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1.
Scand J Immunol ; 90(2): e12776, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31069824

RESUMO

The number of the X chromosome-linked genes has been previously suggested to influence immune responses and the development of autoimmune diseases. In the present study, we aimed at evaluating the level of expression of CD40L (an X-linked gene involved in adaptive immunity) and TLR7 (an X-linked gene involved in innate immunity) in a variety of different karyotypes. Those included males, females and patients with X chromosome aneuploidy. Healthy females (46, XX; n = 10) and healthy males (46, XY; n = 10) were compared to females with Turner syndrome (TS) (45, X; n = 11) and males with Klinefelter syndrome (KS) (47, XXY; n = 5). Stimulation of peripheral blood mononuclear cells (PBMCs) with PMA and ionomycin resulted in higher percentage of CD3 + CD40L+ T cells (P < 0.001) and higher level expression of CD40L in T cell (P < 0.001) in female and KS patients compared with male and TS patients. TLR7-mediated IFN-alpha production by HLADR + CD3- CD19- cells was significantly upregulated in healthy women compared with healthy males, TS and KS patients (P < 0.001). TLR7 agonist-stimulated PBMCs from healthy females and KS patients expressed significantly higher levels of TLR7 mRNA than those from male and TS patients (P < 0.05). The increased expression of the X-linked genes TLR7 and CD40L in healthy females and KS patients suggests that the presence of two X chromosomes plays a major role in enhancing both innate and adaptive immune responses. These results may contribute to the explanation of sex-based differences in immune biology and the sex bias in predisposition to autoimmune diseases.


Assuntos
Imunidade Adaptativa/genética , Ligante de CD40/biossíntese , Ligante de CD40/genética , Cromossomos Humanos X/genética , Dosagem de Genes/genética , Imunidade Inata/genética , Receptor 7 Toll-Like/biossíntese , Receptor 7 Toll-Like/genética , Imunidade Adaptativa/imunologia , Antígenos CD19/biossíntese , Complexo CD3/biossíntese , Células Cultivadas , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Imunidade Inata/imunologia , Interferon-alfa/biossíntese , Ionomicina/farmacologia , Síndrome de Klinefelter/genética , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Ácidos Polimetacrílicos/farmacologia , RNA Mensageiro/biossíntese , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Síndrome de Turner/genética
2.
Histol Histopathol ; 34(3): 241-256, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30024020

RESUMO

This experiment compared the histological characteristics and distribution of CD3 and CD79a among yak lymph nodes, hemal nodes and spleen. The three organs from ten clinically healthy newborn and adult yaks were studied using histology and immunohistochemistry. The yak hemal nodes, which consisted of blood sinuses, lymphoid follicles, diffuse lymphoid tissue and lymphoid cords, appeared to share the histological characteristics of the spleen and lymph nodes: the lymphoid follicles of the hemal nodes were much like those of the lymph nodes, which were not surrounded by the central artery and periarteriolar lymphoid sheath. The lymphoid cords of the hemal node, which contained many erythrocytes, were much like the splenic cords. The sinuses of the hemal nodes had a similar structure to the lymph sinuses of the lymph nodes but were engorged with erythrocytes rather than lymph as in the lymph nodes. Interestingly, the splenic sinuses of yak were of two different types: the sinuses with obvious endothelial cells or those consisting of reticular cells. The CD3+ cells were mainly located in the paracortex area and medulla of the lymph nodes, the diffuse lymphoid tissues of the hemal nodes, and the periarteriolar lymphoid sheaths and red pulp of the spleen. Most CD79a+ cells were mainly detected in the lymphoid follicles of all examined lymphoid organs. The results suggested that although the three organs had specific characteristics, in some respects, they had similar organizational structural characteristics and immune functions. These may be useful to better understand the relationship between the morphology and function of these organs and provide useful references for normal yak lymphoid organs.


Assuntos
Bovinos/anatomia & histologia , Bovinos/imunologia , Tecido Linfoide/anatomia & histologia , Tecido Linfoide/imunologia , Animais , Linfócitos B/citologia , Linfócitos B/imunologia , Complexo CD3/análise , Complexo CD3/biossíntese , Antígenos CD79/análise , Antígenos CD79/biossíntese , Linfonodos/imunologia , Baço/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia
3.
Pathol Res Pract ; 214(10): 1738-1744, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30025593

RESUMO

Aberrant expression of CD3 on diffuse large B-cell lymphoma (DLBCL) is rare, and its mechanism and biological significance are currently unclear. Herein we report a case of Epstein-Barr virus-negative, CD3-positive DLBCL in a 53 year-old male, who had a remote history of renal transplantation. After standard chemotherapy, the patient was in clinical remission. He relapsed three years later, but at this time with apparent loss of CD3 expression. PCR-based IGK gene rearrangement studies demonstrated clonal amplicons with an identical nucleotide size between the primary and secondary DLBCL, confirming the clonal relationship despite their phenotypic differences. To our knowledge, this is the first case of CD3-positive DLBCL that demonstrated a loss of aberrant CD3 on relapse. The chronologic change in phenotype seen in this case suggests that the source of the patient's lymphoma relapse may arise from either a quiescent subclone without CD3 expression, or from an upstream neoplastic precursor cell.


Assuntos
Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Complexo CD3/biossíntese , Complexo CD3/imunologia , Humanos , Hospedeiro Imunocomprometido/imunologia , Imunofenotipagem , Transplante de Rim , Masculino , Pessoa de Meia-Idade
4.
Leuk Res ; 71: 6-12, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29935384

RESUMO

Several conventions have been established in order to define and characterize Mixed Phenotype Acute Leukemia (MPAL). However, megakaryocytic markers have not been included in the definition of MPAL neither in the European Group for the Immunological Characterization of Leukemias (EGIL) proposal nor in any of the WHO Classification of Tumors issues. We report four pediatric acute leukemia (AL) cases (prevalence: 0.18%) with megakaryoblasts co-expressing the T-specific antigen CD3 (cytoplasmic), together with a very homogeneous antigen profile of immature cells and other lymphoid traits. In one case, the presence of epsilon CD3 mRNA was confirmed as well on sorted CD34+ blasts. All four cases were infants, and two of them disclosed trisomy 21 in the blast population (not constitutional) without being children with Down Syndrome. They were homogeneously treated with AML schemes, achieving all four CR. However, 3 patients relapsed early. Only one patient is alive and remain disease-free, with a long follow-up. Even though cyCD3 was the only T cell marker expressed, its specificity entails the consideration of these cases as a new subtype of MPAL Megakaryoblastic/T, keeping this in mind when designing diagnostic panels. Detection and report of these cases are necessary so as to further characterize them in order to define the most appropriate treatment.


Assuntos
Biomarcadores Tumorais/análise , Complexo CD3/biossíntese , Leucemia Megacarioblástica Aguda/imunologia , Complexo CD3/análise , Linhagem da Célula/imunologia , Citoplasma/metabolismo , Feminino , Humanos , Imunofenotipagem , Lactente , Leucemia Megacarioblástica Aguda/classificação , Leucemia Megacarioblástica Aguda/patologia , Masculino
5.
J Int Med Res ; 46(7): 2780-2791, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29785863

RESUMO

Objective Hyperbaric oxygen (HBO) is an emerging complementary alternative medical approach in glioma treatment. However, its mode of action is unknown, so this was investigated in the present study. Methods We constructed an intracranial glioma model of congenic C57BL/6J mice. Glioma growth under HBO stimulation was assessed by bioluminescent imaging and magnetic resonance imaging. Flow cytometry assessed direct effects of HBO on reactive oxygen species (ROS) signaling of transplanted glioma cells and organs, and quantified mature T cells and subgroups in tumors, the brain, and blood. Results HBO promoted the growth of transplanted GL261-Luc glioma in the intracranial glioma mouse model. ROS signaling of glioma cells and brain cells was significantly downregulated under HBO stimulation, but thymus ROS levels were significantly upregulated. CD3+ T cells were significantly downregulated, while both Ti/Th cells (CD3+CD4+) and Ts/Tc cells (CD3+CD8+) were inhibited in tumors of the HBO group. The percentage of regulatory T cells in Ti/Th (CD3+CD4+) cells was elevated in the tumors and thymuses of the HBO group. Conclusion HBO induced ROS signaling in the thymus, inhibited CD3+ T cell generation, and facilitated malignant glioma cell growth in vivo in the intracranial glioma mouse model.


Assuntos
Neoplasias Encefálicas/metabolismo , Complexo CD3/imunologia , Glioma/metabolismo , Oxigenação Hiperbárica/efeitos adversos , Espécies Reativas de Oxigênio/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Animais , Neoplasias Encefálicas/diagnóstico por imagem , Complexo CD3/biossíntese , Modelos Animais de Doenças , Glioma/diagnóstico por imagem , Camundongos , Camundongos Endogâmicos C57BL , Oxigênio/efeitos adversos
6.
J Clin Exp Hematop ; 58(2): 102-106, 2018 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-29657256

RESUMO

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a new clinical entity that was reclassified from enteropathy-associated T-cell lymphoma in the 2016 WHO classification. An 83-year-old man with fever and diarrhea was referred to our hospital because of free air in the abdominal cavity and wall thickening of the large intestine on CT. Colonofiberscopic examination revealed mucosal edema and multiple ulcers at the sigmoid colon, splenic flexure, and transverse colon. Histopathological examination of the mucosal biopsy specimen demonstrated dense infiltration of small lymphocytes with nuclear atypia, some of which exhibited intraepithelial invasion. Immunohistologically, these lymphocytes were positive for CD3, CD56, and perforin. Regarding CD3 expression, the antigen was found to only be expressed in the cytoplasm and not on the surface membrane on flow cytometric analysis. PCR examination of the T-cell receptor (TCR) gene revealed monoclonal gene rearrangements of TCR-γ and TCR-ß. Based on these findings, a diagnosis of colonal MEITL with cyCD3 expression at Lugano clinical stage 1 was made. After conservative management of the peritonitis, we treated the patient with CHOP and DeVIC regimens, but he developed progressive disease and died. The cyCD3 expression in MEITL may be novel, suggesting a thymocyte origin of the tumor cells.


Assuntos
Complexo CD3/biossíntese , Citoplasma , Regulação Neoplásica da Expressão Gênica , Neoplasias Intestinais , Linfoma de Células T , Proteínas de Neoplasias/biossíntese , Idoso de 80 Anos ou mais , Citoplasma/metabolismo , Citoplasma/patologia , Humanos , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Masculino
7.
Cancer Immunol Immunother ; 66(7): 927-939, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28405764

RESUMO

In this study, we investigated the clinical relevance of CD274 (PD-L1) protein expression by tumor cells and tumor-infiltrating immune cells in colorectal cancer (CRC). To this end, 186 microsatellite instability-high (MSI-H) and 153 microsatellite stable (MSS) CRCs were subjected to immunohistochemistry (IHC) analysis for the expression of CD274 and mismatch repair proteins. CD274 expression was evaluated in tumor cells at the center (TC) and periphery (TP), and immune cells at the center (IC) and periphery (IP) of CRC. IHC slides stained for CD3 and CD8 were scanned using an Aperio ScanScope for precise calculation of tumor-infiltrating T cell density. Additionally, samples were screened for the B-Raf (BRAF)-V600E mutation using a Cobas 4800 System and IHC. In total, CD274TC, CD274TP, CD274IC, and CD274IP were observed in 43 (23.1%), 47 (25.3%), 107 (57.5%), and 102 (54.8%) of the MSI-H CRCs examined, and in three (2.0%), four (2.6%), 47 (30.7%), and 56 (36.6%) of the 153 MSS CRCs tested. Meanwhile, intratumoral heterogeneity of CD274 expression in tumor cells and immune cells was detected in 24 (12.9%) and 47 (25.3%) MSI-H CRCs, respectively. Notably, in both MSI-H and MSS CRC, CD274IC and CD274IP were independently associated with improved prognosis (P < 0.05), while BRAF mutation was associated with CD274TP, poor differentiation, sporadic type, and hMLH1(-)/hMSH2(+)/hMSH6(+)/PMS2(-) in MSI-H CRC (P < 0.006). In conclusion, CD274 expression in tumor-infiltrating immune cells was an independent factor for improved prognosis in CRC patients. A deeper understanding of CD274 status may yield improved responses to future CRC immunotherapies.


Assuntos
Antígeno B7-H1/metabolismo , Neoplasias Colorretais/diagnóstico , Linfócitos do Interstício Tumoral/metabolismo , Instabilidade de Microssatélites , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Antígeno B7-H1/genética , Complexo CD3/biossíntese , Antígenos CD8/biossíntese , Estudos de Coortes , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Marcadores Genéticos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/imunologia , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/genética , Prognóstico , Proteínas Proto-Oncogênicas B-raf/metabolismo , Análise Serial de Tecidos
9.
J Med Virol ; 89(1): 55-63, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27301802

RESUMO

We assessed Enterovirus (EV) &Parvovirus B19 (PVB19) genomes and CD3, CD68&HLA-DR detection in dilated cardiomyopathies (DCM). EV&PVB19 genomes and CD3, CD68&HLA-DR were detected by PCR and immunohistochemistry assays in 115 endomyocardial biopsies obtained in 13 idiopathic DCM (iDCM) and 10 explained DCM (eDCM) patients. Results were compared with those of 47 atrial surgical samples (47 surgery controls) and 22 autoptic cardiac samples (11 healthy heart controls) (2008-2014, Reims, France). EV was detected in 23.1% of iDCM patients but not in eDCM and controls (P = 0.003) (viral load 803 copies/µg). PVB19 was detected in 76.9%, 80.0%, 63.6% and 78.2% of iDCM, eDCM, healthy heart and surgery controls (P = 0.99) with a mean viral load of 413, 346, 1,428, and 71 copies/µg. CD3, CD68 or HLA-DR were detected in 100 and 50% of EV and PVB19 "mono-infected" iDCM patients. EV was exclusively detected in iDCM cases in association with CD3, CD68, or HLA-DR indicating that EV could be an etiological cause in a subset of iDCM cases. By contrast the equal frequent detection of PVB19 in iDCM cases and controls without association with CD3, CD68, or HLA-DR suggested that PVB19 could be a bystander in many DCM cases. J. Med. Virol. 89:55-63, 2017. © 2016 Wiley Periodicals, Inc.


Assuntos
Antígenos CD/biossíntese , Antígenos de Diferenciação Mielomonocítica/biossíntese , Complexo CD3/biossíntese , Cardiomiopatia Dilatada/patologia , Cardiomiopatia Dilatada/virologia , Enterovirus/isolamento & purificação , Antígenos HLA-DR/biossíntese , Parvovirus B19 Humano/isolamento & purificação , Adulto , Idoso , Endocárdio/patologia , Feminino , França , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Miocárdio/patologia , Reação em Cadeia da Polimerase , Estudos Prospectivos
10.
Morfologiia ; 149(1): 57-63, 2016.
Artigo em Russo | MEDLINE | ID: mdl-27487665

RESUMO

Biopsy specimens of the thymus were studied in children aged under 11 months (n = 77) with congenital heart defects and circulatory hypoxia of varying severity. Histological sections were stained with hematoxylin-eosin and Shubich's method (to demonstrate mast cells). The expression of Ki-67, CD3 and CD34 was assessed by immunohistochemistry. The ultrastructure of thymic tissues was also examined. It was found that the severity of hypoxia determined the morphological changes in the organ associated with a development of large complex of tissue reactions. A disruption of internal structure and a loss of integrity of epithelio-reticular cells and thymocytes were demonstrated in ultrathin sections. Thymocyte proliferation index (Ki-67) and thymocytopoiesis intensity (CD3+) were reduced in all the zones of the thymus. The degree of hypoxia affected the redistribution of CD3+ lymphocytes leading to their accumulation in the medulla. The processes of endogenous regeneration took place which involved the cells of fibroblastic line and progenitor cells (CD34+) together with active formation of new blood vessels. These findings suggest that the morphological changes identified in the tissues of the thymus are a manifestation of tissue adaptation to hypoxia of varying severity under conditions of endogenous regeneration, simultaneously reflecting the processes of substitution cytogenesis.


Assuntos
Antígenos CD34/biossíntese , Complexo CD3/biossíntese , Regulação da Expressão Gênica , Cardiopatias Congênitas , Antígeno Ki-67/biossíntese , Timócitos , Timo , Feminino , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Humanos , Hipóxia/metabolismo , Hipóxia/patologia , Lactente , Recém-Nascido , Masculino , Timócitos/metabolismo , Timócitos/patologia , Timo/irrigação sanguínea , Timo/metabolismo , Timo/patologia
11.
J Immunol ; 197(4): 1111-7, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27412413

RESUMO

Monoclonal Abs against CD20 reduce the number of relapses in multiple sclerosis (MS); commonly this effect is solely attributed to depletion of B cells. Recently, however, a subset of CD3(+)CD20(+) T cells has been described that is also targeted by the anti-CD20 mAb rituximab. Because the existence of cells coexpressing CD3 and CD20 is controversial and features of this subpopulation are poorly understood, we studied this issue in detail. In this study, we confirm that 3-5% of circulating human T cells display CD20 on their surface and transcribe both CD3 and CD20. We report that these CD3(+)CD20(+) T cells pervade thymus, bone marrow, and secondary lymphatic organs. They are found in the cerebrospinal fluid even in the absence of inflammation; in the cerebrospinal fluid of MS patients they occur at a frequency similar to B cells. Phenotypically, these T cells are enriched in CD8(+) and CD45RO(+) memory cells and in CCR7(-) cells. Functionally, they show a higher frequency of IL-4-, IL-17-, IFN-γ-, and TNF-α-producing cells compared with T cells lacking CD20. CD20-expressing T cells respond variably to immunomodulatory treatments given to MS patients: they are reduced by fingolimod, alemtuzumab, and dimethyl fumarate, whereas natalizumab disproportionally increases them in the blood. After depletion by rituximab, they show earlier and higher repopulation than CD20(+) B cells. Taken together, human CD3(+)CD20(+) T cells pervade lymphatic organs and the cerebrospinal fluid, have a strong ability to produce different cytokines, and respond to MS disease modifying drugs.


Assuntos
Antígenos CD20/biossíntese , Complexo CD3/biossíntese , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Alemtuzumab , Anticorpos Monoclonais Humanizados/farmacologia , Separação Celular , Citocinas/biossíntese , Fumarato de Dimetilo/farmacologia , Cloridrato de Fingolimode/farmacologia , Citometria de Fluxo , Humanos , Fatores Imunológicos/farmacologia , Natalizumab/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos
12.
Ann Hematol ; 95(10): 1671-83, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27431583

RESUMO

Expression of CD3 on a mature B cell neoplasm, such as diffuse large B cell lymphoma (DLBCL), is extremely rare. When it is present, it will cause diagnostic confusion since the classification of lymphoid neoplasms is largely based on immunophenotyping to determine the cell lineage. We report three cases of DLBCL with CD3 and other T cell-associated antigens. A literature search identifies 30 additional cases of DLBCL expressing CD3, with the majority (78.6 %) displaying cytoplasmic expression, while two of our cases demonstrate membranous staining. Additionally, expression of CD3 tends to be partial and weak in both our series and the reported cases. Of the 28 cases reported in the literature that were tested for Epstein Barr Virus (EBV), 16 (57.1 %) are positive, suggesting an important role of EBV in promoting lineage ambiguity/infidelity, whereas, all three cases in our series are negative for the virus. All three cases in our series show homogeneous expression of multiple B cell specific antigens, while the reported cases show variable expression with some having B cell antigens downregulated, particularly in those cases with EBV association or anaplastic morphology. A low threshold for testing EBV status is advocated in DLBCL with phenotypic ambiguity along with panels of immunohistochemical stains and B/T cell receptor gene rearrangement analysis.


Assuntos
Antígenos de Diferenciação de Linfócitos T/análise , Linfócitos B/imunologia , Complexo CD3/análise , Imunofenotipagem , Linfoma Difuso de Grandes Células B/imunologia , Linfócitos T/imunologia , Adulto , Antígenos de Diferenciação de Linfócitos B/análise , Antígenos de Diferenciação de Linfócitos T/biossíntese , Linfócitos B/metabolismo , Complexo CD3/biossíntese , Linhagem da Célula , Feminino , Regulação Neoplásica da Expressão Gênica , Rearranjo Gênico do Linfócito B , Rearranjo Gênico do Linfócito T , Herpesvirus Humano 4 , Humanos , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/genética , Masculino , Estudos Retrospectivos
14.
Cytokine ; 83: 127-135, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27108398

RESUMO

OBJECTIVES: T-cell repertoire dysfunction characterizes human immunodeficiency virus type 1 (HIV-1) infection, but the pathogenic mechanisms remain unclear. Disease progression is probably due to a profound dysregulation of Th1, Th2, Th17 and Treg patterns. The aim of this study was to analyze the features of CD4+ T cells in HIV-positive patients with different viroimmunological profile. METHODS: we used a gene expression dataset of CD4+ T cells from healthy donors, HIV+ naive patients and Elite Controllers (EC), obtained from the NCBI Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/, accession number GSE18233). RESULTS: Principal Component Analysis (PCA) showed an almost complete overlap between the HIV-infected and EC patients, which cannot easily explain the different responses to HIV infection of these two group of patients. We have found that HIV patients and the EC showed an upregulation of the Th1 pro-inflammatory cytokines and chemokines, compared to the controls. Also, we have surprisingly identified IL28B, which resulted downregulated in HIV and EC compared to healthy controls. We focused attention also on genes involved in the constitution of the immunological synapse and we showed that HLA class I and II genes resulted significantly upregulated in HIV and in EC compared to the control. In addition to it, we have found the upregulation of others syncytial molecules, including LAG3, CTLA4, CD28 and CD3, assisting the formation of syncytia with APC cells. CONCLUSIONS: Understanding the mechanisms of HIV-associated immunological chaos is critical to strategically plan focused interventions.


Assuntos
Doadores de Sangue , Linfócitos T CD4-Positivos/metabolismo , Regulação da Expressão Gênica , Infecções por HIV/metabolismo , HIV-1 , Adulto , Antígenos CD/biossíntese , Antígenos CD28/biossíntese , Complexo CD3/biossíntese , Antígeno CTLA-4/biossíntese , Feminino , Antígenos de Histocompatibilidade Classe I/biossíntese , Antígenos de Histocompatibilidade Classe II/biossíntese , Humanos , Masculino
15.
Int J Cancer ; 139(1): 122-9, 2016 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26888626

RESUMO

CD3ζ has emerged as a clinically important immunological marker in head and neck squamous cell carcinoma (HNSCC) with reduced level of expression reported in both tumor infiltrating lymphocytes and peripheral blood lymphocytes. In this prospective study (power = 0.99, α = 0.05), CD3ζ expression was compared in 47 HNSCC patients and 53 controls using standardized flow cytometric method. There was no statistical difference in the percentages of the CD3 ε+ T-cell subset present in the peripheral blood mononuclear cells of the HNSCC patients and the healthy controls; however, T cells from the HNSCC patients produced a significantly weaker IFN-γ response in comparison to the healthy controls, when they were stimulated by the recall viral CEF peptide antigen. All patients were followed up for at least 3 years with a median follow-up of 45 months. Levels of CD3ζ-chain expression were measured at 117 follow-up visits at six-month intervals. Receiver operating characteristic curve identified the optimal cut off as a 12% increase in post treatment CD3ζ-chain expression from the baseline levels to confirm absence of HNSCC with the area under curve of 0.81 (95% CI = 0.68-0.94) for predicting absence of HNSCC. The specificity, sensitivity and positive predictive value were 81.25% 79.21% and 97.56%, respectively. Three-year disease specific survival (DSS) was significantly lower (p = 0.007) at 63.2% for patients who showed <12% increase in CD3ζ-chain level as compared to 96.2% for patients who had ≥12% increase. Our results indicate that the change in CD3ζ-chain expression from the baseline is an independent predictor of residual and recurrent HNSCC.


Assuntos
Biomarcadores Tumorais/biossíntese , Complexo CD3/biossíntese , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeça e Pescoço/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Complexo CD3/genética , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e Pescoço
16.
J Immunol ; 196(1): 156-67, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26608909

RESUMO

Chronic inflammation is associated with immunosuppression and downregulated expression of the TCR CD247. In searching for new biomarkers that could validate the impaired host immune status under chronic inflammatory conditions, we discovered that sorting nexin 9 (SNX9), a protein that participates in early stages of clathrin-mediated endocytosis, is downregulated as well under such conditions. SNX9 expression was affected earlier than CD247 by the generated harmful environment, suggesting that it is a potential marker sensing the generated immunosuppressive condition. We found that myeloid-derived suppressor cells, which are elevated in the course of chronic inflammation, are responsible for the observed SNX9 reduced expression. Moreover, SNX9 downregulation is reversible, as its expression levels return to normal and immune functions are restored when the inflammatory response and/or myeloid-derived suppressor cells are neutralized. SNX9 downregulation was detected in numerous mouse models for pathologies characterized by chronic inflammation such as chronic infection (Leishmania donovani), cancer (melanoma and colorectal carcinoma), and an autoimmune disease (rheumatoid arthritis). Interestingly, reduced levels of SNX9 were also observed in blood samples from colorectal cancer patients, emphasizing the feasibility of its use as a diagnostic and prognostic biomarker sensing the host's immune status and inflammatory stage. Our new discovery of SNX9 as being regulated by chronic inflammation and its association with immunosuppression, in addition to the CD247 regulation under such conditions, show the global impact of chronic inflammation and the generated immune environment on different cellular pathways in a diverse spectrum of diseases.


Assuntos
Complexo CD3/biossíntese , Hospedeiro Imunocomprometido/imunologia , Inflamação/imunologia , Células Mieloides/imunologia , Nexinas de Classificação/biossíntese , Animais , Artrite Reumatoide/imunologia , Biomarcadores Tumorais/sangue , Proliferação de Células , Células Cultivadas , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/patologia , Leishmania donovani/imunologia , Leishmaniose Visceral/imunologia , Leishmaniose Visceral/parasitologia , Masculino , Melanoma/diagnóstico , Melanoma/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Nexinas de Classificação/sangue , Células Th1/imunologia , Células Th2/imunologia
17.
AIDS ; 29(18): 2397-407, 2015 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-26355672

RESUMO

OBJECTIVE: During HIV infection, a down-modulation of CD3ζ was found on T cells, contributing to T-cell anergy. In this work, we studied the correlation between myeloid-derived suppressor cells (MDSC) frequency and T-cell CD3ζ expression. Moreover, we investigated the mechanisms of CD3ζ decrease exploited by MDSC. DESIGN AND METHOD: CD3ζ expression and MDSC frequency were evaluated by flow cytometry on peripheral blood mononuclear cells from 105 HIV-positive (HIV+) patients. The role of MDSC in the modulation of the HIV-specific T-cell response was evaluated. The level of CD3ζ mRNA and ELF-1 protein were analysed by real-time-PCR and western blot, respectively. RESULTS: We found that granulocytic-MDSC (Gr-MDSC) were expanded in HIV+ patients compared with healthy donors; in particular, in cART-treated individuals a higher Gr-MDSC frequency was observed in patients with a CD4 T-cell count below 400 cells/µl. We found an inverse correlation between the percentage of Gr-MDSC and CD3ζ level. Moreover, in-vitro MDSC depletion induced the up-regulation of CD3ζ in T cells, restoring the functionality of αß, but not γδ T cells. The in-vitro effect of isolated MDSC on CD3ζ expression was found cell contact-dependent, and was not mediated by previously described molecules. CD3ζ down-modulation corresponds to the decrease of its mRNA induced by silencing the transcription factor ELF-1. CONCLUSION: Our data provide new knowledge on mechanisms used by Gr-MDSC in immune-modulation and on their role in the immune reconstitution during antiviral treatments.


Assuntos
Complexo CD3/biossíntese , Anergia Clonal , Regulação para Baixo , Infecções por HIV/patologia , Proteínas Nucleares/metabolismo , Linfócitos T/imunologia , Fatores de Transcrição/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Western Blotting , Feminino , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem
18.
PLoS One ; 10(8): e0135945, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26305211

RESUMO

The CD33/CD3-bispecific T-cell engaging (BiTE) antibody construct, AMG 330, potently lyses CD33+ leukemic cells in vitro. Using specimens from 41 patients with acute myeloid leukemia (AML), we studied the factors that might contribute to clinical response or resistance. For this purpose, thawed aliquots of primary AML samples were immunophenotypically characterized and subjected to various doses of AMG 330 in the presence or absence of healthy donor T-cells. After 48 hours, drug-specific cytotoxicity was quantified and correlated with CD33 expression levels, amounts of T-cells present, and other disease characteristics. AMG 330 caused modest cytotoxicity that was correlated with the amount of autologous T-cells (P = 0.0001) but not CD33 expression, as AMG 330 exerted marked cytotoxic effects in several specimens with minimal CD33 expression. With healthy donor T-cells added, AMG 330 cytotoxicity depended on the drug dose and effector:target (E:T) cell ratio. High cytotoxic activity was observed even with minimal CD33 expression, and AMG 330 cytotoxicity and CD33 expression correlated only at high E:T cell ratio and high AMG 330 doses (P<0.003). AMG 330 resulted in significantly higher cytotoxicity in specimens from patients with newly diagnosed AML than those with relapsed/refractory disease despite similar levels of CD33 on myeloblasts. AMG 330 cytotoxicity also appeared greater in specimens from patients with favorable-risk disease as compared to other specimens. Together, our data demonstrate that AMG 330 is highly active in primary AML specimens across the entire disease spectrum, while suggesting the presence of yet undefined, CD33-independent, relative resistance mechanisms in specific patient subsets.


Assuntos
Anticorpos Biespecíficos/administração & dosagem , Citotoxicidade Imunológica/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Biespecíficos/efeitos adversos , Complexo CD3/biossíntese , Feminino , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/biossíntese , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
19.
Cancer Chemother Pharmacol ; 75(5): 1065-73, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25814216

RESUMO

PURPOSE: The aim of the study was to evaluate the safety and determine the maximum tolerated dose (MTD) of intravenous catumaxomab, a trifunctional bispecific antibody that binds to EpCAM on epithelial cancer cells and CD3 on T cells. METHODS: The trial was a dose-escalation study with a 3 + 3 design in epithelial cancers with known EpCAM expression. The dose-limiting toxicity (DLT) period consisted of 4 weeks, with weekly intravenous administration of catumaxomab. Key DLTs were ≥grade 3 optimally treated non-hematological toxicity; ≥grade 3 infusion-related reactions refractory to supportive care; ≥grade 3 increase in liver enzymes and/or bilirubin not resolving to grade 2. RESULTS: Sixteen patients were enrolled receiving doses of 2 (n = 5), 4 (n = 3), 7 (n = 7) and 10 µg catumaxomab (n = 1). The most common treatment-emergent adverse events (TEAEs) were chills (93.8 %) and pyrexia (87.5 %). The most common TEAE of grade ≥3 was transient dose-dependent increases in aspartate aminotransferase (56.3 %). The intensity of toxicities decreased with the number of infusions. Also, serum IL-6 increased in a dose-dependent manner and reverted to low or undetectable levels after four infusions. A reversible decrease in liver function test (prothrombin time) at the 7-µg dose level was considered a DLT. The first patient at 10 µg experienced a fatal hepatic failure related to catumaxomab that led to the termination of the study. CONCLUSIONS: The MTD of weekly intravenous catumaxomab was 7 µg. Major toxicities were cytokine release-related symptoms and hepatotoxicity.


Assuntos
Anticorpos Biespecíficos/administração & dosagem , Neoplasias/tratamento farmacológico , Adulto , Idoso , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/imunologia , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/imunologia , Complexo CD3/biossíntese , Complexo CD3/imunologia , Moléculas de Adesão Celular/biossíntese , Moléculas de Adesão Celular/imunologia , Relação Dose-Resposta a Droga , Molécula de Adesão da Célula Epitelial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/imunologia , Neoplasias/metabolismo , Linfócitos T/imunologia
20.
Cell Physiol Biochem ; 35(3): 1034-51, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25661802

RESUMO

BACKGROUND/AIMS: Several limiting factors for human health and performance in microgravity have been clearly identified arising from the immune system, and substantial research activities are required in order to provide the basic information for appropriate integrated risk management. The gravity-sensitive nature of cells of the immune system renders them an ideal biological model in search for general gravity-sensitive mechanisms and to understand how the architecture and function of human cells is related to the gravitational force and therefore adapted to life on Earth. METHODS: We investigated the influence of altered gravity in parabolic flight and 2D clinostat experiments on key proteins of activation and signaling in primary T lymphocytes. We quantified components of the signaling cascade 1.) in non-activated T lymphocytes to assess the "basal status" of the cascade and 2.) in the process of activation to assess the signal transduction. RESULTS: We found a rapid decrease of CD3 and IL-2R surface expression and reduced p-LAT after 20 seconds of altered gravity in non-activated primary T lymphocytes during parabolic flight. Furthermore, we observed decreased CD3 surface expression, reduced ZAP-70 abundance and increased histone H3-acetylation in activated T lymphocytes after 5 minutes of clinorotation and a transient downregulation of CD3 and stable downregulation of IL-2R during 60 minutes of clinorotation. CONCLUSION: CD3 and IL-2R are downregulated in primary T lymphocytes in altered gravity. We assume that a gravity condition around 1g is required for the expression of key surface receptors and appropriate regulation of signal molecules in T lymphocytes.


Assuntos
Complexo CD3/biossíntese , Ativação Linfocitária/imunologia , Receptores de Interleucina-2/biossíntese , Linfócitos T/metabolismo , Proteína-Tirosina Quinase ZAP-70/biossíntese , Células Cultivadas , Regulação da Expressão Gênica , Gravidade Alterada , Humanos , Sistema Imunitário/metabolismo , Ativação Linfocitária/genética , Rotação , Transdução de Sinais , Voo Espacial , Linfócitos T/imunologia , Ausência de Peso
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