclonal CD8+ effector T-cell population that expands along with CLL progression and controls disease development. We further show that a higher percentage of CD8+ effector T-cells produces IFNγ, and demonstrate that neutralization of IFNγ results in faster CLL progression in mice. Phenotypical and functional analyses of expanded CD8+ effector T-cells show significant differences in disease-affected tissues in mice, with cells in secondary lymphoid organs harboring hallmarks of activation-induced T-cell exhaustion. Notably, we further describe a respective population of exhausted CD8+ T-cells that specifically accumulate in lymph nodes, but not in peripheral blood of CLL patients. Collectively, these data emphasize the non-redundant role of CD8+ T-cells in suppressing CLL progression and highlight their dysfunction that can be exploited as target of immunotherapy in this malignancy.


Assuntos
Linfócitos T CD8-Positivos/patologia , Leucemia Linfocítica Crônica de Células B/patologia , Tecido Linfoide/patologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Humanos , Imunoterapia/métodos , Interferon gama/metabolismo , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfonodos/patologia , Ativação Linfocitária/fisiologia , Tecido Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
14.
Mol Ther ; 27(1): 164-177, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30391142

RESUMO

Broadly neutralizing antibodies (bNAbs) are among the most promising strategies to achieve long-term control of HIV-1 in the absence of combination antiretroviral therapy. Passive administration of such antibodies in patients efficiently decreases HIV-1 viremia, but is limited by the serum half-life of the protein. Here, we investigated whether antibody-secreting hematopoietic cells could overcome this problem. We genetically modified human CD34+ hematopoietic stem and progenitor cells (HSPCs) to secrete bNAbs and transplanted them into immunodeficient mice. We found that the gene-modified cells engraft and stably secrete antibodies in the peripheral blood of the animals for the 9 months of the study. Antibodies were predominantly expressed by human HSPC-derived T- and B cells. Importantly, we found that secreted PGT128 was able to delay HIV-1 viremia in vivo and also prevent a decline in CD4+ cells. Gene-modified cells were maintained in bone marrow and were also detected in spleen, thymus, lymph nodes, and gut-associated lymphoid tissue. These data indicate that the bNAb secretion from HSPC-derived cells in mice is functional and can affect viral infection and CD4+ cell maintenance. This study paves the way for potential applications to other diseases requiring long-lasting protein or antibody delivery.


Assuntos
Anticorpos Neutralizantes/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Animais , Animais Recém-Nascidos , Antígenos CD34/metabolismo , Linfócitos B/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Humanos , Antígenos Comuns de Leucócito/metabolismo , Fígado/metabolismo , Tecido Linfoide/metabolismo , Camundongos , RNA Viral/genética , RNA Viral/metabolismo , Linfócitos T/metabolismo , Carga Viral , Viremia/genética , Viremia/metabolismo
15.
Int J Mol Sci ; 20(1)2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30577453

RESUMO

Cysteine-X-cysteine chemokine receptor 4 (CXCR4) is a broadly expressed and multifunctional G protein-coupled chemokine receptor critical for organogenesis, hematopoiesis, and antimicrobial host defense. In the hematopoietic system, the binding of CXCR4 to its cognate chemokine ligand, CXCL12, mediates leukocyte trafficking, distribution, survival, activation, and proliferation. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the C-terminus of CXCR4 that prevent receptor downregulation and therefore result in pathologically increased signaling. The "M" in the acronym WHIM refers to myelokathexis, the retention of neutrophils in the bone marrow resulting in neutropenia, which explains in part the increased susceptibility to bacterial infection. However, WHIM patients also present with B and T lymphopenia, which may explain the susceptibility to human papillomavirus (HPV), the cause of warts. The impact of WHIM mutations on lymphocytes and adaptive immunity has received less attention than myelokathexis and is the focus of this review.


Assuntos
Imunidade Adaptativa , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/etiologia , Verrugas/diagnóstico , Verrugas/etiologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Gerenciamento Clínico , Humanos , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/terapia , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Verrugas/metabolismo , Verrugas/terapia
16.
Cell Rep ; 25(11): 3059-3073.e10, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30540939

RESUMO

Mitochondria are key players in the regulation of T cell biology by dynamically responding to cell needs, but how these dynamics integrate in T cells is still poorly understood. We show here that the mitochondrial pro-fission protein Drp1 fosters migration and expansion of developing thymocytes both in vitro and in vivo. In addition, we find that Drp1 sustains in vitro clonal expansion and cMyc-dependent metabolic reprogramming upon activation, also regulating effector T cell numbers in vivo. Migration and extravasation defects are also exhibited in Drp1-deficient mature T cells, unveiling its crucial role in controlling both T cell recirculation in secondary lymphoid organs and accumulation at tumor sites. Moreover, the observed Drp1-dependent imbalance toward a memory-like phenotype favors T cell exhaustion in the tumor microenvironment. All of these findings support a crucial role for Drp1 in several processes during T cell development and in anti-tumor immune-surveillance.


Assuntos
Movimento Celular , Dinaminas/metabolismo , Vigilância Imunológica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Contagem de Células , Diferenciação Celular , Proliferação de Células , Sobrevivência Celular , Homeostase , Ativação Linfocitária/imunologia , Tecido Linfoide/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos Knockout , Fenótipo , Receptores de Antígenos de Linfócitos T , Timócitos/citologia , Timócitos/metabolismo
17.
Br J Nutr ; 120(12): 1349-1358, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30387407

RESUMO

Zn serves as a powerful feed additive to reduce post-weaning diarrhoea in pigs. However, the mechanisms responsible for Zn-associated effects on the adaptive immune responses following feeding of a very high dosage of Zn remain elusive. In this study, we examined the T-cell response in gut-associated lymphatic tissues of seventy-two weaned piglets. Piglets received diets with 57 mg Zn/kg (low Zn concentration, LZn), 164 mg Zn/kg (medium Zn concentration, MZn) or 2425 mg Zn/kg (high Zn concentration, HZn) mg Zn/kg feed for 1, 2 or 4 weeks. We observed that feeding the HZn diet for 1 week increased the level of activated T-helper cells (CD4+ and CD8α dim) compared with feeding MZn and LZn (P<0·05). In addition, we observed higher transcript amounts of interferon γ and T-box 21 (TBET) in the HZn group compared with the MZn and LZn groups (P<0·05). A gene set enrichment analysis revealed an over-representation of genes associated with 'cytokine signalling in immune system'. Remarkably, feeding of a very high Zn dosage led to a switch in the immune response after 2 weeks. We detected higher relative cell counts of CD4+CD25high regulatory T-helper cells (P<0·05) and a higher expression of forkhead box P3 (FOXP3) transcripts (P<0·05). After 4 weeks of feeding a high-dosage Zn diet, the relative CD4+ T-cell count (P<0·05) and the relative CD8ß + T-cell count (P<0·1) were reduced compared with the MZn group. We hypothesise that after 1 week the cellular T-helper 1 response is switched on and after 2 weeks it is switched off, leading to decreased numbers of T-cells.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Intestinos/efeitos dos fármacos , Tecido Linfoide/metabolismo , Zinco/farmacologia , Ração Animal , Animais , Citocinas/metabolismo , Dieta , Feminino , Regulação da Expressão Gênica , Sistema Imunitário , Intestinos/patologia , Leucócitos/efeitos dos fármacos , Tecido Linfoide/efeitos dos fármacos , Masculino , Micronutrientes/química , Análise de Sequência de RNA , Sus scrofa , Suínos , Células Th1/efeitos dos fármacos , Desmame , Óxido de Zinco/química
18.
Front Immunol ; 9: 2375, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30369933

RESUMO

CD1d-restricted Natural Killer T (NKT) cells are regarded as sentinels of tissue integrity by sensing local cell stress and damage. This occurs via recognition of CD1d-restricted lipid antigens, generated by stress-related metabolic changes, and stimulation by inflammatory cytokines, such as IL-12 and IL-18. Increasing evidence suggest that this occurs mainly upon NKT cell interaction with CD1d-expressing cells of the Mononuclear Phagocytic System, i.e., monocytes, macrophages and DCs, which patrol parenchymatous organs and mucosae to maintain tissue homeostasis and immune surveillance. In this review, we discuss critical examples of this crosstalk, presenting the known underlying mechanisms and their effects on both cell types and the environment, and suggest that the interaction with CD1d-expressing mononuclear phagocytes in tissues is the fundamental job of NKT cells.


Assuntos
Comunicação Celular , Suscetibilidade a Doenças , Sistema Fagocitário Mononuclear/imunologia , Sistema Fagocitário Mononuclear/metabolismo , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Especificidade de Órgãos/imunologia , Fagócitos/imunologia , Fagócitos/metabolismo , Microambiente Tumoral
19.
Blood Adv ; 2(19): 2533-2542, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30291111

RESUMO

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) constitutes a heterogeneous category of lymphomas, which do not fit into any of the specifically defined T-cell lymphoma entities. Both the pathogenesis and tumor biology in PTCL-NOS are poorly understood. Protein expression in pretherapeutic PTCL-NOS tumors was analyzed by proteomics. Differentially expressed proteins were compared in 3 distinct scenarios: (A) PTCL-NOS tumor tissue (n = 18) vs benign lymphoid tissue (n = 8), (B) clusters defined by principal component analysis (PCA), and (C) tumors from patients with chemosensitive vs refractory PTCL-NOS. Selected differentially expressed proteins identified by proteomics were correlated with clinico-pathological features and outcome in a larger cohort of patients with PTCL-NOS (n = 87) by immunohistochemistry (IHC). Most proteins with altered expression were identified comparing PTCL-NOS vs benign lymphoid tissue. PCA of the protein profile defined 3 distinct clusters. All benign samples clustered together, whereas PTCL-NOS tumors separated into 2 clusters with different patient overall survival rates (P = .001). Differentially expressed proteins reflected large biological diversity among PTCL-NOS, particularly associated with alterations of "immunological" pathways. The 2 PTCL-NOS subclusters defined by PCA showed disturbance of "stress-related" and "protein metabolic" pathways. α-Enolase 1 (ENO1) was found differentially expressed in all 3 analyses, and high intratumoral ENO1 expression evaluated by IHC correlated with poor outcome (hazard ratio, 2.09; 95% confidence interval, 1.17-3.73; P = .013). High expression of triosephosphate isomerase (TPI1) also showed a tendency to correlate with poor survival (P = .057). In conclusion, proteomic profiling of PTCL-NOS provided evidence of markedly altered protein expression and identified ENO1 as a novel potential prognostic marker.


Assuntos
Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/mortalidade , Proteoma , Proteômica , Aldeído-Desidrogenase Mitocondrial/metabolismo , Biomarcadores Tumorais/metabolismo , Cromatografia Líquida , Biologia Computacional , Proteínas de Ligação a DNA/metabolismo , Feminino , Humanos , Tecido Linfoide/metabolismo , Linfoma de Células T Periférico/genética , Masculino , Fosfopiruvato Hidratase/metabolismo , Prognóstico , Proteômica/métodos , Espectrometria de Massas em Tandem , Proteínas Supressoras de Tumor/metabolismo
20.
Int J Mol Sci ; 19(10)2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30314337

RESUMO

The risk of developing lymphoma in patients with Sjögren's syndrome (SS) is 44 times higher than in the normal population with the most common lymphomas derived from marginal zone B (MZB) cells. Current understanding of the role of MZB cells in SS is primarily based on salivary gland pathology, while their contextual association with lacrimal glands and ocular manifestations largely remains unknown. We examined this possibility using a SS mouse model (thrombospondin-1 deficient (TSP1-/-)) with well-characterized ocular disease. We determined the frequency, localization, and cytokine profiles of MZB cells and their association with an antibody response in TSP1-/- mice treated with a TSP-derived peptide. A significantly increased frequency of MZB cells was detected in the spleens and lacrimal glands of TSP1-/- mice in comparison to wild-type tissues as detected by immunostaining. An altered cytokine profile of TSP1-/- MZB cells was supportive of T helper 17 (Th17)-related pathogenesis. A significantly reduced antibody response and the splenic MZB compartment against an eye-derived antigen were noted in TSP-derived peptide-treated mice. These changes correspond with the previously reported ability of the peptide to ameliorate SS-related ocular manifestations. Collectively, our results demonstrate dysregulation of MZB cells in TSP1-/- mice and highlight their role in the context of SS-related chronic ocular surface disease.


Assuntos
Subpopulações de Linfócitos B/imunologia , Endoftalmite/etiologia , Síndrome de Sjogren/etiologia , Animais , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/metabolismo , Citocinas/biossíntese , Modelos Animais de Doenças , Endoftalmite/metabolismo , Endoftalmite/patologia , Imunidade Inata , Mediadores da Inflamação/metabolismo , Aparelho Lacrimal/imunologia , Aparelho Lacrimal/metabolismo , Aparelho Lacrimal/patologia , Contagem de Linfócitos , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Tecido Linfoide/patologia , Masculino , Camundongos , Camundongos Knockout , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Glândulas Salivares/patologia , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Baço/imunologia , Baço/metabolismo , Trombospondina 1/genética , Trombospondina 1/imunologia , Trombospondina 1/metabolismo
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