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1.
Chinese Journal of Traumatology ; (6): 1-10, 2024.
Article in English | WPRIM | ID: wpr-1009507

ABSTRACT

Programmed cell death 1 ligand 1 (PD-L1) is an important immunosuppressive molecule, which inhibits the function of T cells and other immune cells by binding to the receptor programmed cell death-1. The PD-L1 expression disorder plays an important role in the occurrence, development, and treatment of sepsis or other inflammatory diseases, and has become an important target for the treatment of these diseases. Mesenchymal stem cells (MSCs) are a kind of pluripotent stem cells with multiple differentiation potential. In recent years, MSCs have been found to have a strong immunosuppressive ability and are used to treat various inflammatory insults caused by hyperimmune diseases. Moreover, PD-L1 is deeply involved in the immunosuppressive events of MSCs and plays an important role in the treatment of various diseases. In this review, we will summarize the main regulatory mechanism of PD-L1 expression, and discuss various biological functions of PD-L1 in the immune regulation of MSCs.


Subject(s)
Humans , B7-H1 Antigen/metabolism , Mesenchymal Stem Cells/immunology , T-Lymphocytes/metabolism , Immunomodulation
2.
Chinese Journal of Biotechnology ; (12): 4004-4028, 2023.
Article in Chinese | WPRIM | ID: wpr-1008008

ABSTRACT

T cells play central roles in anti-tumor immune responses. Immune checkpoint therapy, which is based on modulation of T cell reactivity, has achieved breakthrough in clinical treatment of multiple tumors. Moreover, adoptive T cell therapy, which includes mainly genetically engineered T cells, has shown substantial treatment efficacy in hematoma. Immune therapy has tremendously changed the scenario of clinical tumor treatment and become critical strategies for treating multiple tumors. T cell receptor (TCR) is the fundamental molecule responsible for the specificity of T cell recognition. TCRs could recognize peptides, which are derived from intracellular or extracellular tumor antigens, presented by major histocompatibility complex (MHC) and are therefore highly sensitive to low antigen level. Thereby, TCRs are broadly recognized as promising molecules for the development of anti-tumor drugs. The approval of the first TCR drug in 2022 has initiated a new era for TCR-based therapeutics and since then, multiple TCR drugs have shown substantial treatment efficacy in multiple tumors. This review summarizes the progress of TCR-based immune therapeutic strategies, including T cell receptor-engineered T cell (TCR-T), TCR-based protein drugs, and other cell therapies based on TCR signaling, providing useful information for future design of immune therapeutics based on TCR.


Subject(s)
Humans , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/metabolism , Neoplasms/metabolism , Immunotherapy , Antigens, Neoplasm
3.
Chinese Journal of Biotechnology ; (12): 3787-3799, 2023.
Article in Chinese | WPRIM | ID: wpr-1007993

ABSTRACT

The aim of this study was to investigate the functional characteristics and in vitro specific killing effect of EGFRvIII CAR-T cells co-expressing interleukin-15 and chemokine CCL19, in order to optimize the multiple functions of CAR-T cells and improve the therapeutic effect of CAR-T cells targeting EGFRvIII on glioblastoma (GBM). The recombinant lentivirus plasmid was obtained by genetic engineering, transfected into 293T cells to obtain lentivirus and infected T cells to obtain the fourth generation CAR-T cells targeting EGFRvIII (EGFRvIII-IL-15-CCL19 CAR-T). The expression rate of CAR molecules, proliferation, chemotactic ability, in vitro specific killing ability and anti-apoptotic ability of the fourth and second generation CAR-T cells (EGFRvIII CAR-T) were detected by flow cytometry, cell counter, chemotaxis chamber and apoptosis kit. The results showed that compared with EGFRvIII CAR-T cells, EGFRvIII-IL-15-CCL19 CAR-T cells successfully secreted IL-15 and CCL19, and had stronger proliferation, chemotactic ability and anti-apoptosis ability in vitro (all P < 0.05), while there was no significant difference in killing ability in vitro. Therefore, CAR-T cells targeting EGFRvIII and secreting IL-15 and CCL19 are expected to improve the therapeutic effect of glioblastoma and provide an experimental basis for clinical trials.


Subject(s)
Humans , Receptors, Chimeric Antigen/metabolism , Glioblastoma/metabolism , Interleukin-15/metabolism , Chemokine CCL19/metabolism , Cell Line, Tumor , T-Lymphocytes/metabolism
4.
Chinese Journal of Cellular and Molecular Immunology ; (12): 481-487, 2023.
Article in Chinese | WPRIM | ID: wpr-981889

ABSTRACT

Objective To investigate the effects of miR-877-3p on migration and apoptotic T lymphocytes of bone mesenchymal stem cells (BMSCs). Methods The model of osteoporosis induced by bilateral ovariectomy (OVX) and sham operation was established. At 8 weeks after operation, the bone parameters of the two groups were detected by micro-CT. The levels of monocyte chemotactic protein 1(MCP-1) in BMSCs were detected by ELISA. BMSC in OVX group and sham group were co-cultured with T lymphocytes, respectively. The migration ability of T lymphocytes in the two groups was observed by TranswellTM assay with PKH26 staining and apoptosis of T lymphocytes were detected by flow cytometry. Reverse transcription PCR was used to detect the expression of miR-877-3p in BMSCs. miR-877-3p was overexpressed or down-regulated by cell transfection. The level of MCP-1 secreted by BMSCs in each group was detected by ELISA. The migration and apoptosis of T lymphocytes were detected by the above methods. Results The number of trabecular bone and bone mineral density in OVX group were lower than those in sham group. The levels of MCP-1 secretion, chemotactic and apoptotic T lymphocyte ability of BMSCs in OVX group were also lower than those in sham group. The expression level of miR-877-3p in BMSC in OVX group was higher than that in sham group. After overexpression of BMSC miR-877-3p, the levels of MCP-1 secreted from BMSCs, and apoptotic T lymphocytes decreased, while the results were opposite after down-regulation of miR-877-3p. Conclusion miR-877-3p may be one of the causes of osteoporosis by inhibiting MCP-1 secretion of BMSCs and the migration and apoptosis of T lymphocytes.


Subject(s)
Animals , Female , Mice , Apoptosis/genetics , Bone Marrow Cells/metabolism , Cell Differentiation , Chemokine CCL2/metabolism , Mesenchymal Stem Cells/metabolism , MicroRNAs/metabolism , Osteogenesis , Osteoporosis/genetics , T-Lymphocytes/metabolism
5.
Chinese Medical Journal ; (24): 1897-1909, 2023.
Article in English | WPRIM | ID: wpr-980976

ABSTRACT

Endometriosis, a heterogeneous, inflammatory, and estrogen-dependent gynecological disease defined by the presence and growth of endometrial tissues outside the lining of the uterus, affects approximately 5-10% of reproductive-age women, causing chronic pelvic pain and reduced fertility. Although the etiology of endometriosis is still elusive, emerging evidence supports the idea that immune dysregulation can promote the survival and growth of retrograde endometrial debris. Peritoneal macrophages and natural killer (NK) cells exhibit deficient cytotoxicity in the endometriotic microenvironment, leading to inefficient eradication of refluxed endometrial fragments. In addition, the imbalance of T-cell subtypes results in aberrant cytokine production and chronic inflammation, which contribute to endometriosis development. Although it remains uncertain whether immune dysregulation represents an initial cause or merely a secondary enhancer of endometriosis, therapies targeting altered immune pathways exhibit satisfactory effects in preventing disease onset and progression. Here, we summarize the phenotypic and functional alterations of immune cells in the endometriotic microenvironment, focusing on their interactions with microbiota and endocrine and nervous systems, and how these interactions contribute to the etiology and symptomology of endometriosis.


Subject(s)
Female , Humans , Endometriosis/metabolism , Killer Cells, Natural/metabolism , T-Lymphocytes/metabolism , Estrogens , Endometrium/metabolism
6.
Journal of Experimental Hematology ; (6): 1797-1803, 2023.
Article in Chinese | WPRIM | ID: wpr-1010040

ABSTRACT

OBJECTIVE@#To investigate the effect of miR-125b on T cell activation in patients with aplastic anemia (AA) and its molecular mechanism.@*METHODS@#A total of 30 AA patients were enrolled in department of hematology, Binzhou Medical University Hospital from January 2018 to October 2021, as well as 15 healthy individuals as healthy control (HC) group. Peripheral blood mononuclear cells (PBMCs) were isolated, in which the levels of miR-125b and B7-H4 mRNA were detected by RT-qPCR. Immunomagnetic beads were used to separate naive T cells and non-naive T cells from AA patients and healthy people to detect the levels of miR-125b and B7-H4 mRNA. Lentivirus LV-NC inhibitor and LV-miR-125b inhibitor were transfected into cells, and T cell activation was detected by flow cytometry. The dual-luciferase reporter gene assay was used to detect the targetting relationship between miR-125b and B7-H4. RT-qPCR and Western blot were used to detect the levels of miR-125b, CD40L, ICOS, IL-10 mRNA and B7-H4 protein.@*RESULTS@#Compared with HC group, the expression of miR-125b was up-regulated but B7-H4 mRNA was down-regulated in PBMCs of AA patients (P <0.05), and the proportions of CD4+CD69+ T cells and CD8+CD69+ T cells in PBMCs of AA patients were higher (P <0.05). The expression of miR-125b was significantly up-regulated but B7-H4 mRNA was down-regulated in both naive T cells and non-naive T cells of AA patients (P <0.05), and non-naive T cells was more significant than naive T cells (P <0.05). Compared with NC inhibitor group, the expression of miR-125b was significantly decreased, the expression level of CD69 on CD4+ and CD8+ T cells in PBMCs was also significantly decreased, while the luciferase activity was significantly increased after co-transfection of miR-125b inhibitor and B7-H4-3'UTR-WT in the miR-125b inhibitor group (P <0.05). Compared with NC inhibitor group, the mRNA and protein levels of B7-H4 were significantly increased in the miR-125b inhibitor group (P <0.05). Compared with miR-125b inhibitor+shRNA group, the expression levels of CD69 on CD4+ and CD8+ T cells were significantly increased, and the levels of CD40L, ICOS and IL-10 mRNA were also significantly increased in the miR-125b inhibitor+sh-B7-H4 group (P <0.05).@*CONCLUSION@#MiR-125b may promote T cell activation by targetting B7-H4 in AA patients.


Subject(s)
Humans , Anemia, Aplastic/genetics , CD40 Ligand/metabolism , Interleukin-10 , Leukocytes, Mononuclear/metabolism , Luciferases , MicroRNAs/genetics , RNA, Messenger/metabolism , Lymphocyte Activation , T-Lymphocytes/metabolism
7.
Frontiers of Medicine ; (4): 442-458, 2022.
Article in English | WPRIM | ID: wpr-939877

ABSTRACT

T-cell acute lymphoblastic leukemia (T-ALL) is one of the most dangerous hematological malignancies, with high tumor heterogeneity and poor prognosis. More than 60% of T-ALL patients carry NOTCH1 gene mutations, leading to abnormal expression of downstream target genes and aberrant activation of various signaling pathways. We found that chidamide, an HDAC inhibitor, exerts an antitumor effect on T-ALL cell lines and primary cells including an anti-NOTCH1 activity. In particular, chidamide inhibits the NOTCH1-MYC signaling axis by down-regulating the level of the intracellular form of NOTCH1 (NICD1) as well as MYC, partly through their ubiquitination and degradation by the proteasome pathway. We also report here the preliminary results of our clinical trial supporting that a treatment by chidamide reduces minimal residual disease (MRD) in patients and is well tolerated. Our results highlight the effectiveness and safety of chidamide in the treatment of T-ALL patients, including those with NOTCH1 mutations and open the way to a new therapeutic strategy for these patients.


Subject(s)
Humans , Aminopyridines , Benzamides , Cell Line, Tumor , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Receptor, Notch1/metabolism , Signal Transduction , T-Lymphocytes/metabolism
8.
Revista Digital de Postgrado ; 6(2): 29-35, dic. 2017. ilus
Article in Spanish | LILACS, LIVECS | ID: biblio-1097249

ABSTRACT

La psoriasis es una enfermedad inflamatoria crónica de la piel. Su etiología es multifactorial e incluye susceptibilidad genética, factores inmunológicos y múltiples elementos ambientales, que pueden desencadenar y/o exacerbar la enfermedad. En las últimas décadas se han realizado investigaciones minuciosas sobre la patogénesis de la psoriasis, han sido reconocidos varios subtipos de células T que tienen un papel fundamental en el establecimiento de la inflamación en lesiones cutáneas. Los estudios genéticos brindan las bases para la construcción del modelo de la enfermedad, demostrando que las células dendríticas, los linfocitos T y los queratinocitos desempeñan un rol clave en la patología de esta entidad, así como también un conjunto de citoquinas que impulsan la inflamación psoriásica, dentro de las que se incluyen TNFα, IL-22, IL-23 e IL-17, las cuales promueven la respuesta inflamatoria de queratinocitos, y la producción de péptidos antimicrobianos, citoquinas y quimiocinas, perpetuando así la respuesta inflamatoria. En la actualidad, el desarrollo de varios fármacos biológicos altamente eficaces ha revolucionado el tratamiento de la psoriasis en placas de moderada a severa. Estos medicamentos son un reflejo de una mayor comprensión de la patogénesis de la psoriasis, incluyendo la importancia central de IL-23 e IL17 y las diferentes vías de señalización. El objetivo de este trabajo es realizar una revisión crítica de la literatura sobre la psoriasis y los mecanismos implicados en su imnunopatogenia(AU)


Psoriasis is a chronic inflammatory disease of the skin. Its etiology involves several agents such as genetic susceptibility, immunological factors and multiple environmental elements, which can trigger and / or exacerbate the disease. In recent decades thorough research has been conducted on the pathogenesis of psoriasis, several T-cell subtypes that play a key role in the establishment of inflammation in skin lesions have been recognized. Genetic studies provide the basis for the construction of the disease model, demonstrating that dendritic cells, T lymphocytes and keratinocytes play a key role in the pathology of this entity, as well as a set of cytokines that drive psoriatic inflammation , such as include TNF , IL-22, IL-23 and IL-17, which promote the inflammatory response of keratinocytes, and the production of antimicrobial peptides, cytokines and chemokines, thus perpetuating the inflammatory response. At present, the development of several highly effective biological drugs has revolutionized the treatment of moderate to severe plaque psoriasis. These drugs are a reflection of a greater understanding of the pathogenesis of psoriasis, including the central importance of IL-23 and IL-17 and different signaling pathways. The objective of this work is to perform a critical review of the literature on psoriasis and the mechanisms involved in its imnunopathogenesi(AU)


Subject(s)
Humans , Psoriasis/physiopathology , Skin Diseases/immunology , T-Lymphocytes/metabolism , Adalimumab/therapeutic use , Autoimmune Diseases , Immune System
9.
Rev. bras. reumatol ; 57(3): 190-196, May-June 2017. tab, graf
Article in English | LILACS | ID: biblio-899423

ABSTRACT

ABSTRACT Objective: The goal of this study was to analyze the role of aryl hydrocarbon receptor in peripheral blood CCR6+CD4+ and CD4+CD25+T cells of patients with rheumatoid arthritis. Methods: Flow cytometry was applied to determine the proportion of AhR positive cells in CCR6+CD4+T, CD4+CD25+T and peripheral blood peripheral mononuclear cells from each subject. AhR mRNA and CYP1A1 mRNA relative expression levels were tested by real-time PCR. Results: The percentage of AhR positive cells in peripheral blood mononuclear cells was higher in RA group than that in healthy cases [(35.23 ± 10.71)% vs. (18.83 ± 7.32)%, p < 0.01]. The expression levels of AhR and CYP1A1 were both increased in patients with RA while compared to controls [(3.71 ± 1.63) vs. (2.00 ± 1.27), p = 0.002; (2.62 ± 2.08) vs. (0.62 ± 0.29), p < 0.01, respectively]. In RA patients, the percentage of AhR positive cells in CD4+CD25+T cells was significantly lower than that from controls [17.90 (6.10 ± 80.10)% vs. (52.49 ± 19.18)%, p < 0.01]; In healthy controls, the percentage of AhR positive cells in CD4+CD25+T cells was significantly higher than that in CCR6+CD4+T cells, and was also significantly higher than that in PBMCs [(52.49 ± 19.18)% vs. (23.18 ± 5.62)% vs. (18.06 ± 7.80)%, X 2 = 24.03, p < 0.01]; in RA patients, the percentage of AhR positive cells in CCR6+CD4+T cells was significantly increased than that in CD4+CD25+T cells and PBMCs [(46.02 ± 14.68)% vs. 17.90 (6.10 ± 80.10)% vs. (34.22 ± 10.33)%, X 2 = 38.29, p < 0.01]; Nevertheless, no statistically significant relationship was found between clinical data and AhR positive cells in CCR6+CD4+T and CD4+CD25+T cells. Conclusion: AhR may participate in the pathological progress of RA by controlling the differentiation of Th17 and Treg cells in peripheral blood.


RESUMO Objetivo: Analisar o papel do receptor de hidrocarboneto arílico (AhR) nos linfócitos T CCR6+ CD4+ e CD4+ CD25+ no sangue periférico de pacientes com artrite reumatoide (AR). Métodos: Foi aplicada citometria de fluxo para determinar a proporção de células AhR positivas em linfócitos CCR6+ CD4+ e CD4+ CD25+ do sangue periférico e células mononucleares periféricas de cada indivíduo. Os níveis de expressão relativa de ácido ribonucleico mensageiro (do inglês ribonucleic acid, RNAm,) de AhR e RNAm de enzima de primeiro estágio essencial para o AhR (CYP1A1) foram testados por reação em cadeia de polimerase (do inglês polymerase chain reaction, PCR,) em tempo real. Resultados: A percentagem de células AhR positivas nas células mononucleares do sangue periférico foi maior no grupo com AR do que nos indivíduos saudáveis [(35,23 ± 10,71)% vs. (18,83 ± 7,32)%, (p < 0,01)]. Os níveis de expressão de AhR e CYP1A1 estavam aumentados em pacientes com AR quando comparados com os controles [(3,71 ± 1,63) vs. (2,00 ± 1,27), p = 0,002; (2,62 ± 2,08) vs. (0,62 ± 0,29), p < 0,01, respectivamente]. Em pacientes com AR, a percentagem de células AhR positivas nos linfócitos T CD4+ CD25+ foi significativamente inferior à dos controles [17,90 (6,10 ± 80,10)]% vs. (52,49 ± 19,18)%, p < 0,01]; em controles saudáveis, a percentagem de células AhR positivas nos linfócitos T CD4+ CD25+ foi significativamente mais elevada do que nos linfócitos T CCR6+ CD4+ e também foi significativamente maior do que nas células mononucleares do sangue periférico (do inglês peripheral blood mononuclear cells, PBMC,) [(52,49 ± 19,18)% vs. (23,18 ± 5,62)% vs. (18,06 ± 7,80)%, X 2 = 24,03, p < 0,01]; em pacientes com AR, a percentagem de células AHR positivas nos linfócitos T CCR6+ CD4+ era significativamente maior em comparação com os linfócitos T CD4+ CD25+ e PBMC (46,02 ± 14,68)% vs. [17,90 (6,10 ± 80.10)]% vs. (34,22 ± 10,33)%, X2 = 38,29, p < 0,01]; no entanto, não foi encontrada correlação estatisticamente significativa entre os dados clínicos e células AhR positivas em linfócitos T CCR6+ CD4+ e CD4+ CD25+. Conclusão: O Ahr pode participar do progresso patológico da AR ao controlar a diferenciação de linfócitos Th17 e Treg no sangue periférico.


Subject(s)
Humans , Female , Child , Arthritis, Rheumatoid/immunology , T-Lymphocytes/metabolism , Receptors, Aryl Hydrocarbon/blood , Basic Helix-Loop-Helix Transcription Factors/blood , Arthritis, Rheumatoid/blood , Biomarkers/blood , CD4-Positive T-Lymphocytes/metabolism , Case-Control Studies , T-Lymphocytes, Regulatory/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Interleukin-2 Receptor alpha Subunit/blood , Receptors, CCR6/blood , Th17 Cells/metabolism , Real-Time Polymerase Chain Reaction , Flow Cytometry , Middle Aged
10.
Gut and Liver ; : 288-294, 2016.
Article in English | WPRIM | ID: wpr-193416

ABSTRACT

BACKGROUND/AIMS: The immunoregulatory molecules programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are associated with the dysfunction of antiviral effector T-cells, which leads to T-cell exhaustion and persistent viral infection in patients with chronic hepatitis C and chronic hepatitis B. Little is known about the role of PD-1 and CTLA-4 in patients with symptomatic acute hepatitis A (AHA). METHODS: Peripheral blood mononuclear cells were isolated from seven patients with AHA and from six patients with nonviral acute toxic hepatitis (ATH) during the symptomatic and convalescent phases of the respective diseases; five healthy subjects acted as controls. The expression of PD-1 and CTLA-4 on T-cells was measured by flow cytometry. RESULTS: PD-1 and CTLA-4 expression during the symptomatic phase was significantly higher in the T-cells of AHA patients than in those of ATH patients or healthy controls (PD-1: 18.3% vs 3.7% vs 1.6%, respectively, p<0.05; CTLA-4: 23.5% vs 6.1% vs 5.9%, respectively, p<0.05). The levels of both molecules decreased dramatically during the convalescent phase of AHA, whereas a similar pattern was not seen in ATH. CONCLUSIONS: Our findings are consistent with a viral-protective effect of PD-1 and CTLA-4 as inhibitory molecules that suppress cytotoxic T-cells and thereby prevent the destruction of virus-infected hepatocytes in AHA.


Subject(s)
Adult , Female , Humans , Male , Acute Disease , CTLA-4 Antigen/genetics , Case-Control Studies , Flow Cytometry , Hepatitis/genetics , Hepatitis A/genetics , Hepatitis A Virus, Human , Phenotype , Programmed Cell Death 1 Receptor/genetics , T-Lymphocytes/metabolism
12.
Braz. j. med. biol. res ; 49(4): e5062, 2016. tab, graf
Article in English | LILACS | ID: biblio-951667

ABSTRACT

Type 2 diabetes mellitus (T2D) is a metabolic disease with inflammation as an important pathogenic background. However, the pattern of immune cell subsets and the cytokine profile associated with development of T2D are unclear. The objective of this study was to evaluate different components of the immune system in T2D patients' peripheral blood by quantifying the frequency of lymphocyte subsets and intracellular pro- and anti-inflammatory cytokine production by T cells. Clinical data and blood samples were collected from 22 men (51.6±6.3 years old) with T2D and 20 nonsmoking men (49.4±7.6 years old) who were matched for age and sex as control subjects. Glycated hemoglobin, high-sensitivity C-reactive protein concentrations, and the lipid profile were measured by a commercially available automated system. Frequencies of lymphocyte subsets in peripheral blood and intracellular production of interleukin (IL)-4, IL-10, IL-17, tumor necrosis factor-α, and interferon-γ cytokines by CD3+ T cells were assessed by flow cytometry. No differences were observed in the frequency of CD19+ B cells, CD3+CD8+ and CD3+CD4+ T cells, CD16+56+ NK cells, and CD4+CD25+Foxp3+ T regulatory cells in patients with T2D compared with controls. The numbers of IL-10- and IL-17-producing CD3+ T cells were significantly higher in patients with T2D than in controls (P<0.05). The frequency of interferon-γ-producing CD3+ T cells was positively correlated with body mass index (r=0.59; P=0.01). In conclusion, this study shows increased numbers of circulating IL-10- and IL-17-producing CD3+ T cells in patients with T2D, suggesting that these cytokines are involved in the immune pathology of this disease.


Subject(s)
Humans , Male , Adult , Middle Aged , Cytokines/blood , T-Lymphocyte Subsets/metabolism , Diabetes Mellitus, Type 2/blood , Reference Values , C-Reactive Protein/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Case-Control Studies , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , Statistics, Nonparametric , Lymphocyte Count , Diabetes Mellitus, Type 2/immunology , Flow Cytometry , Immunity, Cellular
13.
Braz. j. infect. dis ; 19(6): 578-584, Nov.-Dec. 2015. tab, graf
Article in English | LILACS | ID: lil-769622

ABSTRACT

ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1) is a human retrovirus related to the chronic neuroinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). CD4+ T cells activation appears to play a key role on HTLV-1 infection. Here we investigated the expression of genes associated to T cell activation CD3e molecule, epsilon (CD3?), lymphocyte-specific protein tyrosine kinase (LCK), vav 1 guanine nucleotide exchange factor (VAV1), and zeta-chain (TCR) associated protein kinase 70 kDa (ZAP70) on T lymphocytes of HTLV-1-infected individuals and compared to healthy uninfected individuals (CT). We observed that CD3?, LCK, ZAP70, and VAV1 gene expression were increased in CD4+ T cells from HAM/TSP group compared to HTLV-1 asymptomatic patients (HAC). Moreover, ZAP70 and VAV1 were also upregulated in HAM/TSP compared to CT group. We detected a positive correlation among all these genes. We also observed that CD3?, LCK, and VAV1 genes had a positive correlation with the proviral load (PVL) and Tax expression. These results suggest that PVL and Tax protein could drive CD3?, LCK, and VAV1 gene expression in CD4+ T cells, and these genes function on a synchronized way on the CD4+ T cell activation. The elucidation of the mechanisms underlying T cell receptor signaling pathway is of considerable interest and might lead to new insights into the mechanism of HAM/TSP.


Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , /immunology , Gene Expression Profiling , Paraparesis, Tropical Spastic/immunology , Receptors, Antigen, T-Cell/immunology , Signal Transduction/immunology , /metabolism , Case-Control Studies , /enzymology , /virology , Gene Expression , Paraparesis, Tropical Spastic/genetics , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins c-vav/metabolism , Real-Time Polymerase Chain Reaction , T-Lymphocytes/metabolism , Viral Load , /metabolism
14.
Mem. Inst. Oswaldo Cruz ; 108(4): 446-452, jun. 2013. tab, graf
Article in English | LILACS | ID: lil-678278

ABSTRACT

American cutaneous leishmaniasis (ACL) presents distinct active clinical forms with different grades of severity, known as localised (LCL), intermediate (ICL) and diffuse (DCL) cutaneous leishmaniasis. LCL and DCL are associated with a polarised T-helper (Th)1 and Th2 immune response, respectively, whereas ICL, or chronic cutaneous leishmaniasis, is associated with an exacerbated immune response and a mixed cytokine expression profile. Chemokines and chemokine receptors are involved in cellular migration and are critical in the inflammatory response. Therefore, we evaluated the expression of the chemokines CXCL10, CCL4, CCL8, CCL11 and CXCL8 and the chemokine receptors CCR3, CXCR3, CCR5 and CCR7 in the lesions of patients with different clinical forms of ACL using immunohistochemistry. LCL patients exhibited a high density of CXCL10+, CCL4+ and CCL8+ cells, indicating an important role for these chemokines in the local Th1 immune response and the migration of CXCR3+ cells. LCL patients showed a higher density of CCR7+ cells than ICL or DCL patients, suggesting major dendritic cell (DC) migration to lymph nodes. Furthermore, DCL was associated with low expression levels of Th1-associated chemokines and CCL11+ epidermal DCs, which contribute to the recruitment of CCR3+ cells. Our findings also suggest an important role for epidermal cells in the induction of skin immune responses through the production of chemokines, such as CXCL10, by keratinocytes.


Subject(s)
Adolescent , Adult , Humans , Chemokines/metabolism , Leishmaniasis, Cutaneous/immunology , Receptors, Chemokine/immunology , Receptors, Chemokine/metabolism , Immunohistochemistry , Leishmaniasis, Cutaneous/pathology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism
15.
Recife; s.n; 2013. 81 p. ilus, graf, tab.
Thesis in Portuguese | LILACS | ID: biblio-870264

ABSTRACT

As leishmanioses são um grave problema de saúde em todo o mundo e a forma cutânea é encontrada em todas as regiões do Brasil, sendo endêmica no estado de Pernambuco. Infecções por Leishmania levam à ativação da resposta imunológica no hospedeiro, destacando-se a resposta celular. Esta é caracterizada por expansão de vários tipos celulares, sobretudo de linfócitos T, com produção de diferentes perfis de citocinas. Este estudo teve como objetivo caracterizar imunofenotipicamente pacientes portadores de leishmaniose tegumentar ativa quanto à produção das citocinas IL-17, IL-21, IL-22, IL-23, IFN-gama, TNF-alfa, IL-10 e IL-4. Verificou-se a produção sérica de IL-6, IL-10, TNF-alfa, IFN-gama e IL-17 em pacientes com doença ativa (AT), após tratamento (PT) e de pacientes que apresentaram cura espontânea das lesões (CE). Buscou-se também a associação entre produção de citocinas na resposta imune celular de pacientes AT, relacionando a resposta imune dos perfis Th1, Th2 e Th17. Foi observada maior proporção de linfócitos T CD3+ e T CD4+, maior produção de IL-17 e IL-23 por linfócitos T CD4+ e de IL-4 por linfócitos T CD4+ e T CD8+ em AT, em comparação aos controles, e também maior produção de IL-10 por linfócitos T CD8+ em AT. Os resultados revelaram maior concentração sérica de IL-6 em CE em comparação aos outros grupos. Além disso, observou-se associação positiva significativa entre citocinas Th1 (IFN-gama) e Th2 (IL-4) em AT. Os resultados mostram que a proporção de linfócitos T CD3+ e T CD4+ é importante no processo de cura das lesões...


Leishmaniasis is a serious health problem in the world and the cutaneous form is found in all regions of Brazil, being endemic in the state of Pernambuco. Leishmania infections lead to an activation of the host immune response, mainly the cellular immune response. This respons e is characterized by expansion of various cell types, especially T lymphocytes, with production of different cytokine profiles. This study aimed to characterize immunophenotypically patients with active cutaneous leishmaniasis regarding the production of the cytokines IL-17, IL-21, IL-22, IL-23, IFN-γ, TNF-α, IL-10 and IL-4. It also verified the serum production of IL-6, IL-10, TNF-α, IFN-γ and IL-17 by patients with active lesions (AC) and after Chemotherapy (PT), and patients with spontaneously healing lEsions (SH). This project sought the association between the cytokine production in AC, specially relating the immune response by the Th1, Th2 and Th17 subsets. It was observed higher proportion of CD3+ and CD4+ T lymphocytes, higher production of IL-17 and IL-23 by CD4+ T lymphocytes and of IL-4 by CD4+ and CD8+ T lymphocytes in AC, when compared to controls, and also higher production of IL-10 by CD8+ T lymphocytes in AC. The results showed a higher IL-6 serum concentration inSH in comparison to the other groups. Furthermore, it was observed a positive association between Th1 (IFN-γ) and Th2 (IL-4) cytokines in AC. Thus, the results observed demonstrate that CD3+ and CD4+ T lymphocytes proportion is important in the lesion healing process. The predominance of Th2 cytokines in the active disease suggestsan initial temporary immunologic deregulation.


Subject(s)
Humans , Cytokines , Flow Cytometry , Immunity, Cellular , Leishmaniasis, Cutaneous/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Health Profile , T-Lymphocyte Subsets
16.
Experimental & Molecular Medicine ; : 694-705, 2012.
Article in English | WPRIM | ID: wpr-149759

ABSTRACT

IL-17-producing CD4+ T cells (Th17) play important functions in autoimmune diseases and allograft rejection of solid organs. We examined the effects of IL 17 and its mechanism of action on arthritis in a murine collagen-induced arthritis (CIA) model using bone marrow transplantation (BMT) system. DBA/1J mice were administered a lethal radiation dose and then rescued with bone marrow derived from either wild-type (WT) or IL-17-/- mice on C57BL/6 background mice. CIA was induced after the bone marrow transplant, and disease progression was characterized. DBA/1J mice with CIA that received IL-17-/- donor bone marrow showed potently inhibited development and severity of clinical arthritis as compared with CIA mice that received WT bone marrow. Reduced secretion of the pro-inflammatory cytokines tumor necrosis factor-alpha, IL-1beta, and IL-6, and collagen-specific T cell responses were observed in mice that received IL-17-/- bone marrow. IL-17 blockade also inhibited effector T cell proliferation by reciprocally regulating the Treg/Th17 ratio. IL-17 blockade prevented joint destruction in mice with CIA. These findings suggest that CIA with BMT is a viable method of immunological manipulation and that IL-17 deficiency suppresses severe joint destruction and inflammation in CIA mice. There may be clinical benefits in blocking IL-17 and BMT in the treatment of rheumatoid arthritis.


Subject(s)
Animals , Humans , Male , Mice , Antigens, Differentiation/metabolism , Arthritis, Experimental/pathology , Bone Marrow Transplantation , Cell Differentiation , Cell Proliferation , Cells, Cultured , Collagen Type II , Cytokines/metabolism , Interleukin-17/deficiency , Joints/pathology , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Knockout , Osteoclasts/metabolism , Signal Transduction , T-Lymphocytes/metabolism , Transplantation, Homologous
17.
Article in English | IMSEAR | ID: sea-135768

ABSTRACT

Background & objectives: The unique immunological functions of γδ T lymphocytes to contribute immunity against Mycobacterium tuberculosis attracted interest of researchers. However, little is known about the specificity of γδ Τ cell in tuberculosis patients and the lack of exact tuberculosis antigen recognized by γδ T cells limited its application. The analysis of complementary determinant region (CDR)3 sequence characteristic in γδ T cells of tuberculosis patients would contribute to understand the distribution specificity of γδ T cell. In present study, we investigated the diversity of the γ9/δ2 T cell immunorepertoire and analysed the specificity of the expressed CDR3 in pulmonary tuberculosis patients. Methods: The total RNA in peripheral blood mononuclear cell of 50 pulmonary tuberculosis patients and 10 healthy controls was extracted. The polymerase chain reaction was used to specifically amplify the CDR3 region of γ9 and δ2 chain. The PCR products were ligated into the pGEM-T easy vector. The plasmid DNA was sequenced using the ABI3700 and the T7 primer. Results: Our findings showed that predominant CDR3 sequence of δ2 chain in pulmonary tuberculosis patients was CACDTLVSTDKLIFGKG. The sequence specifically exists in almost all pulmonary tuberculosis patients. The conserved hydrophobic acid residue in 97 positions is present in the γδ T cell reactive to M. tuberculosis. The length of δ2 CDR3 in pulmonary tuberculosis patients has no relation with the disease progress. Interpretation & conclusions: Our results suggest that γδ T cells appear to use CDR3 sequence to recognise M. tuberculosis antigen. γδ T cells reactive to M. tuberculosis were diverse and polyclonal.


Subject(s)
Amino Acid Motifs/genetics , Complementarity Determining Regions/metabolism , DNA Primers/genetics , Female , Genetic Vectors , Humans , Male , Molecular Sequence Data , Mycobacterium tuberculosis/immunology , Polymerase Chain Reaction , Receptors, Antigen, T-Cell, gamma-delta/immunology , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNA , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tuberculosis, Pulmonary/immunology
18.
Mem. Inst. Oswaldo Cruz ; 106(6): 662-669, Sept. 2011.
Article in English | LILACS | ID: lil-602048

ABSTRACT

This study was designed to assess the effect of GB virus (GBV)-C on the immune response to human immunodeficiency virus (HIV) in chronically HIV-infected and HIV- hepatitis C virus (HCV)-co-infected patients undergoing antiretroviral therapy. A cohort of 159 HIV-seropositive patients, of whom 52 were HCV-co-infected, was included. Epidemiological data were collected and virological and immunological markers, including the production of interferon gamma (IFN-γ) and interleukin (IL)-2 by CD4, CD8 and Tγδ cells and the expression of the activation marker, CD38, were assessed. A total of 65 patients (40.8 percent) presented markers of GBV-C infection. The presence of GBV-C did not influence HIV and HCV replication or TCD4 and TCD8 cell counts. Immune responses, defined by IFN-γ and IL-2 production and CD38 expression did not differ among the groups. Our results suggest that neither GBV-C viremia nor the presence of E2 antibodies influence HIV and HCV viral replication or CD4 T cell counts in chronically infected patients. Furthermore, GBV-C did not influence cytokine production or CD38-driven immune activation among these patients. Although our results do not exclude a protective effect of GBV-C in early HIV disease, they demonstrate that this effect may not be present in chronically infected patients, who represent the majority of patients in outpatient clinics.


Subject(s)
Adult , Female , Humans , Male , Coinfection/immunology , GB virus C/immunology , HIV Infections/immunology , Hepatitis C, Chronic/immunology , T-Lymphocytes/immunology , /metabolism , Biomarkers/metabolism , Cohort Studies , Coinfection/virology , HIV Infections/virology , Hepatitis C, Chronic/virology , Interferon-gamma/biosynthesis , /biosynthesis , T-Lymphocytes/metabolism
19.
Braz. j. med. biol. res ; 43(5): 425-430, May 2010.
Article in English | LILACS | ID: lil-546330

ABSTRACT

Mesenchymal stem cells (MSC) are multipotential nonhematopoietic progenitor cells capable of differentiating into multiple mesenchymal tissues. MSC are able to reconstitute the functional human hematopoietic microenvironment and promote engraftment of hematopoietic stem cells. MSC constitutively express low levels of major histocompatibility complex-I molecules and do not express costimulatory molecules such as CD80, CD86 or CD40, thus lacking immunogenicity. Furthermore, they are able to suppress T- and B-lymphocyte activation and proliferation and may also affect dendritic cell maturation. Based on these properties, MSC are being used in regenerative medicine and also for the treatment of autoimmune diseases and graft-versus-host disease. On the other hand, MSC from patients diagnosed with myelodysplastic syndromes or multiple myeloma display abnormalities, which could play a role in the physiopathology of the disease. Finally, in patients with immune thrombocytopenic purpura, MSC have a reduced proliferative capacity and a lower inhibitory effect on T-cell proliferation compared with MSC from healthy donors.


Subject(s)
Humans , Mesenchymal Stem Cells , T-Lymphocytes/immunology , Autoimmune Diseases/therapy , Cell Proliferation , Graft vs Host Disease/therapy , Hematopoietic Stem Cell Transplantation , Lymphocyte Activation , Mesenchymal Stem Cells , Multipotent Stem Cells/immunology , T-Lymphocytes/metabolism
20.
Experimental & Molecular Medicine ; : 805-810, 2010.
Article in English | WPRIM | ID: wpr-122578

ABSTRACT

Tumor necrosis factor receptor-related 2 (TR2, HVEM or TNFRSF-14) plays an important role in immune responses, however, the mechanisms regulating its expression are unclear. To understand the control of TR2 gene expression, we studied the upstream region of the gene. Gel supershift assays revealed inducible binding of nuclear factor of activated T cells (NFAT) to a putative NFAT site within the TR2 promoter. Furthermore, cotransfection of a dominant negative NFAT construct, or siRNA for NFAT, resulted in increased expression of a TR2 reporter gene. Our findings demonstrate that NFAT negatively regulates TR2 expression in activated T cells.


Subject(s)
Animals , Mice , Base Sequence , CD4-Positive T-Lymphocytes/metabolism , Cells, Cultured , Down-Regulation , Mice, Inbred C57BL , Molecular Sequence Data , NFATC Transcription Factors/physiology , Receptors, Tumor Necrosis Factor, Member 14/biosynthesis , T-Lymphocytes/metabolism
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