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1.
PLoS Biol ; 17(10): e3000383, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31661488

RESUMO

Thymic involution and proliferation of naive T cells both contribute to shaping the naive T-cell repertoire as humans age, but a clear understanding of the roles of each throughout a human life span has been difficult to determine. By measuring nuclear bomb test-derived 14C in genomic DNA, we determined the turnover rates of CD4+ and CD8+ naive T-cell populations and defined their dynamics in healthy individuals ranging from 20 to 65 years of age. We demonstrate that naive T-cell generation decreases with age because of a combination of declining peripheral division and thymic production during adulthood. Concomitant decline in T-cell loss compensates for decreased generation rates. We investigated putative mechanisms underlying age-related changes in homeostatic regulation of CD4+ naive T-cell turnover, using mass cytometry to profile candidate signaling pathways involved in T-cell activation and proliferation relative to CD31 expression, a marker of thymic proximity for the CD4+ naive T-cell population. We show that basal nuclear factor κB (NF-κB) phosphorylation positively correlated with CD31 expression and thus is decreased in peripherally expanded naive T-cell clones. Functionally, we found that NF-κB signaling was essential for naive T-cell proliferation to the homeostatic growth factor interleukin (IL)-7, and reduced NF-κB phosphorylation in CD4+CD31- naive T cells is linked to reduced homeostatic proliferation potential. Our results reveal an age-related decline in naive T-cell turnover as a putative regulator of naive T-cell diversity and identify a molecular pathway that restricts proliferation of peripherally expanded naive T-cell clones that accumulate with age.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem da Célula/imunologia , Homeostase/imunologia , Timo/imunologia , Adulto , Idoso , Envelhecimento/genética , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Linhagem da Célula/genética , Proliferação de Células , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Homeostase/genética , Humanos , Imunofenotipagem , Interleucina-7/genética , Interleucina-7/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/imunologia , Fosforilação , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Transdução de Sinais , Timo/citologia , Timo/crescimento & desenvolvimento
2.
BMC Med Genet ; 20(1): 140, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420016

RESUMO

BACKGROUND: Severe malarial anemia (SMA) is a leading cause of malaria-related morbidity and mortality in children. The genetic factors that influence development of SMA and inefficient erythropoiesis, a central pathogenic feature of SMA, are only partially understood. METHODS: We performed a pilot Genome-wide Association Study (GWAS) on children with Plasmodium falciparum. The GWAS was performed using the Illumina® Infinium® HD Super Assay in conjunction with Illumina's® Human Omni2.5-8v1 BeadChip (with > 2.45 M markers). Data were analyzed using single SNP logistic regression analysis with an additive model of inheritance controlling for covariates. Results from our pilot global genomics study identified that variation in interleukin (IL)-7 was associated with enhanced risk of SMA. To validate this finding, we investigated the relationship between genotypes and/or haplotypes of two single nucleotide polymorphisms (SNPs) in IL7 [72194 T/C and - 2440 A/G] and susceptibility to both SMA and inefficient erythropoiesis [i.e., reticulocyte production index (RPI) < 2.0 in anemic children (Hb < 11.0 g/dL). Children presenting with P. falciparum malaria (< 3 years, n = 883) were stratified into two groups: Uncomplicated malaria (UM, n = 718) and SMA (n = 165). RESULTS: Regression modeling, controlling for anemia-related confounders, revealed that carriage of the TC genotype at position 72194 T/C was associated with enhanced susceptibility to inefficient erythropoiesis (OR = 1.90; 95% CI 1.09-3.30; P = 0.02) as was homozygous CC (OR 5.14; 95% CI = 1.20-21.99; P = 0.03). Consistent with this finding, individuals with the CA (72194C/-2440A) haplotype had an increased risk of inefficient erythropoiesis (OR = 1.90; 95% CI = 1.10-3.30; P = 0.02), whereas TA haplotype carriers had marginal protection against inefficient erythropoiesis (OR = 0.24; 95% CI = 0.06-1.21; P = 0.05). These observations were supported by Cochran-Armitage trend test for inefficient erythropoiesis (CA > TA > CG; P < 0.01). Although none of the genotype and/or haplotypic variants were significantly associated with SMA, the direction of the risk profiles were consistent with the erythropoiesis results. CONCLUSION: Taken together, variation in IL7 is associated with erythropoietic responses in children with falciparum malaria, a central physiological feature contributing to development of SMA.


Assuntos
Eritropoese/genética , Variação Genética , Interleucina-7/genética , Malária Falciparum/complicações , Anemia/etiologia , Anemia/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Lactente , Quênia , Masculino , Projetos Piloto , Plasmodium falciparum/patogenicidade , Polimorfismo de Nucleotídeo Único
3.
J Immunol Res ; 2019: 7453236, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31276000

RESUMO

The rationale for a type 17 signature in the pathogenesis of spondyloarthritis (SpA) has been increasing and being ratified in studies recently. IL-7 is a cytokine whose ability to stimulate IL-17 production in both innate and adaptive immunity cells has made it a promising target not only for a better understanding of the disease as well as an important potential therapeutic target in patients with SpA.


Assuntos
Citocinas/metabolismo , Suscetibilidade a Doenças , Interleucina-7/metabolismo , Espondilartrite/etiologia , Espondilartrite/metabolismo , Imunidade Adaptativa , Animais , Citocinas/genética , Fibrose , Humanos , Imunidade Inata , Interleucina-7/genética , Ligação Proteica , Receptores de Citocinas/metabolismo , Transdução de Sinais , Espondilartrite/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia
4.
Life Sci Alliance ; 2(2)2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30936185

RESUMO

The immune system encompasses acquired and innate immunity that matures through interaction with microenvironmental components. Cytokines serve as environmental factors that foster functional maturation of immune cells. Although NOD/SCID/IL2rgKO (NSG) humanized mice support investigation of human immunity in vivo, a species barrier between human immune cells and the mouse microenvironment limits human acquired as well as innate immune function. To study the roles of human cytokines in human acquired and innate immune cell development, we created NSG mice expressing hIL-7 and hIL-15. Although hIL-7 alone was not sufficient for supporting human NK cell development in vivo, increased frequencies of human NK cells were confirmed in multiple organs of hIL-7 and hIL-15 double knockin (hIL-7xhIL-15 KI) NSG mice engrafted with human hematopoietic stem cells. hIL-7xhIL-15 KI NSG humanized mice provide a valuable in vivo model to investigate development and function of human NK cells.


Assuntos
Diferenciação Celular , Técnicas de Introdução de Genes , Interleucina-15/sangue , Interleucina-15/genética , Interleucina-7/sangue , Interleucina-7/genética , Células Matadoras Naturais/fisiologia , Animais , Antígeno CD56/metabolismo , Feminino , Sangue Fetal/citologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Modelos Animais , Timo/citologia , Transcriptoma , Transplante Heterólogo
5.
Biol Pharm Bull ; 42(3): 468-474, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828078

RESUMO

Skin dryness is a characteristic of rheumatoid arthritis (RA) model mice. However, the mechanism underlying the induction of dry skin by RA is unclear. We hypothesized that T helper (Th)2 and Th17 cells mediate this process. A mouse model of DBA/1JJmsSlc collagen-induced arthritis was treated with Th2 or Th17 cell inhibitor, and transepidermal water loss (TEWL) and the expression of markers associated with allergic reaction and inflammation were evaluated. TEWL and plasma levels of thymic stromal lymphopoietin, interleukin (IL)-6 and -17, and tumor necrosis factor (TNF)-α were increased in the arthritis mouse model compared to that in control mice. Administration of Th2 cell inhibitor abolished the increase in TEWL, IL-6, and TNF-α levels, whereas Th17 cell inhibitor reversed TEWL and decreased IL-17 level. Th2 and Th17 cells contribute to the induction of dry skin, but via distinct mechanisms.


Assuntos
Artrite Experimental , Fenômenos Fisiológicos da Pele , Células Th17/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Perda Insensível de Água , Animais , Antracenos/administração & dosagem , Antracenos/farmacologia , Sulfonatos de Arila/administração & dosagem , Sulfonatos de Arila/farmacologia , Biomarcadores , Regulação da Expressão Gênica , Interleucina-17/sangue , Interleucina-17/genética , Interleucina-17/metabolismo , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-7/sangue , Interleucina-7/genética , Interleucina-7/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Distribuição Aleatória , Compostos de Sulfônio/administração & dosagem , Compostos de Sulfônio/farmacologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
6.
Australas J Dermatol ; 60(2): e132-e137, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30671936

RESUMO

BACKGROUND/OBJECTIVES: Psoriasis is one of the immune-mediated inflammatory diseases where CD4+ T lymphocytes, mainly Th1 cells, and B lymphocytes contribute in their pathogenesis through a pro-inflammatory effect, production of antibodies, activation of T cells and cytokine synthesis. B and T lymphocyte attenuator (BTLA) is a co-inhibitory molecule expressed on T and B lymphocytes as well as other immune cells, and it is necessary to inhibit homoeostatic expansion and activation of lymph node and skin-resident γδ T cells. BTLA expression is regulated by RORγt and IL-7. The study aimed at adding more insight on the role played by co-inhibitory molecule BTLA in psoriasis vulgaris and its inter-relation with RORγt and IL-7 to establish a basis for novel treatment strategies. METHODS: This case-control study included 25 patients and 25 controls examined for gene expression of BTLA, RORγt and IL-7. RESULTS: B and T lymphocyte attenuator was significantly lower in psoriasis patients, whereas both RORγt and IL-7 were higher in comparison with controls. A significant positive correlation between disease severity (PASI) and both RORγt and IL-7 as well as between RORγt and IL-7 was found. A significant negative correlation between BTLA and both RORγt and IL-7 was found. Neither the age nor the duration of disease had any correlation with BTLA, RORγt or IL-7. BTLA had no correlation with PASI. Regarding the control group, a significant negative correlation between RORγt and IL-7 was found. CONCLUSION: B and T lymphocyte attenuator, RORγt and IL-7 play an important role in psoriasis.


Assuntos
Interleucina-7/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Isoformas de Proteínas/metabolismo , Psoríase/metabolismo , Receptores Imunológicos/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Interleucina-7/genética , Masculino , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Isoformas de Proteínas/genética , Psoríase/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores Imunológicos/genética , Índice de Gravidade de Doença , Adulto Jovem
7.
Nanotechnology ; 30(16): 165702, 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-30641491

RESUMO

Uveitis is a recurrent, sight-threatening intraocular inflammatory disease and is treated with glucocorticoids in clinical practice. In the present study, methoxypoly(ethyleneglycol)-poly(dl-lactide-co-glycolic acid) (mPEG-PLGA) nanoparticles in combination with triamcinolone acetonide (TA) were fabricated using a modified double emulsification method. Further, we characterized the TA-loaded nanoparticles, and investigated the effects of TA-loaded nanoparticles on experimental autoimmune uveitis rats, including histopathological examination and the alterations in interleukin (IL)-17 and IL-10 at mRNA and protein levels in either aqueous humor or serum. As a result, the TA-loaded nanoparticles were a well-defined spherical shape with a mean particle size of 82 nm. The in vitro release profile showed that the TA-loaded nanoparticles could sustain for more than 45 days, and possessed higher anti-inflammatory effects compared to TA alone after pathological examination, resulting in decreased IL-17 and elevated IL-10 levels in both aqueous humor and serum. Based on these findings, it can be concluded that TA-loaded mPEG-PLGA nanoparticles can potentially provide a better anti-inflammatory effect in treating chronic and recurrent uveitis in clinical practice.


Assuntos
Anti-Inflamatórios/administração & dosagem , Interleucina-10/genética , Interleucina-7/genética , Poliésteres/química , Polietilenoglicóis/química , Triancinolona Acetonida/administração & dosagem , Uveíte/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Linhagem Celular , Sobrevivência Celular , Preparações de Ação Retardada , Modelos Animais de Doenças , Portadores de Fármacos/química , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-10/metabolismo , Interleucina-7/metabolismo , Nanopartículas/química , Tamanho da Partícula , Ratos , Triancinolona Acetonida/química , Triancinolona Acetonida/farmacologia , Uveíte/genética , Uveíte/metabolismo
8.
J Clin Lab Anal ; 33(2): e22675, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30239047

RESUMO

BACKGROUND: Recently studies uncovered associations between polymorphisms of interleukin genes and the risk of asthma. However, the relationship between polymorphisms of interleukin-7 gene and the risk of children asthma has not been discovered yet. This study aims to investigate the relationship between single nucleotide polymorphisms (SNPs) on interleukin-7 gene and the risk of children asthma. METHODS: We genotyped eight SNPs of interleukin-7 gene in blood samples from 437 asthma patients and 489 healthy controls to analyze potential associations of these SNPs with the risk of asthma in children. RESULTS: A missense SNP rs766736182 (odds ratio (OR) = 2.185, 95% confidence interval (CI) = 1.561-2.252, P-value = 8.69468E-19) of the interleukin-7 gene is associated with the risk of children asthma. CONCLUSIONS: This study reveals that SNP rs766736182 of interleukin-7 is the risk factor for children asthma and implies potential role of immune system in the pathogenesis of children asthma.


Assuntos
Asma/epidemiologia , Asma/genética , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Interleucina-7/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino
9.
Int Immunopharmacol ; 67: 202-210, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30557823

RESUMO

Interleukin (IL)-7 enhances cytokines secretion by CD14+ monocytes, and induces recruitment of monocytes to endothelium. As an important regulator to different types of immune cells, the role of IL-7 in modulation of CD14+ monocytes is still not fully elucidated. Thus, the aim of current study was to investigate the immunoregulatory activity of IL-7 to peripheral and lung-resident CD14+ monocytes in lung squamous carcinoma patients. Thirty-seven lung squamous carcinoma patients and eighteen healthy individuals were enrolled. CD14+ monocytes and CD4+ T cells were purified from both peripheral bloods and bronchoalveolar lavage fluids (BALF). IL-7 expression in plasma and BALF was measured by ELISA, and CD127 expression in peripheral and lung-resident CD14+ monocytes was investigated by real-time PCR and flow cytometry, respectively. Cellular proliferation, cytokine production, and molecules in IL-7 signaling pathway was assessed in CD14+ monocytes in response to IL-7 stimulation. IL-7-induced CD14+ monocytes activity to CD4+ T cells was also assessed in direct and indirect contact co-culture system. There were no remarkable differences of plasma IL-7 concentration or CD127 level between healthy individuals and lung squamous carcinoma patients. However, IL-7 expression was significantly reduced in BALF from tumor site in squamous carcinoma patients, especially in stage III and IV. IL-7 stimulation not only promoted proliferation, cytokines secretion, and STAT-5 phosphorylation in lung-resident CD14+ monocytes, but also enhanced CD14+ monocytes-induced Th1 and T follicular helper cells activation, which presented as elevated interferon-γ and IL-21 secretion by CD4+ T cells. This process required direct cell-to-cell contact, and was dependent on IL-6 secretion. The current data revealed a potential immunopromotive property of IL-7 to lung-resident CD14+ monocytes in lung squamous carcinoma.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Interleucina-7/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Neoplasias Pulmonares/metabolismo , Monócitos/metabolismo , Adulto , Idoso , Líquido da Lavagem Broncoalveolar/química , Estudos de Casos e Controles , Regulação para Baixo , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-7/genética , Receptores de Lipopolissacarídeos/genética , Pulmão/citologia , Masculino , Pessoa de Meia-Idade
10.
PLoS Negl Trop Dis ; 12(12): e0006998, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30517089

RESUMO

BACKGROUND: The severity of cardiac disease in chronic Chagas disease patients is associated with different features of T-cell exhaustion. Here, we assessed whether the ability of T cells to secrete IFN-γ in response to T. cruzi was linked to disruption in immune homeostasis and inflammation in patients with chronic Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: PBMCs from chronic Chagas disease patients and uninfected controls were examined for frequencies of T. cruzi-responsive IFN-γ-producing cells by ELISPOT and cellular expression and function of IL-7R using flow cytometry. Serum levels of IL-7, IL-21, IL-27, soluble IL-7R, and inflammatory cytokines were also evaluated by ELISA or CBA techniques. Patients possessing T. cruzi-specific IFN-γ-producing cells (i.e. IFN-γ producers) had higher levels of memory T cells capable of modulating the alpha chain of IL-7R and an efficient response to IL-7 compared to that in patients lacking (i.e. IFN-γ nonproducers) parasite-specific T-cell responses. IFN-γ producers also showed low levels of soluble IL-7R, high basal expression of Bcl-2 in T cells and low basal frequencies of activated CD25+ T cells. Modulation of IL-7R was inversely associated with serum IL-6 levels and positively associated with serum IL-8 levels. Circulating IL-21 and IL-27 levels were not associated with the frequency of IFN-γ producing cells but were reduced in less severe clinical forms of the disease. In vitro stimulation of PBMCs with IL-7 or IL-27 enhanced IFN-γ production in IFN-γ producers but not in IFN-γ nonproducers. CONCLUSIONS/SIGNIFICANCE: Alterations of the IL-7/IL-7R axis and in the levels of inflammatory cytokines were linked to impaired T. cruzi-specific IFN-γ production. These alterations might be responsible of the process of immune exhaustion observed in chronic Chagas disease.


Assuntos
Doença de Chagas/sangue , Interferon gama/sangue , Interleucina-7/sangue , Receptores de Interleucina-7/metabolismo , Trypanosoma cruzi/fisiologia , Adulto , Idoso , Doença de Chagas/genética , Doença de Chagas/parasitologia , Doença Crônica , ELISPOT , Feminino , Humanos , Interferon gama/genética , Interleucina-7/genética , Interleucinas/sangue , Leucócitos Mononucleares/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-7/genética , Linfócitos T/metabolismo , Trypanosoma cruzi/genética , Adulto Jovem
11.
Cardiovasc Ther ; 36(6): e12479, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30451388

RESUMO

AIMS: Mesenchymal stem cells (MSCs) hold significant promise as potential therapeutic candidates following cardiac injury. However, to ensure survival of transplanted cells in ischemic environment, it is beneficial to precondition them with growth factors that play important role in cell survival and proliferation. Aim of this study is to use interleukin-7 (IL-7), a cell survival growth factor, to enhance the potential of rat bone marrow MSCs in terms of cell fusion in vitro and cardiac function in vivo. METHODS: Mesenchymal stem cells were transfected with IL-7 gene through retroviral vector. Normal and transfected MSCs were co-cultured with neonatal cardiomyocytes (CMs) and cell fusion was analyzed by flow cytometry and fluorescence microscopy. These MSCs were also transplanted in rat model of myocardial infarction (MI) and changes at tissue level and cardiac function were assessed by histological analysis and echocardiography, respectively. RESULTS: Co-culture of IL-7 transfected MSCs and CMs showed significantly higher (P < 0.01) number of fused cells as compared to normal MSCs. Histological analysis of hearts transplanted with IL-7 transfected MSCs showed significant reduction (P < 0.001) in infarct size and better preservation (P < 0.001) of left ventricular wall thickness as compared to normal MSCs. Presence of cardiac-specific proteins, α-actinin, and troponin-T showed that the transplanted MSCs were differentiated into cardiomyocytes. Echocardiographic recordings of the experimental group transplanted with transfected MSCs showed significant increase in the ejection fraction and fractional shortening (P < 0.01), and decrease in diastolic and systolic left ventricular internal diameters (P < 0.001) and end systolic and diastolic volumes (P < 0.01 and P < 0.001, respectively). CONCLUSION: Interleukin-7 is able to enhance the fusogenic properties of MSCs and improve cardiac function. This improvement may be attributed to the supportive action of IL-7 on cell proliferation and cell survival contributing to the regeneration of damaged myocardium.


Assuntos
Fusão Celular , Interleucina-7/biossíntese , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/cirurgia , Miócitos Cardíacos/metabolismo , Animais , Animais Recém-Nascidos , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Feminino , Interleucina-7/genética , Masculino , Contração Miocárdica , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Regeneração , Volume Sistólico , Transfecção , Função Ventricular Esquerda , Remodelação Ventricular
12.
Front Immunol ; 9: 2258, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364182

RESUMO

Interleukin-7 (IL-7) and Flt3-ligand (FL) are two cytokines important for the generation of B cells, as manifested by the impaired B cell development in mice deficient for either cytokine or their respective receptors and by the complete block in B cell differentiation in the absence of both cytokines. IL-7 is an important survival and proliferation factor for B cell progenitors, whereas FL acts on several early developmental stages, prior to B cell commitment. We have generated mice constitutively over-expressing both IL-7 and FL. These double transgenic mice develop splenomegaly and lymphadenopathy characterized by tremendously enlarged lymph nodes even in young animals. Lymphoid, myeloid and dendritic cell numbers are increased compared to mice over-expressing either of the two cytokines alone and the effect on their expansion is synergistic, rather than additive. B cell progenitors, early progenitors with myeloid and lymphoid potential (EPLM), common lymphoid progenitors (CLP) and lineage-, Sca1+, kit+ (LSK) cells are all increased not only in the bone marrow but also in peripheral blood, spleen and even lymph nodes. When transplanted into irradiated wild-type mice, lymph node cells show long-term multilineage reconstitution, further confirming the presence of functional hematopoietic progenitors therein. Our double transgenic mouse model shows that sustained and combined over-expression of IL-7 and FL leads to a massive expansion of most bone marrow hematopoietic progenitors and to their associated presence in peripheral lymphoid organs where they reside and potentially differentiate further, thus leading to the synergistic increase in mature lymphoid and myeloid cell numbers. The present study provides further in vivo evidence for the concerted action of IL-7 and FL on lymphopoiesis and suggests that extramedullary niches, including those in lymph nodes, can support the survival and maintenance of hematopoietic progenitors that under physiological conditions develop exclusively in the bone marrow.


Assuntos
Células-Tronco Hematopoéticas/imunologia , Interleucina-7/imunologia , Células Progenitoras Linfoides/imunologia , Proteínas de Membrana/imunologia , Células-Tronco Multipotentes/imunologia , Animais , Proliferação de Células/genética , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Expressão Gênica/imunologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Interleucina-7/genética , Interleucina-7/metabolismo , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Células-Tronco Multipotentes/citologia , Células-Tronco Multipotentes/metabolismo
13.
Eur Rev Med Pharmacol Sci ; 22(19): 6436-6447, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30338812

RESUMO

OBJECTIVE: This research aimed to investigate the therapeutic effects of transplanted human umbilical cord mesenchymal stem cells (hUCMSCs) on spinal cord injury in mice and to explore its molecular mechanism. MATERIALS AND METHODS: Spinal cord injury model in C57BL/6J mice was established. On the 10th day of SCI, hUCMSCs were injected into the center of spinal cord injury area (hUCMSC), and control groups (Control) were injected with an equal amount of medium. Western blotting, Real Time-PCR, immunohistochemistry, and flow cytometry, were used to analyze the content of IL-7, inflammatory cytokines, and macrophages after spinal cord injury in different groups. Open field and Rota-Rod tests were used to determine the effect of hUCMSC transplantation on motor function recovery in SCI mice. RESULTS: Compared with the control mice, hUCMSC transplantation therapy significantly improved the motor function, myelin, and nerve cell survival in spinal cord injury site in SCI mice. It also reduced the expression of IL-7, IFN-γ, and TNF-α in injured sites but increased IL-4 and IL-13 expression and promoted the activation of M2 macrophages at the site of injury. CONCLUSIONS: Transplantation of hUCMSCs in SCI mice can promote the polarization of M2 macrophages by reducing the expression of IL-7 in the injured site, thereby weakening the inflammatory response at the injured site, promoting the repair of the injured site and improving the motor function.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Interleucina-7/metabolismo , Macrófagos/metabolismo , Traumatismos da Medula Espinal/cirurgia , Medula Espinal/cirurgia , Animais , Comportamento Animal , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Humanos , Interleucina-7/genética , Ativação de Macrófagos , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora , Fenótipo , Recuperação de Função Fisiológica , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia
14.
Int J Mol Sci ; 19(11)2018 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-30373315

RESUMO

IL-7 is an essential, nonredundant growth factor for T and B cell generation and maintenance. While IL-7 deficiency results in lymphopenia, overexpression of IL-7 can cause neoplasia in experimental models. IL-7's involvement in neoplasia has been appreciated through studies of IL-7 transgenic (Tg) mice models and human lymphoma patients. Since we recently found that a soluble form of the common γ-chain (γc) cytokine receptor (sγc) antagonistically regulates IL-7 signaling, IL-7 and sγc double-Tg mice were generated to investigate the effects of sγc overexpression in IL-7-mediated lymphoproliferative disorders (LPDs). The overexpression of sγc prevents IL-7Tg-induced abnormal increase of LN cell numbers and the development of splenomegaly, resulting in striking amelioration of mortality and disease development. These results suggest that modification of γc cytokine responsiveness by sγc molecules might control various γc cytokine-associated hematologic malignancy, and also provide an alternative view to approach antitumor therapy.


Assuntos
Subunidade gama Comum de Receptores de Interleucina/metabolismo , Interleucina-7/metabolismo , Transtornos Linfoproliferativos/metabolismo , Animais , Subunidade gama Comum de Receptores de Interleucina/genética , Interleucina-7/genética , Transtornos Linfoproliferativos/genética , Camundongos , Camundongos Endogâmicos C57BL
15.
J Exp Med ; 215(10): 2586-2599, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30158115

RESUMO

B cell progenitors require paracrine signals such as interleukin-7 (IL-7) provided by bone marrow stromal cells for proliferation and survival. Yet, how B cells regulate access to these signals in vivo remains unclear. Here we show that proB and IL-7+ cells form a cell circuit wired by IL-7R signaling, which controls CXCR4 and focal adhesion kinase (FAK) expression and restricts proB cell movement due to increased adhesion to IL-7+CXCL12Hi cells. PreBCR signaling breaks this circuit by switching the preB cell behavior into a fast-moving and lower-adhesion state via increased CXCR4 and reduced FAK/α4ß1 expression. This behavioral change reduces preB cell exposure to IL-7, thereby attenuating IL-7R signaling in vivo. Remarkably, IL-7 production is downregulated by signals provided by preB cells with unrepaired double-stranded DNA breaks and by preB acute lymphoblastic leukemic cells. Combined, these studies revealed that distinct cell circuits control the quality and homeostasis of B cell progenitors.


Assuntos
Interleucina-7/imunologia , Células-Tronco Mesenquimais/imunologia , Células Precursoras de Linfócitos B/imunologia , Receptores de Interleucina-7/imunologia , Transdução de Sinais/imunologia , Animais , Quimiocina CXCL12/genética , Interleucina-7/genética , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Knockout , Células Precursoras de Linfócitos B/citologia , Receptores de Interleucina-7/genética , Transdução de Sinais/genética
16.
Cell Immunol ; 331: 1-8, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29903664

RESUMO

Adoptive cell therapy (ACT) of autologous tumor-infiltrating lymphocytes (TILs) has shown an effect on mediating tumor regression in some patients with highly advanced, refractory metastatic malignancy. Here, the in vitro generation of TILs isolated from malignant pleural effusion and ascites was compared with which using engineered cells for costimulatory enhancement (ECCE) and 3 common γ-chain cytokines, interleukin (IL)-2, IL-7, and IL-15, alone or in combination. We showed the robust clinical-scale production of TILs with a less differentiated 'young' phenotype by expansion in the presence of ECCE combined with IL-2/7/15. Furthermore, a major fraction of the TILs generated in this fashion was shown to produce much more IFN-γ and TNF-α, and displayed cytolytic activity against target cells expressing the relevant antigens. To our knowledge, this is the first time that the combination of ECCE and IL-2/7/15 has been applied for the generation of TILs isolated from malignant pleural effusion and ascites.


Assuntos
Ascite/imunologia , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Derrame Pleural Maligno/imunologia , Ligante 4-1BB/genética , Ligante 4-1BB/imunologia , Ligante 4-1BB/metabolismo , Adulto , Idoso , Ascite/patologia , Divisão Celular/imunologia , Células Cultivadas , Feminino , Humanos , Imunoterapia Adotiva/métodos , Interleucina-15/genética , Interleucina-15/imunologia , Interleucina-15/metabolismo , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-2/metabolismo , Interleucina-7/genética , Interleucina-7/imunologia , Interleucina-7/metabolismo , Células K562 , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Derrame Pleural Maligno/patologia
17.
J Cell Mol Med ; 22(7): 3353-3363, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29566311

RESUMO

In schistosomiasis japonica and mansoni, parasite eggs trapped in host liver elicit severe liver granulomatous inflammation that subsequently leads to periportal fibrosis, portal hypertension, haemorrhage or even death. Macrophages are critical for granuloma formation and the development of liver fibrosis during schistosomiasis. However, whether the aberrant regulation of macrophage autophagy has an effect on the development of liver immunopathology in schistosomiasis remains to be elucidated. In this study, we showed that Schistosoma japonicum (S. japonicum) egg antigen (SEA)-triggered macrophage autophagy limited the development of pathology in host liver. However, engagement of IL-7 receptor (IL-7R/CD127) on macrophages by S. japonicum infection-induced IL-7 significantly suppressed SEA-triggered macrophage autophagy, which led to an enhanced liver pathology. In addition, anti-IL-7 neutralizing antibody or anti-CD127 blocking antibody treatment increased macrophage autophagy and suppressed liver pathology. Finally, we demonstrated that IL-7 protects macrophage against SEA-induced autophagy through activation of AMP-activated protein kinase (AMPK). Our study reveals a novel role for IL-7 in macrophage autophagy and identifies AMPK as a novel downstream mediator of IL-7-IL-7R signalling and suggests that manipulation of macrophage autophagy by targeting IL-7-IL-7R signalling may have the potential to lead to improved treatment options for liver pathogenesis in schistosomiasis.


Assuntos
Interleucina-7/metabolismo , Fígado/patologia , Macrófagos Peritoneais/patologia , Esquistossomose Japônica/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Autofagia , Feminino , Interações Hospedeiro-Parasita/fisiologia , Interleucina-7/genética , Interleucina-7/farmacologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Fígado/metabolismo , Fígado/parasitologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Camundongos Endogâmicos C57BL , Schistosoma japonicum/patogenicidade , Esquistossomose Japônica/metabolismo
18.
Nat Biotechnol ; 36(4): 346-351, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29505028

RESUMO

Infiltration, accumulation, and survival of chimeric antigen receptor T (CAR-T) cells in solid tumors is crucial for tumor clearance. We engineered CAR-T cells to express interleukin (IL)-7 and CCL19 (7 × 19 CAR-T cells), as these factors are essential for the maintenance of T-cell zones in lymphoid organs. In mice, 7 × 19 CAR-T cells achieved complete regression of pre-established solid tumors and prolonged mouse survival, with superior anti-tumor activity compared to conventional CAR-T cells. Histopathological analyses showed increased infiltration of dendritic cells (DC) and T cells into tumor tissues following 7 × 19 CAR-T cell therapy. Depletion of recipient T cells before 7 × 19 CAR-T cell administration dampened the therapeutic effects of 7 × 19 CAR-T cell treatment, suggesting that CAR-T cells and recipient immune cells collaborated to exert anti-tumor activity. Following treatment of mice with 7 × 19 CAR-T cells, both recipient conventional T cells and administered CAR-T cells generated memory responses against tumors.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos , Quimiocina CCL19/administração & dosagem , Interleucina-7/administração & dosagem , Receptores de Antígenos de Linfócitos T/administração & dosagem , Receptores de Antígenos Quiméricos/administração & dosagem , Aloenxertos , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Quimiocina CCL19/genética , Células Dendríticas/imunologia , Células Dendríticas/transplante , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-7/genética , Camundongos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia
19.
Sci Rep ; 8(1): 3495, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29472568

RESUMO

Galectin-3 (Gal-3) is a ß-galactoside binding protein that controls cell-cell and cell-extracellular matrix interactions. In lymphoid organs, gal-3 inhibits B cell differentiation by mechanisms poorly understood. The B cell development is dependent on tissue organization and stromal cell signaling, including IL-7 and Notch pathways. Here, we investigate possible mechanisms that gal-3 interferes during B lymphocyte differentiation in the bone marrow (BM) and spleen. The BM of gal-3-deficient mice (Lgals3-/- mice) was evidenced by elevated numbers of B220+CD19+c-Kit+IL-7R+ progenitor B cells. In parallel, CD45- bone marrow stromal cells expressed high levels of mRNA IL-7, Notch ligands (Jagged-1 and Delta-like 4), and transcription factors (Hes-1, Hey-1, Hey-2 and Hey-L). The spleen of Lgals3-/- mice was hallmarked by marginal zone disorganization, high number of IgM+IgD+ B cells and CD138+ plasma cells, overexpression of Notch ligands (Jagged-1, Delta-like 1 and Delta-like 4) by stromal cells and Hey-1. Morever, IgM+IgD+ B cells and B220+CD138+ CXCR4+ plasmablasts were significantly increased in the BM and blood of Lgals3-/- mice. For the first time, we demonstrated that gal-3 inhibits Notch signaling activation in lymphoid organs regulating earlier and terminal events of B cell differentiation.


Assuntos
Diferenciação Celular/genética , Galectina 3/genética , Células Secretoras de Insulina/metabolismo , Receptores Notch/genética , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Regulação da Expressão Gênica/genética , Células Secretoras de Insulina/citologia , Interleucina-7/genética , Ligantes , Camundongos , Transdução de Sinais/genética , Baço/crescimento & desenvolvimento , Baço/metabolismo , Células Estromais/citologia , Células Estromais/metabolismo , Estruturas Linfoides Terciárias/genética , Fatores de Transcrição/genética
20.
Cancer Sci ; 109(2): 279-288, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29224228

RESUMO

Interleukin 15 (IL15) and IL7 are two cytokines essential for T cell development and homeostasis. In order to improve the antitumor activity by Newcastle disease virus (NDV)-modified tumor vaccine, we generated a recombinant NDV co-expressing IL15 and IL7 (LX/IL(15+7)) through incorporation of a 2A self-processing peptide into IL15 and IL7 using reverse genetics. B16 cells infected with LX/IL(15+7) expressed both IL15 and IL7 stably. The cytotoxicity assay showed that murine melanoma cells modified with LX/IL(15+7) could significantly enhance the antitumor immune response in vitro. Then, the antitumor effects of tumor vaccine modified with recombinant virus were tested in the murine tumor models. We observed strong antitumor responses induced by LX/IL(15+7)-modified tumor cells both in prophylaxis and therapeutic models. Although the tumor-infiltrating CD4+ T cells and CD8+ T cells were both increased, the antitumor activity of the tumor vaccine modified with LX/IL(15+7) was dependent on CD8+ T cells. Taken together, our data strongly indicated that tumor vaccine modified with NDV strain LX/IL(15+7) is a promising agent for cancer immunotherapy.


Assuntos
Interleucina-15/metabolismo , Interleucina-7/metabolismo , Melanoma Experimental/terapia , Vírus da Doença de Newcastle/genética , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Sobrevivência Celular , Vetores Genéticos/administração & dosagem , Imunoterapia , Interleucina-15/genética , Interleucina-7/genética , Melanoma Experimental/imunologia , Camundongos , Vírus da Doença de Newcastle/crescimento & desenvolvimento , Genética Reversa
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