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[PMID]:28466476
[Au] Autor:Li H; Hao Y; Zhang D; Liu W; Li Y; Lyu M; Fu R; Xue F; Liu X; Yang R
[Ad] Endereço:State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
[Ti] Título:Numerical and functional defects in CD8 CD28 T-suppressor lymphocytes from patients with primary immune thrombocytopenia.
[So] Source:Br J Haematol;178(2):292-301, 2017 07.
[Is] ISSN:1365-2141
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder, and loss of immune tolerance has been implicated in ITP pathogenesis. CD8 CD28 suppressor (Ts) cells have an immunosuppression function and are involved in several autoimmune disorders. However, the role of Ts cells in ITP is currently not clear. Here, flow cytometry was used to detect the CD8 CD28 CD127 proportion, which was decreased in active ITP patients compared with that of controls. Function analysis showed that immunosuppression of CD8 CD28 Ts cells in ITP patients was impaired. Mechanistic studies have shown that CD8 CD28 Ts cells from controls can downregulate CD80 and upregulate LILRB4 (ITL3) and LILRB2 (ILT4) expression on CD14 monocytes, whereas these abilities were not found in Ts cells from ITP patients. Furthermore, Inducible T-cell costimulatory (ICOS) expression on the Ts cell surface after activation was decreased whereas programmed death 1 and interleukin 10 expression was not changed in ITP patients compared with those of controls. In summary, the down-regulated quantity and function of Ts cells in active patients indicated that a Ts defect was involved in ITP. Moreover, decreased ICOS expression and the loss of the ability to regulate co-stimulator expression on antigen-presenting cells partly explained the defective Ts-mediated suppression.
[Mh] Termos MeSH primário: Antígenos CD28/metabolismo
Linfócitos T CD8-Positivos/fisiologia
Púrpura Trombocitopênica Idiopática/imunologia
Linfócitos T Reguladores/fisiologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Idoso
Citocinas/metabolismo
Feminino
Seres Humanos
Tolerância Imunológica/fisiologia
Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo
Interferon gama/biossíntese
Interleucina-10/fisiologia
Subpopulações de Linfócitos/fisiologia
Masculino
Meia-Idade
Receptor de Morte Celular Programada 1/metabolismo
Fator de Crescimento Transformador beta1/metabolismo
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (CD28 Antigens); 0 (Cytokines); 0 (Inducible T-Cell Co-Stimulator Protein); 0 (PDCD1 protein, human); 0 (Programmed Cell Death 1 Receptor); 0 (Transforming Growth Factor beta1); 130068-27-8 (Interleukin-10); 82115-62-6 (Interferon-gamma)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180209
[Lr] Data última revisão:
180209
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170504
[St] Status:MEDLINE
[do] DOI:10.1111/bjh.14661


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[PMID]:28608562
[Au] Autor:Chaudhuri S; Singh MK; Bhattacharya D; Datta A; Hazra I; Mondal S; Faruk Sk Md O; Ronsard L; Ghosh TK; Chaudhuri S
[Ad] Endereço:Department of Laboratory Medicine, Cellular and Molecular Immunology Lab, School of Tropical Medicine, Kolkata, West Bengal 700073, India.
[Ti] Título:T11TS immunotherapy repairs PI3K-AKT signaling in T-cells: Clues toward enhanced T-cell survival in rat glioma model.
[So] Source:J Cell Physiol;233(2):759-770, 2018 Feb.
[Is] ISSN:1097-4652
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Malignant glioma is the most fatal of astrocytic lineage tumors despite therapeutic advances. Onset and progression of gliomas is accompanied by severe debilitation of T-cell defense and T-cell survival. One of the chief contributors to T-cell survival downstream of activation is the PI3K-AKT pathway. Our prior studies showed that the novel immunotherapeutic molecule T11-target structure (T11TS) blocks T-cell apoptosis in glioma. We also showed activation of immunological synapse components and calcineurin-NFAT pathway following T11TS immunotherapy of glioma-bearing rats. This lead to investigations whether such T-cell activation upon T11TS therapy translates into activation of downstream PI3K/AKT signals which may be related to observed blockade of T-cell apoptosis. For the purpose, we assessed by flowcytometry and immunoblotting, expressions of PI3K, PDK1, AKT, p-AKT, and PTEN in splenic T-cells of normal, experimentally-induced glioma-bearing rats and glioma-bearing rats receiving first, second and third doses of T11TS. We also determined comparative nuclear translocation of NF-κB across groups. We found significant increases in T-cell expressions of PDK1, PI3K, and p-AKT in T11TS-treated animal groups compared to sharp downregulations in glioma. AKT levels remained unchanged across groups. PTEN levels declined sharply after T11TS immunotherapy. T11TS also caused enhanced NF-κB translocation to the T-cell nucleus compared to glioma group. Results showed heightened activation of the PI3K-AKT pathway in glioma-bearing rats following T11TS immunotherapy. These results illustrate the novel role of T11TS immunotherapy in ameliorating the PI3K pathway in T-cells in glioma-bearing animals to enhance T-cell survival, according greater defense against glioma. The study thus has far-reaching clinical outcomes.
[Mh] Termos MeSH primário: Antineoplásicos/farmacologia
Neoplasias Encefálicas/tratamento farmacológico
Antígenos CD58/farmacologia
Glioma/tratamento farmacológico
Imunoterapia/métodos
Fosfatidilinositol 3-Quinase/metabolismo
Proteínas Proto-Oncogênicas c-akt/metabolismo
Linfócitos T/efeitos dos fármacos
Evasão Tumoral/efeitos dos fármacos
[Mh] Termos MeSH secundário: Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo
Transporte Ativo do Núcleo Celular
Animais
Neoplasias Encefálicas/enzimologia
Neoplasias Encefálicas/imunologia
Neoplasias Encefálicas/patologia
Antígenos CD28/imunologia
Antígenos CD28/metabolismo
Sobrevivência Celular
Etilnitrosoureia
Feminino
Glioma/enzimologia
Glioma/imunologia
Glioma/patologia
Masculino
NF-kappa B/metabolismo
PTEN Fosfo-Hidrolase/metabolismo
Fosforilação
Ratos
Transdução de Sinais/efeitos dos fármacos
Linfócitos T/enzimologia
Linfócitos T/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (CD28 Antigens); 0 (CD58 Antigens); 0 (NF-kappa B); 0 (T11TS protein, sheep); EC 2.7.1.137 (Phosphatidylinositol 3-Kinase); EC 2.7.11.1 (3-Phosphoinositide-Dependent Protein Kinases); EC 2.7.11.1 (Pdpk1 protein, rat); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (Pten protein, rat); P8M1T4190R (Ethylnitrosourea)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170614
[St] Status:MEDLINE
[do] DOI:10.1002/jcp.26047


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[PMID]:29017923
[Au] Autor:Shinjo Y; Makide K; Satoh K; Fukami F; Inoue A; Kano K; Otani Y; Ohwada T; Aoki J
[Ad] Endereço:Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Miyagi 980-8578, Japan.
[Ti] Título:Lysophosphatidylserine suppresses IL-2 production in CD4 T cells through LPS /GPR174.
[So] Source:Biochem Biophys Res Commun;494(1-2):332-338, 2017 Dec 09.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lysophosphatidylserine (LysoPS) has been shown to have lipid mediator-like actions to induce mast cell degranulation and suppress T lymphocyte proliferation. Recently, three G protein-coupled receptors (GPCRs), LPS /GPR34, LPS /P2Y10, and LPS /GPR174, were found to react specifically with LysoPS, raising the possibility that LysoPS exerts its roles through these receptors. In this study, we show that LPS is expressed in various T cell subtypes and is involved in suppression of Interleukin-2 (IL-2) production in CD4 T cells. We found that LysoPS suppressed the IL-2 production from activated T cells at the mRNA and protein levels. In addition, LysoPS did not have such an effect on the splenocytes and CD4 T cells isolated from LPS -deficient mice. In LPS -deficient splenocytes and CD4 T cells, anti-CD3/anti-CD28-triggered IL-2 production is somewhat increased. Interestingly, LysoPS with various fatty acids was up-regulated upon T cell activation. The present study raised the possibility that LysoPS exerts its immunosuppressive roles by down-regulating IL-2 production through a LysoPS-LPS axis in T cells.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/efeitos dos fármacos
Interleucina-2/genética
Lisofosfolipídeos/farmacologia
Receptores Acoplados a Proteínas-G/genética
Receptores de Lisofosfolipídeos/genética
Receptores Purinérgicos P2/genética
[Mh] Termos MeSH secundário: Animais
Anticorpos/farmacologia
Antígenos CD28/antagonistas & inibidores
Antígenos CD28/genética
Antígenos CD28/imunologia
Complexo CD3/genética
Complexo CD3/imunologia
Linfócitos T CD4-Positivos/citologia
Linfócitos T CD4-Positivos/imunologia
Separação Celular
Regulação da Expressão Gênica
Interleucina-2/imunologia
Lisofosfolipídeos/imunologia
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Cultura Primária de Células
Receptores Acoplados a Proteínas-G/imunologia
Receptores de Lisofosfolipídeos/imunologia
Receptores Purinérgicos P2/imunologia
Transdução de Sinais
Baço/citologia
Baço/efeitos dos fármacos
Baço/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies); 0 (CD28 Antigens); 0 (CD3 Complex); 0 (G-protein-coupled receptor 34); 0 (GPR174 protein, mouse); 0 (Interleukin-2); 0 (Lysophospholipids); 0 (Receptors, G-Protein-Coupled); 0 (Receptors, Lysophospholipid); 0 (Receptors, Purinergic P2); 0 (lysophosphatidylserine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171012
[St] Status:MEDLINE


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[PMID]:28954890
[Au] Autor:Seu L; Tidwell C; Timares L; Duverger A; Wagner FH; Goepfert PA; Westfall AO; Sabbaj S; Kutsch O
[Ad] Endereço:Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294 lillian.seu@gmail.com okutsch@uab.edu.
[Ti] Título:CD151 Expression Is Associated with a Hyperproliferative T Cell Phenotype.
[So] Source:J Immunol;199(9):3336-3347, 2017 Nov 01.
[Is] ISSN:1550-6606
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The tetraspanin CD151 is a marker of aggressive cell proliferation and invasiveness for a variety of cancer types. Given reports of CD151 expression on T cells, we explored whether CD151 would mark T cells in a hyperactivated state. Consistent with the idea that CD151 could mark a phenotypically distinct T cell subset, it was not uniformly expressed on T cells. CD151 expression frequency was a function of the T cell lineage (CD8 > CD4) and a function of the memory differentiation state (naive T cells < central memory T cells < effector memory T cells < T effector memory RA cells). CD151 and CD57, a senescence marker, defined the same CD28 T cell populations. However, CD151 also marked a substantial CD28 T cell population that was not marked by CD57. Kinome array analysis demonstrated that CD28 CD151 T cells form a subpopulation with a distinct molecular baseline and activation phenotype. Network analysis of these data revealed that cell cycle control and cell death were the most altered process motifs in CD28 CD151 T cells. We demonstrate that CD151 in T cells is not a passive marker, but actively changed the cell cycle control and cell death process motifs of T cells. Consistent with these data, long-term T cell culture experiments in the presence of only IL-2 demonstrated that independent of their CD28 expression status, CD151 T cells, but not CD151 T cells, would exhibit an Ag-independent, hyperresponsive proliferation phenotype. Not unlike its reported function as a tumor aggressiveness marker, CD151 in humans thus marks and enables hyperproliferative T cells.
[Mh] Termos MeSH primário: Linfócitos T CD4-Positivos/imunologia
Linfócitos T CD8-Positivos/imunologia
Proliferação Celular
Regulação da Expressão Gênica/imunologia
Tetraspanina 24/imunologia
[Mh] Termos MeSH secundário: Antígenos CD28/genética
Antígenos CD28/imunologia
Antígenos CD57/genética
Antígenos CD57/imunologia
Senescência Celular/genética
Senescência Celular/imunologia
Regulação da Expressão Gênica/genética
Seres Humanos
Tetraspanina 24/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD151 protein, human); 0 (CD28 Antigens); 0 (CD57 Antigens); 0 (Tetraspanin 24)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170929
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1700648


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[PMID]:28919076
[Au] Autor:Klein Geltink RI; O'Sullivan D; Corrado M; Bremser A; Buck MD; Buescher JM; Firat E; Zhu X; Niedermann G; Caputa G; Kelly B; Warthorst U; Rensing-Ehl A; Kyle RL; Vandersarren L; Curtis JD; Patterson AE; Lawless S; Grzes K; Qiu J; Sanin DE; Kretz O; Huber TB; Janssens S; Lambrecht BN; Rambold AS; Pearce EJ; Pearce EL
[Ad] Endereço:Department of Immunometabolism, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
[Ti] Título:Mitochondrial Priming by CD28.
[So] Source:Cell;171(2):385-397.e11, 2017 Oct 05.
[Is] ISSN:1097-4172
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand. Early CD28-dependent mitochondrial engagement is needed for T cells to remodel cristae, develop SRC, and rapidly produce cytokines upon restimulation-cardinal features of protective memory T cells. Our data show that initial CD28 signals during T cell activation prime mitochondria with latent metabolic capacity that is essential for future T cell responses.
[Mh] Termos MeSH primário: Antígenos CD28/metabolismo
Ativação Linfocitária
Mitocôndrias/metabolismo
Linfócitos T/citologia
Linfócitos T/imunologia
[Mh] Termos MeSH secundário: Animais
Carnitina O-Palmitoiltransferase
Inibidores Enzimáticos/farmacologia
Compostos de Epóxi/farmacologia
Seres Humanos
Interleucina-15/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Receptores de Antígenos de Linfócitos T/metabolismo
Estresse Fisiológico
Linfócitos T/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD28 Antigens); 0 (Enzyme Inhibitors); 0 (Epoxy Compounds); 0 (Interleukin-15); 0 (Receptors, Antigen, T-Cell); EC 2.3.1.21 (CPT1B protein, mouse); EC 2.3.1.21 (Carnitine O-Palmitoyltransferase); EC 2.3.1.21 (carnitine palmitoyltransferase 1A, human); MSB3DD2XP6 (etomoxir)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170919
[St] Status:MEDLINE


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[PMID]:28805662
[Au] Autor:Ramos CA; Ballard B; Zhang H; Dakhova O; Gee AP; Mei Z; Bilgi M; Wu MF; Liu H; Grilley B; Bollard CM; Chang BH; Rooney CM; Brenner MK; Heslop HE; Dotti G; Savoldo B
[Ad] Endereço:Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital and Texas Children's Hospital, Houston, Texas, USA.
[Ti] Título:Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes.
[So] Source:J Clin Invest;127(9):3462-3471, 2017 Sep 01.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Targeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. However, adverse events, mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients. Targeting CD30 with T cells expressing a CD30-specific chimeric antigen receptor (CAR) may reduce the side effects and augment antitumor activity. METHODS: We conducted a phase I dose escalation study in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30.CAR-Ts) encoding the CD28 costimulatory endodomain. Three dose levels, from 0.2 × 108 to 2 × 108 CD30.CAR-Ts/m2, were infused without a conditioning regimen. All other therapy for malignancy was discontinued at least 4 weeks before CD30.CAR-T infusion. Seven patients had previously experienced disease progression while being treated with brentuximab. RESULTS: No toxicities attributable to CD30.CAR-Ts were observed. Of 7 patients with relapsed HL, 1 entered complete response (CR) lasting more than 2.5 years after the second infusion of CD30.CAR-Ts, 1 remained in continued CR for almost 2 years, and 3 had transient stable disease. Of 2 patients with ALCL, 1 had a CR that persisted 9 months after the fourth infusion of CD30.CAR-Ts. CD30.CAR-T expansion in peripheral blood peaked 1 week after infusion, and CD30.CAR-Ts remained detectable for over 6 weeks. Although CD30 may also be expressed by normal activated T cells, no patients developed impaired virus-specific immunity. CONCLUSION: CD30.CAR-Ts are safe and can lead to clinical responses in patients with HL and ALCL, indicating that further assessment of this therapy is warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01316146. FUNDING: National Cancer Institute (3P50CA126752, R01CA131027 and P30CA125123), National Heart, Lung, and Blood Institute (R01HL114564), and Leukemia and Lymphoma Society (LLSTR 6227-08).
[Mh] Termos MeSH primário: Doença de Hodgkin/terapia
Antígeno Ki-1/metabolismo
Linfoma Anaplásico de Células Grandes/terapia
Receptores de Antígenos de Linfócitos T/química
Linfócitos T/citologia
[Mh] Termos MeSH secundário: Adulto
Antineoplásicos/química
Antígenos CD28/química
Progressão da Doença
Relação Dose-Resposta a Droga
Feminino
Doença de Hodgkin/imunologia
Seres Humanos
Imunoconjugados/administração & dosagem
Imunoconjugados/uso terapêutico
Imunofenotipagem
Linfoma Anaplásico de Células Grandes/imunologia
Masculino
Meia-Idade
Terapia de Alvo Molecular
Recidiva Local de Neoplasia
Condicionamento Pré-Transplante
Resultado do Tratamento
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (CD28 Antigens); 0 (Immunoconjugates); 0 (Ki-1 Antigen); 0 (Receptors, Antigen, T-Cell); 7XL5ISS668 (brentuximab vedotin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170815
[St] Status:MEDLINE


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[PMID]:28798231
[Au] Autor:Khalafalla MG; Woods LT; Camden JM; Khan AA; Limesand KH; Petris MJ; Erb L; Weisman GA
[Ad] Endereço:From the Department of Biochemistry.
[Ti] Título:P2X7 receptor antagonism prevents IL-1ß release from salivary epithelial cells and reduces inflammation in a mouse model of autoimmune exocrinopathy.
[So] Source:J Biol Chem;292(40):16626-16637, 2017 Oct 06.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Salivary gland inflammation is a hallmark of Sjögren's syndrome (SS), a common autoimmune disease characterized by lymphocytic infiltration of the salivary gland and loss of saliva secretion, predominantly in women. The P2X7 receptor (P2X7R) is an ATP-gated nonselective cation channel that induces inflammatory responses in cells and tissues, including salivary gland epithelium. In immune cells, P2X7R activation induces the production of proinflammatory cytokines, including IL-1ß and IL-18, by inducing the oligomerization of the multiprotein complex NLRP3-type inflammasome. Here, our results show that in primary mouse submandibular gland (SMG) epithelial cells, P2X7R activation also induces the assembly of the NLRP3 inflammasome and the maturation and release of IL-1ß, a response that is absent in SMG cells isolated from mice deficient in P2X7Rs (P2X7R ). P2X7R-mediated IL-1ß release in SMG epithelial cells is dependent on transmembrane Na and/or K flux and the activation of heat shock protein 90 (HSP90), a protein required for the activation and stabilization of the NLRP3 inflammasome. Also, using the reactive oxygen species (ROS) scavengers -acetyl cysteine and Mito-TEMPO, we determined that mitochondrial reactive oxygen species are required for P2X7R-mediated IL-1ß release. Lastly, administration of the P2X7R antagonist A438079 in the CD28 , IFNγ , NOD.H-2 mouse model of salivary gland exocrinopathy ameliorated salivary gland inflammation and enhanced carbachol-induced saliva secretion. These findings demonstrate that P2X7R antagonism represents a promising therapeutic strategy to limit salivary gland inflammation and improve secretory function.
[Mh] Termos MeSH primário: Células Epiteliais/metabolismo
Interleucina-1beta/metabolismo
Antagonistas do Receptor Purinérgico P2X/farmacologia
Piridinas/farmacologia
Receptores Purinérgicos P2X7/metabolismo
Síndrome de Sjogren/metabolismo
Glândula Submandibular/metabolismo
Tetrazóis/farmacologia
[Mh] Termos MeSH secundário: Animais
Antígenos CD28/genética
Antígenos CD28/metabolismo
Modelos Animais de Doenças
Células Epiteliais/patologia
Inflamassomos
Interferon gama/genética
Interferon gama/metabolismo
Interleucina-18/genética
Interleucina-18/metabolismo
Transporte de Íons/efeitos dos fármacos
Transporte de Íons/genética
Camundongos
Camundongos Knockout
Proteína 3 que Contém Domínio de Pirina da Família NLR/genética
Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
Potássio/metabolismo
Receptores Purinérgicos P2X7/genética
Síndrome de Sjogren/genética
Síndrome de Sjogren/patologia
Sódio/metabolismo
Glândula Submandibular/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methylpyridine); 0 (CD28 Antigens); 0 (IFNG protein, mouse); 0 (IL1B protein, mouse); 0 (Inflammasomes); 0 (Interleukin-18); 0 (Interleukin-1beta); 0 (NLR Family, Pyrin Domain-Containing 3 Protein); 0 (Nlrp3 protein, mouse); 0 (Purinergic P2X Receptor Antagonists); 0 (Pyridines); 0 (Receptors, Purinergic P2X7); 0 (Tetrazoles); 82115-62-6 (Interferon-gamma); 9NEZ333N27 (Sodium); RWP5GA015D (Potassium)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170812
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.790741


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[PMID]:28716895
[Au] Autor:Herrmann A; Lahtz C; Nagao T; Song JY; Chan WC; Lee H; Yue C; Look T; Mülfarth R; Li W; Jenkins K; Williams J; Budde LE; Forman S; Kwak L; Blankenstein T; Yu H
[Ad] Endereço:Department of Onco-Immunology, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California. aherrmann@coh.org hyu@coh.org.
[Ti] Título:CTLA4 Promotes Tyk2-STAT3-Dependent B-cell Oncogenicity.
[So] Source:Cancer Res;77(18):5118-5128, 2017 Sep 15.
[Is] ISSN:1538-7445
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:CTL-associated antigen 4 (CTLA4) is a well-established immune checkpoint for antitumor immune responses. The protumorigenic function of CTLA4 is believed to be limited to T-cell inhibition by countering the activity of the T-cell costimulating receptor CD28. However, as we demonstrate here, there are two additional roles for CTLA4 in cancer, including via CTLA4 overexpression in diverse B-cell lymphomas and in melanoma-associated B cells. CTLA4-CD86 ligation recruited and activated the JAK family member Tyk2, resulting in STAT3 activation and expression of genes critical for cancer immunosuppression and tumor growth and survival. CTLA4 activation resulted in lymphoma cell proliferation and tumor growth, whereas silencing or antibody-blockade of CTLA4 in B-cell lymphoma tumor cells in the absence of T cells inhibits tumor growth. This inhibition was accompanied by reduction of Tyk2/STAT3 activity, tumor cell proliferation, and induction of tumor cell apoptosis. The CTLA4-Tyk2-STAT3 signal pathway was also active in tumor-associated nonmalignant B cells in mouse models of melanoma and lymphoma. Overall, our results show how CTLA4-induced immune suppression occurs primarily via an intrinsic STAT3 pathway and that CTLA4 is critical for B-cell lymphoma proliferation and survival. .
[Mh] Termos MeSH primário: Linfócitos B/patologia
Biomarcadores Tumorais/metabolismo
Antígeno CTLA-4/metabolismo
Linfoma de Células B/patologia
Fator de Transcrição STAT3/metabolismo
TYK2 Quinase/metabolismo
[Mh] Termos MeSH secundário: Adulto
Idoso
Animais
Apoptose
Linfócitos B/imunologia
Linfócitos B/metabolismo
Antígenos CD28/metabolismo
Proliferação Celular
Feminino
Seres Humanos
Ativação Linfocitária
Linfoma de Células B/imunologia
Linfoma de Células B/metabolismo
Masculino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Meia-Idade
Estadiamento de Neoplasias
Prognóstico
Transdução de Sinais
Linfócitos T/imunologia
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (CD28 Antigens); 0 (CTLA-4 Antigen); 0 (CTLA4 protein, human); 0 (STAT3 Transcription Factor); 0 (STAT3 protein, human); EC 2.7.10.2 (TYK2 Kinase); EC 2.7.10.2 (TYK2 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170719
[St] Status:MEDLINE
[do] DOI:10.1158/0008-5472.CAN-16-0342


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[PMID]:28711152
[Au] Autor:Gmyrek GB; Pingel J; Choi J; Green JM
[Ad] Endereço:Washington University School of Medicine, St Louis, MO 63110, USA.
[Ti] Título:Functional analysis of acquired CD28 mutations identified in cutaneous T cell lymphoma.
[So] Source:Cell Immunol;319:28-34, 2017 Sep.
[Is] ISSN:1090-2163
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:CD28 is the major costimulatory receptor on T cells regulating proliferation, survival and effector function. Acquired mutations in the extracellular domain of CD28 have been identified in patients with cutaneous T cell lymphoma, angioimmunoblastic T cell lymphoma and other T cell neoplasms, suggesting it may contribute to disease pathogenesis. We used a heterologous system in which mutant human CD28 was expressed on primary murine T cells deficient in CD28 to ascertain how specific mutations identified in a genetic screen of patients with cutaneous T cell lymphoma affected normal T cell function. All three mutant CD28 proteins examined enhanced CD28-dependent T cell proliferation and effector function. These data suggest that the mutant CD28 isoforms could accelerate tumor cell growth and increase tumor burden in affected patients. Interruption of CD28:ligand interactions may be an effective, targeted therapy for a subset of patients whose tumors bear the mutant CD28 receptor.
[Mh] Termos MeSH primário: Antígenos CD28/genética
Antígeno CTLA-4/genética
Linfoma Cutâneo de Células T/genética
Mutação
Linfócitos T/imunologia
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Antígenos CD28/imunologia
Antígeno CTLA-4/imunologia
Proliferação Celular
Sobrevivência Celular
DNA Complementar/genética
DNA Complementar/imunologia
Expressão Gênica
Seres Humanos
Ativação Linfocitária
Linfoma Cutâneo de Células T/imunologia
Linfoma Cutâneo de Células T/patologia
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Knockout
Proteínas Mutantes Quiméricas/genética
Proteínas Mutantes Quiméricas/imunologia
Cultura Primária de Células
Linfócitos T/patologia
Transfecção
Transgenes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CD28 Antigens); 0 (CTLA-4 Antigen); 0 (CTLA4 protein, human); 0 (DNA, Complementary); 0 (Mutant Chimeric Proteins)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170717
[St] Status:MEDLINE


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[PMID]:28710773
[Au] Autor:Carvajal Gonczi CM; Tabatabaei Shafiei M; East A; Martire E; Maurice-Ventouris MHI; Darlington PJ
[Ad] Endereço:The Center for Structural and Functional Genomics, Concordia University, Montreal, QC, Canada.
[Ti] Título:Reciprocal modulation of helper Th1 and Th17 cells by the ß2-adrenergic receptor agonist drug terbutaline.
[So] Source:FEBS J;284(18):3018-3028, 2017 Sep.
[Is] ISSN:1742-4658
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Catecholamine hormones are powerful regulators of the immune system produced by the sympathetic nervous system (SNS). They regulate the adaptive immune system by altering T-cell differentiation into T helper (Th) 1 and Th2 cell subsets, but the effect on Th17 cells is not known. Th17 cells, defined, in part, by chemokine receptor CCR6 and cytokine interleukin (IL)-17A, are crucial for mediating certain pathogen-specific responses and are linked with several autoimmune diseases. We demonstrated that a proportion of human Th17 cells express beta 2-adrenergic receptor (ß2AR), a G protein-coupled receptor that responds to catecholamines. Activation of peripheral blood mononuclear cells, which were obtained from venous blood drawn from healthy volunteers, with anti-cluster of differentiation 3 (CD3) and anti-CD28 and with a ß2-agonist drug, terbutaline (TERB), augmented IL-17A levels (P < 0.01) in the majority of samples. TERB reduced interferon gamma (IFNγ) indicating that IL-17A and IFNγ are reciprocally regulated. Similar reciprocal regulation was observed with dbcAMP. Proliferation of Th cells was monitored by carboxyfluorescein diacetate N-succinimidyl ester labeling and flow cytometry with antibody staining for CD3 and CD4. TERB increased proliferation by a small but significant margin (P < 0.001). Next, Th17 cells (CD4 CXCR3 CCR6 ) were purified using an immunomagnetic positive selection kit, which removes all other mononuclear cells. TERB increased IL-17A from purified Th17 cells, which argues that TERB acts directly on Th17 cells. Thus, hormone signals from the SNS maintain a balance of Th cells subtypes through the ß2AR.
[Mh] Termos MeSH primário: Agonistas de Receptores Adrenérgicos beta 2/farmacologia
Interleucina-17/genética
Receptores Adrenérgicos beta 2/genética
Terbutalina/farmacologia
Células Th1/efeitos dos fármacos
Células Th17/efeitos dos fármacos
[Mh] Termos MeSH secundário: Anticorpos Monoclonais/farmacologia
Bucladesina/imunologia
Antígenos CD28/antagonistas & inibidores
Antígenos CD28/genética
Antígenos CD28/imunologia
Complexo CD3/genética
Complexo CD3/imunologia
Separação Celular
Regulação da Expressão Gênica
Seres Humanos
Interferon gama/genética
Interferon gama/imunologia
Interleucina-17/imunologia
Cultura Primária de Células
Receptores Adrenérgicos beta 2/imunologia
Transdução de Sinais
Células Th1/citologia
Células Th1/imunologia
Células Th17/citologia
Células Th17/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Adrenergic beta-2 Receptor Agonists); 0 (Antibodies, Monoclonal); 0 (CD28 Antigens); 0 (CD3 Complex); 0 (IL17A protein, human); 0 (Interleukin-17); 0 (Receptors, Adrenergic, beta-2); 63X7MBT2LQ (Bucladesine); 82115-62-6 (Interferon-gamma); N8ONU3L3PG (Terbutaline)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170716
[St] Status:MEDLINE
[do] DOI:10.1111/febs.14166



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