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2.
Biosci Microbiota Food Health ; 38(4): 141-149, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31763117

RESUMO

Propolis possesses several immunological functions. We recently generated a conditional Ca2+ biosensor yellow cameleon (YC3.60) transgenic mouse line and established a five-dimensional (5D) (x, y, z, time, and Ca2+ signaling) system for intravital imaging of lymphoid tissues, including Peyer's patches (PPs). To assess the effects of propolis on immune cells, we analyzed Ca2+ signaling in vitro and in vivo using CD11c-Cre/YC3.60flox transgenic mice, in which CD11c+ dendritic cells (DCs) specifically express YC3.60. We found that propolis induced Ca2+ signaling in DCs in the PPs. Intravital imaging of PPs also showed that an intraperitoneal injection of propolis augmented Ca2+ signaling in CD11c+ cells, suggesting that propolis possesses immune-stimulating activity. Furthermore, CD11c+ cells in PPs in mice administrated propolis indicated an increase in Ca2+ signaling. Our results indicate that propolis induces immunogenicity under physiological conditions.

3.
ACS Nano ; 13(7): 7705-7715, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31241885

RESUMO

Strengthening the antitumor immune response to surpass the activation energy barrier associated with the immunosuppressive tumor microenvironment is an active area of cancer immunotherapy. Emerging evidence suggests that delivery of immunostimulatory molecules with the aid of a carrier system is essential for cancer immunotherapy. However, the size-dependent effect of the delivery system on immune-targeted sites and anticancer immune responses is yet to be comprehensively understood. Herein, to clarify the size-dependent effect of the delivery system on the underlying anticancer immune mechanism, rod-shaped hydroxyapatite (HA) particles with lengths from 100 nm to 10 µm are designed. HA rods stimulate anticancer immunity in a size-dependent manner. Shorter HA rods with lengths ranging from 100 to 500 nm promote antigen cellular uptake, dendritic cell (DC) maturation, and lymph node targeting antigen. In contrast, longer HA rods with lengths ranging from 500 nm to 10 µm prolong antigen retention and increase DC accumulation. Medium-sized HA rods with a length of 500 nm, taking advantage of both short and long rods, show optimized antigen release and uptake, increased DCs accumulation and maturation, highest CD4+ and CD8+ T cell population, and the best anticancer immunity in vivo. The present study provides a rod-scale design strategy for an immune-targeted delivery system toward cancer immunotherapy in the future.

4.
J Clin Exp Hematop ; 59(1): 1-16, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918139

RESUMO

The microenvironment influences the behavior of follicular lymphoma (FL) but the specific roles of the immunomodulatory BTLA and TNFRSF14 (HVEM) are unknown. Therefore, we examined their immunohistochemical expression in the intrafollicular, interfollicular and total histological compartments in 106 FL cases (57M/49F; median age 57-years), and in nine relapsed-FL with transformation to DLBCL (tFL). BTLA expression pattern was of follicular T-helper cells (TFH) in the intrafollicular and of T-cells in the interfollicular compartments. The mantle zones were BTLA+ in 35.6% of the cases with similar distribution of IgD. TNFRSF14 expression pattern was of neoplastic B lymphocytes (centroblasts) and "tingible body macrophages". At diagnosis, the averages of total BTLA and TNFRSF14-positive cells were 19.2%±12.4STD (range, 0.6%-58.2%) and 46.7 cells/HPF (1-286.5), respectively. No differences were seen between low-grade vs. high-grade FL but tFL was characterized by low BTLA and high TNFRSF14 expression. High BTLA correlated with good overall survival (OS) (total-BTLA, Hazard Risk=0.479, P=0.022) and with high PD-1 and FOXP3+Tregs. High TNFRSF14 correlated with poor OS and progression-free survival (PFS) (total-TNFRSF14, HR=3.9 and 3.2, respectively, P<0.0001), with unfavorable clinical variables and higher risk of transformation (OR=5.3). Multivariate analysis including BTLA, TNFRSF14 and FLIPI showed that TNFRSF14 and FLIPI maintained prognostic value for OS and TNFRSF14 for PFS. In the GSE16131 FL series, high TNFRSF14 gene expression correlated with worse prognosis and GSEA showed that NFkB pathway was associated with the "High-TNFRSF14/dead-phenotype".In conclusion, the BTLA-TNFRSF14 immune modulation pathway seems to play a role in the pathobiology and prognosis of FL.


Assuntos
Linfoma Folicular/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Receptores Imunológicos/metabolismo , Membro 14 de Receptores do Fator de Necrose Tumoral/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/química , Linfócitos B/patologia , Transformação Celular Neoplásica , Feminino , Humanos , Fatores Imunológicos , Linfoma Folicular/mortalidade , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Linfócitos T/química
5.
Colloids Surf B Biointerfaces ; 174: 300-307, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30469051

RESUMO

Recombinant protein-based vaccines generally show limited immunogenicity and need adjuvants to achieve robust immune responses. Herein, to combine the excellent biocompatibility of hydroxyapatite (HA) and exciting adjuvant activity of silica, Si-doped HA nanorods with Si/P molar ratio from 0 to 0.65 were hydrothermally synthesized and evaluated as immunoadjuvants. Si-doping decreases the size and increases the BET surface area of the nanorods. Si-doping in HA nanorods increases the in vitro adjuvant activity, including CD11c+CD86+ expression and cytokine secretion of bone marrow derived dendritic cells (BMDCs). Moreover, Si-doping in HA increases the ex vivo adjuvant activity as shown by the increase in both Th1 and Th2 cytokines secretion. Si-doped HA nanorods are promising as a new immunoadjuvant.


Assuntos
Adjuvantes Imunológicos/química , Durapatita/química , Durapatita/imunologia , Nanotubos/química , Dióxido de Silício/química , Animais , Citocinas/biossíntese , Citocinas/imunologia , Feminino , Linfonodos/química , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Tamanho da Partícula , Dióxido de Silício/imunologia , Propriedades de Superfície
6.
Sci Rep ; 8(1): 5065, 2018 03 22.
Artigo em Inglês | MEDLINE | ID: mdl-29567956

RESUMO

IgA secretion at mucosal sites is important for host defence against pathogens as well as maintaining the symbiosis with microorganisms present in the small intestine that affect IgA production. In the present study, we tested the ability of 5 strains of lactic acid bacteria stimulating IgA production, being Pediococcus acidilactici K15 selected as the most effective on inducing this protective immunoglobulin. We found that this response was mainly induced via IL-10, as efficiently as IL-6, secreted by K15-stimulated dendritic cells. Furthermore, bacterial RNA was largely responsible for the induction of these cytokines; double-stranded RNA was a major causative molecule for IL-6 production whereas single-stranded RNA was critical factor for IL-10 production. In a randomized, double-blind, placebo-controlled clinical trial, ingestion of K15 significantly increased the secretory IgA (sIgA) concentration in saliva compared with the basal level observed before this intervention. These results indicate that functional lactic acid bacteria induce IL-6 and IL-10 production by dendritic cells, which contribute to upregulating the sIgA concentration at mucosal sites in humans.


Assuntos
Imunoglobulina A Secretora/biossíntese , Interleucina-10/biossíntese , Interleucina-6/biossíntese , Intestino Delgado/metabolismo , Pediococcus acidilactici/metabolismo , Adulto , Animais , Células Dendríticas/metabolismo , Células Dendríticas/microbiologia , Feminino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Humanos , Imunoglobulina A Secretora/metabolismo , Interleucina-10/genética , Interleucina-6/genética , Intestino Delgado/microbiologia , Lactobacillales/imunologia , Lactobacillales/metabolismo , Masculino , Pessoa de Meia-Idade , Pediococcus acidilactici/imunologia , RNA Bacteriano/genética , RNA Bacteriano/metabolismo , RNA de Cadeia Dupla/genética , RNA de Cadeia Dupla/metabolismo , Saliva/metabolismo , Saliva/microbiologia
7.
Front Immunol ; 9: 27, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29410667

RESUMO

Lactic acid bacteria (LAB) are one of the major commensal species in the small intestine and known for contributing to maintenance of protective immunity and immune homeostasis. However, currently there has been no evidence regarding the cellular mechanisms involved in the probiotic effects of LAB on human immune cells. Here, we demonstrated that LAB double-stranded RNA (dsRNA) triggered interferon-ß (IFN-ß) production by human dendritic cells (DCs), which activated IFN-γ-producing T cells. Interleukin-12 (IL-12) secretion from human DCs in response to LAB was abrogated by depletion of bacterial dsRNA, and was attenuated by neutralizing IFN-ß, indicating LAB dsRNA primarily activated the IFN-ß/IL-12 pathway. Moreover, the induction of IL-12 secretion from DCs by LAB was abolished by the inhibition of endosomal acidification, confirming the critical role of the endosomal digestion of LAB. In a coculture of human naïve CD4+ T cells and BDCA1+ DCs, DCs stimulated with LAB containing dsRNA induced IFN-γ-producing T cells. These results indicate that human DCs activated by LAB enhance Th1 immunity depending on IFN-ß secretion in response to bacterial dsRNA.


Assuntos
Células Dendríticas/imunologia , Interferon beta/imunologia , Lactobacillales/imunologia , RNA de Cadeia Dupla/imunologia , Células Th1/imunologia , Antígenos CD1/metabolismo , Células Cultivadas , Glicoproteínas/metabolismo , Humanos , Interferon beta/biossíntese , Interferon gama/biossíntese , Interferon gama/imunologia , Subunidade p35 da Interleucina-12/metabolismo , Lactobacillales/genética , RNA Bacteriano/imunologia , Células Th2/metabolismo
8.
Chem Commun (Camb) ; 54(9): 1057-1060, 2018 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-29323387

RESUMO

Stellated fibrous mesoporous silica nanospheres significantly improve the cellular uptake of cancer antigen and the maturation of bone marrow derived dendritic cells in vitro. Moreover, the combination of poly(I:C) with stellated fibrous MS nanospheres markedly decreases the necessary dose of poly(I:C) for anti-tumor immunity, and thus opens new opportunities for the future clinical application of poly(I:C) in cancer immunotherapy.


Assuntos
Imunoterapia/métodos , Neoplasias/imunologia , Neoplasias/terapia , Poli I-C/imunologia , RNA de Cadeia Dupla/síntese química , RNA de Cadeia Dupla/imunologia , Dióxido de Silício/química , Células Dendríticas/imunologia , Humanos , Tamanho da Partícula , Poli I-C/administração & dosagem , Poli I-C/química , Porosidade , RNA de Cadeia Dupla/química , Propriedades de Superfície
9.
ACS Appl Mater Interfaces ; 9(50): 43538-43544, 2017 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-29192493

RESUMO

Modern vaccines usually require accompanying adjuvants to increase the immune response to antigens. Aluminum (alum) compounds are the most commonly used adjuvants in human vaccinations for infection diseases. However, alum adjuvants are nondegradable, cause side effects due to the persistence of alum at injection sites, and are rather ineffective for cancer immunotherapy, which requires the Th1 immune response. Recently, we have shown that a plain mesoporous silica (MS) adjuvant can stimulate Th1 anticancer immunity for cancer vaccines. Herein, MS nanospheres doped with Ca, Mg, and Zn (MS-Ca, MS-Mg, and MS-Zn) showed significantly higher degradation rates than pure MS. Moreover, MS-Ca, MS-Mg, and MS-Zn nanospheres  stimulated anticancer immune response and increased the CD4+ and CD8+ T cell populations in spleen. The MS-Ca, MS-Mg, and MS-Zn nanospheres with improved biodegradability and excellent ability to induce Th1 anticancer immunity show potential for clinical applications as cancer immunoadjuvants.


Assuntos
Nanosferas , Adjuvantes Imunológicos , Animais , Vacinas Anticâncer , Metais , Camundongos Endogâmicos BALB C , Dióxido de Silício , Células Th1
10.
Small ; 13(38)2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28834273

RESUMO

Appropriate adjuvant aiding in generating robust anticancer immunity is crucial for cancer immunotherapy. Herein, hollow ZnO (HZnO) nanospheres are synthesized by a facile method using carbon nanospheres as the template. The HZnO nanospheres significantly promote the cellular uptake of a model antigen, and cytokine secretion by antigen-presenting cells in vitro. HZnO loaded with ovalbumin and polyinosinic-polycytidylic acid (poly(I:C)) inhibits cancer growth and metastasis to inguinal lymph node in a cancer cell challenge model. Moreover, HZnO loaded with autologous cancer antigens inhibits cancer cell growth in a cancer cell re-challenge model. HZnO nanospheres significantly improve the CD4+ and/or CD8+ T cell population in splenocytes of mice in both cancer cell challenge model and re-challenge model. The HZnO nanospheres can be used for cancer immunotherapy as adjuvant.


Assuntos
Antineoplásicos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade , Nanosferas/química , Óxido de Zinco/química , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Feminino , Imunidade/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Nanosferas/ultraestrutura , Poli I-C/farmacologia
11.
Sci Rep ; 7: 40447, 2017 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-28071766

RESUMO

Advances in Next Generation Sequencing technologies have enabled the generation of millions of sequences from microorganisms. However, distinguishing the sequence of a novel species from sequencing errors remains a technical challenge when the novel species is highly divergent from the closest known species. To solve such a problem, we developed a new method called Optimistic Protein Assembly from Reads (OPAR). This method is based on the assumption that protein sequences could be more conserved than the nucleotide sequences encoding them. By taking advantage of metagenomics, bioinformatics and conventional Sanger sequencing, our method successfully identified all coding regions of the mouse picobirnavirus for the first time. The salvaged sequences indicated that segment 1 of this virus was more divergent from its homologues in other Picobirnaviridae species than segment 2. For this reason, only segment 2 of mouse picobirnavirus has been detected in previous studies. OPAR web tool is available at http://bioinformatics.czc.hokudai.ac.jp/opar/.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Picobirnavirus/genética , Proteínas Virais/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Feminino , Genoma Viral , Camundongos Endogâmicos BALB C , Filogenia
12.
Microorganisms ; 5(1)2016 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-28025548

RESUMO

Lactic acid bacteria (LAB) form a major component of gut microbiota and are often used as probiotics for fermented foods, such as yoghurt. In this study, we aimed to evaluate immunomodulatory activity of LAB, especially that of Lactobacillus bulgaricus ME-552 (ME552) and Streptococcus thermophilus ME-553 (ME553). In vivo/in vitro assay was performed in order to investigate their effects on T cell function. After oral administration of ME553 to C57BL/6 mice, the amount of both interferon γ (IFN-γ) and interleukin 17 (IL-17) produced by cluster of differentiation (CD) 4⁺ T cells from Peyer's patches (PPs) were significantly enhanced. On the other hand, ME552 only up-regulated the production of IL-17 from PP cells. The extent of induction for IFN-γ production differed between ME552 and ME553. These results suggest that LAB modulate T cell effector functions and mucosal immunity.

13.
Front Immunol ; 7: 601, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28018362

RESUMO

Probiotics, such as lactic acid bacteria (LAB) and Bacillus subtilis var. natto, have been shown to modulate immune responses. It is important to understand how probiotic bacteria impact intestinal epithelial cells (IECs), because IECs are the first line of defense at the mucosal surface barrier and their activities substantially affect the gut microenvironment and immunity. However, to date, their precise mechanism remains unknown due to a lack of analytical systems available for live animal models. Recently, we generated a conditional Ca2+ biosensor Yellow Cameleon (YC3.60) transgenic mouse line and established 5D (x, y, z, time, and Ca2+) intravital imaging systems of lymphoid tissues including those in Peyer's patches and bone marrow. In the present study, we further advance our intravital imaging system for intestinal tracts to visualize IEC responses against orally administrated food compounds in real time. Using this system, heat-killed B. subtilis natto, a probiotic TTCC012 strain, is shown to directly induce Ca2+ signaling in IECs in mice housed under specific pathogen-free conditions. In contrast, this activation is not observed in the Lactococcus lactis strain C60; however, when we generate germ-free YC3.60 mice and observe the LAB stimulation of IECs in the absence of gut microbiota, C60 is capable of inducing Ca2+ signaling. This is the first study to successfully visualize the direct effect of probiotics on IECs in live animals. These data strongly suggest that probiotic strains stimulate IECs under physiological conditions and that their activity is affected by the microenvironment of the small intestine, such as commensal bacteria.

14.
Small ; 12(26): 3510-5, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27191183

RESUMO

Hollow and non-hollow mesoporous silica nanospheres are synthesized and used for cancer vaccine adjuvants. The hollow structure of mesoporous silica nanospheres significantly promote cellular uptake of a model cancer antigen by macrophage-like cells in vitro, improve anti-cancer immunity, CD4(+) and CD8(+) T cell populations in splenocytes of mice in vivo.


Assuntos
Adjuvantes Imunológicos/química , Nanosferas/química , Dióxido de Silício/química , Adjuvantes Imunológicos/efeitos adversos , Animais , Vacinas Anticâncer/administração & dosagem , Vacinas Anticâncer/química , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Microscopia Eletroquímica de Varredura , Microscopia Eletrônica de Transmissão , Células NIH 3T3 , Nanosferas/efeitos adversos , Nanosferas/ultraestrutura , Porosidade
15.
Adv Healthc Mater ; 5(10): 1246, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27226038

RESUMO

A plain mesoporous silica (MS) nanoparticle without any immunomodulatory molecules enhances anti-cancer immunity in vivo. On page 1169, X.P. Wang, N. M. Tsuji, A. Ito and co-workers show that a plain MS nanoparticle promotes both Th1 and Th2 immune responses, and enhances the effector memory of CD4(+) and CD8(+) T cell populations in the three most important immune organs (bone marrow, lymph node and spleen) of mice.

16.
Chem Commun (Camb) ; 52(44): 7078-81, 2016 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-27121009

RESUMO

Herein, rod-shaped and fluorine-substituted hydroxyapatite nanoparticles (FHA) were synthesized using a facile hydrothermal method. The rod-shaped FHA significantly increased the cellular uptake of a model antigen by bone marrow dentritic cells in vitro, improved antigen presentation in vivo, stimulated immune-related cytokine secretion in vitro and ex vivo, and enhanced the anti-cancer immunity in vivo.


Assuntos
Durapatita/farmacologia , Flúor/química , Imunidade , Imunoterapia , Neoplasias/terapia , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Durapatita/síntese química , Durapatita/química , Camundongos , Células NIH 3T3 , Nanopartículas/química , Neoplasias/imunologia , Neoplasias/patologia
17.
Adv Healthc Mater ; 5(10): 1169-76, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26987867

RESUMO

A plain mesoporous silica nanoparticle without any immunomodulatory molecules significantly enhances anticancer immunity in vivo. Comprehensive mechanism of mesoporous-silica-nanoparticle-induced cancer immunotherapy is analyzed in this paper. The mesoporous silica nanoparticle promotes both Th1 and Th2 immune responses, as it accelerates lymphocytes proliferation, stimulates IFN-γ, IL-2, IL-4, and IL-10 cytokine secretion by lymphocytes ex vivo, and increases IgG, IgG1, IgG2a, IgM, and IgA antibody titers in mice serum compared with those of alum and adjuvant-free groups. Moreover, the mesoporous silica nanoparticle enhances effector memory CD4(+) and CD8(+) T cell populations in three most important immune organs (bone marrow, lymph node, and spleen) of mice compared with those of alum and adjuvant-free groups three months after adjuvant injection. The present study paves the way for the application of mesoporous silica nanoparticle as immunoadjuvant for cancer immunotherapy.


Assuntos
Nanopartículas/administração & dosagem , Neoplasias/imunologia , Neoplasias/terapia , Dióxido de Silício/administração & dosagem , Dióxido de Silício/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Feminino , Imunoglobulinas/imunologia , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/imunologia , Imunoterapia/métodos , Interferon gama/imunologia , Interleucinas/imunologia , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Baço/efeitos dos fármacos , Baço/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th2/efeitos dos fármacos , Células Th2/imunologia
18.
Colloids Surf B Biointerfaces ; 139: 10-6, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26700228

RESUMO

A Th1 immune response is required for modern vaccines as the most commonly used alum adjuvant has weak capacity for inducing Th1 immune response. Herein, rod-shaped hydroxyapatite (HA), magnesium-substituted HA (MgHA) and zinc-substituted HA (ZnHA) nanoparticles with irregular nanopores were synthesized and used as immunoadjuvants. Magnesium and zinc substitution in HA showed no influence on morphology, particle size, zeta potential and surface area of the nanoparticles. The rod-shaped MgHA and ZnHA nanoparticles promoted the cellular uptake of a molecular immunopotentiator, stimulated both type 1 and 2 cytokine secretion in vitro that relate to Th1 and Th2 immunity of bone marrow dentritic cells, respectively. The MgHA and ZnHA nanoparticles may be useful as immunoadjuvants for human.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Durapatita/farmacologia , Interferon gama/metabolismo , Interleucina-4/metabolismo , Nanopartículas/química , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Durapatita/química , Fêmur/citologia , Fêmur/imunologia , Interferon gama/biossíntese , Interleucina-4/biossíntese , Magnésio/química , Camundongos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Cultura Primária de Células , Equilíbrio Th1-Th2/efeitos dos fármacos , Zinco/química
19.
Angew Chem Int Ed Engl ; 55(5): 1899-903, 2016 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-26404897

RESUMO

The use of appropriate adjuvants that support the generation of robust and long-lasting antitumor immune responses is crucial for tumor immunotherapy owing to the immunosuppressive environment of the growing tumor. However, the most commonly used adjuvant, aluminum hydroxide, is ineffective for generating such immune responses and therefore not suitable for cancer immunotherapy. It is now shown that plain hollow mesoporous silica nanospheres markedly improve the antitumor immunity, the Th1 and Th2 immunity, and the CD4(+) and CD8(+) effector memory T cell population in bone marrow in vivo and may thus be used as immunoadjuvants to treat cancer in humans.


Assuntos
Antineoplásicos/farmacologia , Nanosferas , Neoplasias/terapia , Dióxido de Silício/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunoterapia , Neoplasias/imunologia
20.
J Exp Med ; 213(1): 123-38, 2016 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-26694968

RESUMO

Naive T cells differentiate into various effector T cells, including CD4(+) helper T cell subsets and CD8(+) cytotoxic T cells (CTL). Although cytotoxic CD4(+) T cells (CD4 +: CTL) also develop from naive T cells, the mechanism of development is elusive. We found that a small fraction of CD4(+) T cells that express class I-restricted T cell-associated molecule (CRTAM) upon activation possesses the characteristics of both CD4(+) and CD8(+) T cells. CRTAM(+) CD4(+) T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRTAM(+) T cells are the precursor of CD4(+)CTL. Indeed, ectopic expression of CRTAM in T cells induced the production of IFN-γ, expression of CTL-related genes, and cytotoxic activity. The induction of CD4(+)CTL and IFN-γ production requires CRTAM-mediated intracellular signaling. CRTAM(+) T cells traffic to mucosal tissues and inflammatory sites and developed into CD4(+)CTL, which are involved in mediating protection against infection as well as inducing inflammatory response, depending on the circumstances, through IFN-γ secretion and cytotoxic activity. These results reveal that CRTAM is critical to instruct the differentiation of CD4(+)CTL through the induction of Eomes and CTL-related gene.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Imunoglobulinas/genética , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Linhagem Celular , Movimento Celular/genética , Movimento Celular/imunologia , Colite/genética , Colite/imunologia , Colite/patologia , Regulação da Expressão Gênica , Humanos , Imunoglobulinas/metabolismo , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Interferon gama/biossíntese , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Membrana Mucosa/imunologia , Membrana Mucosa/metabolismo , Membrana Mucosa/patologia , Fenótipo , Proteínas com Domínio T/metabolismo , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia
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