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Análise da imunogenicidade de uma vacina de DNA codificando epitopos CD4 promíscuos e conservados do HIV-1 em camundongos BALB/c e transgênicos para moléculas de HLA classe II; Immunogenicity analysis of a DNA vaccine encoding promiscuous and conserved HIV-1 CD4 epitopes in BALB/c and HLA class II transgenic mice

Ribeiro, Susan Pereira
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 26/08/2010 Português
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Abordagens atuais no desenho de vacinas contra o HIV-1 estão focadas em imunógenos que codificam proteínas inteiras do HIV-1 e visam induzir respostas citotóxicas específicas. É concebível que vacinas bem-sucedidas devem induzir respostas contra múltiplos epitopos do HIV-1, coincidindo com seqüências das cepas circulantes do vírus, conhecido por sua grande variabilidade genética. Sabe-se que células T CD4+ são necessárias para indução de respostas efetivas de linfócitos T CD8+ citotóxicos. Neste trabalho, nós avaliamos a imunogenicidade de uma vacina de DNA codificando 18 epitopos para linfócitos T CD4+, conservados e ligadores de múltiplas moléculas HLA-DR em camundongos BALB/c e em quatro linhagens de camundongos transgênicos para moléculas de HLA classe II. Os camundongos imunizados apresentaram respostas de amplitude e magnitude significativas com proliferação e secreção de citocinas por linfócitos T CD4+ e T CD8+. Onze dos 18 epitopos para linfócitos T CD4+ presentes na vacina foram reconhecidos pelas linhagens de camundongos transgênicos para moléculas de HLA classe II. Em suma, 17 dos 18 epitopos codificados pela vacina foram reconhecidos. As células induzidas pela vacina apresentaram um perfil polifuncional com tipo 1 de citocinas...

Teste tuberculínico em indivíduos com infecção pelo vírus da imunodeficiência humana: relação com número de linfócitos T periféricos e atividade tuberculosa

Souza, Lenice do Rosário de; Galvão, Marli Teresinha Gimeniz; Machado, Jussara Marcondes; Meira, Domingos Alves; Cunha, Karlla
Fonte: Sociedade Brasileira de Pneumologia e Tisiologia Publicador: Sociedade Brasileira de Pneumologia e Tisiologia
Tipo: Artigo de Revista Científica Formato: 438-443
Português
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OBJETIVO: Avaliar os resultados do teste tuberculínico e relacioná-los com a presença ou não de tuberculose em atividade e com a contagem de linfócitos T CD4+/CD8+. MÉTODOS: Foram revisados 802 prontuários de pacientes com síndrome da imunodeficiência adquirida atendidos no período de agosto de 1985 a março de 2003. Cento e oitenta e cinco pacientes realizaram o teste tuberculínico (23,1%) e, destes, 107 eram do sexo masculino (57,8%). A média de idade no grupo de reatores ao teste tuberculínico foi de 30,6 anos, com desvio-padrão de 6,62 anos, e entre os não reatores de 34,45 anos com desvio-padrão de 10,32 anos. Foram constituídos dois grupos de estudo: reatores ao teste tuberculínico, com 28 pacientes, e não reatores ao teste tuberculínico, com 157 pacientes. RESULTADOS: Grande parte dos indivíduos foi pouco responsiva ao teste tuberculínico. Constatou-se, no grupo de reatores, maior porcentagem de indivíduos com tuberculose ativa à época da realização do teste, quando se comparou com os não reatores. Dez pacientes entre os reatores e onze entre os não reatores apresentavam alguma forma clínica de tuberculose em atividade à época da realização do teste, sendo que seis do primeiro grupo e oito do segundo tinham contagem de linfócitos T CD4+ menor que 200 células/mm³. CONCLUSÃO: Indurações maiores do que 5 mm não se relacionaram com contagens absolutas mais altas de células T CD4+.; OBJECTIVE: To evaluate tuberculin test results and relate them to the presence or absence of active tuberculosis...

Glutamine or whey-protein supplementation on alloxan-induced diabetic rats. Effects on CD4+ and CD8+ lymphocytes

Motta Neto,Renato; Guimarães,Sergio Botelho; Silva,Sônia Leite da; Cruz,José Napoleão da; Dias,Thiago; Vasconcelos,Paulo Roberto Leitão de
Fonte: Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia Publicador: Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2007 Português
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89.239%
PURPOSE: To evaluate the effects of glutamine (L-Gln) or whey-protein supplementation on CD4+ and CD8+ lymphocytes in alloxan-induced diabetic rats. METHODS: Thirty-two healthy male Wistar rats were used in the experiment. Eight rats served as baseline controls (G-1). The remaining 24 animals received alloxan 150mg/Kg intraperitonially dissolved in buffer solution and were equally distributed in 3 subgroups, upon induction of diabetes mellitus, and treated as follows: (G2): saline, 2.0ml; (G3): glutamine solution (0.7g/kg), 2.0 ml; and (G4): whey-protein (WPS) solution (0.7g/kg), 2.0 ml. All solutions were administered by daily 7:00 AM gavages during 30 days. Next, arterial blood samples (3.0 ml) were collected from anesthetized rats for CD4+ and CD8+ lymphocyte count through flow cytometry technology. RESULTS: CD4+ and CD8+ counts decreased significantly in all groups compared with baseline values (G1). G2 rats CD4+/CD8+ ratio decreased significantly compared with G1. CD4+/CD8+ ratio increased significantly (>260%) in L-Gln treated group (G3) compared with saline-treated rats (G2). There were no statistical differences in lymphocyte counts (CD4+ and CD8+) between L-Gln (G3) and saline-treated (G2) groups. There was a significant reduction in CD8+ cell count compared with CD4+ cell count in L-Gln treated rats (G3). CONCLUSION: The offer of L-Gln to experimental diabetic rats enhances the immunologic response to infection.

Characterization of the MRC OX40 antigen of activated CD4 positive T lymphocytes--a molecule related to nerve growth factor receptor.

Mallett, S; Fossum, S; Barclay, A N
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /04/1990 Português
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The antigen recognized by the monoclonal antibody (mAb) MRC OX40 is present on activated rat CD4 positive T lymphocytes but not other cells. cDNA clones were isolated from an expression library using the MRC OX40 mAb and the protein sequence for the OX40 antigen deduced. It contains a typical signal sequence and a single putative transmembrane sequence of 25 predominantly hydrophobic amino acids giving an extracellular domain of 191 amino acids and a cytoplasmic domain of 36 amino acids. The sequence of the extracellular domain includes a cysteine-rich region with sequence similarities with the low affinity nerve growth factor receptor (NGFR) of neurons and the CD40 antigen present on human B cells. Within this region three cysteine-rich motifs can be recognized in OX40 compared with four similar motifs in both NGFR and CD40. OX40, CD40 and NGFR constitute a new superfamily of molecules with expression including lymphoid cells (OX40, CD40) and neuronal cells (NGFR). This is reminiscent of the immunoglobulin superfamily whose molecules are variously found at the surface of lymphoid or brain cells or both.

Hemodialysis Affects Phenotype and Proliferation of CD4-Positive T Lymphocytes

Lisowska, Katarzyna A.; Dębska-Ślizień, Alicja; Jasiulewicz, Aleksandra; Heleniak, Zbigniew; Bryl, Ewa; Witkowski, Jacek M.
Fonte: Springer US Publicador: Springer US
Tipo: Artigo de Revista Científica
Português
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CD4+ T lymphocytes of patients with chronic kidney disease (CKD) are characterized by reduced levels of crucial surface antigens and changes in the cell cycle parameters. Recombinant human erythropoietin (rhEPO) normalizes their altered phenotype and proliferative capacity. Mechanisms leading to the deficient responses of T lymphocytes are still not clear but it is postulated that immunological changes are deepened by hemodialysis (HD). Study of activation parameters of CD4+ T lymphocytes in hemodialyzed and predialysis CKD patients could bring insight into this problem. Two groups of patients, treated conservatively (predialysis, PD) and hemodialyzed (HD), as well as healthy controls, were included into the study; neither had received rhEPO. Proportions of main CD4+CD28+, CD4+CD25+, CD4+CD69+, CD4+CD95+, and CD4+HLA-DR+ lymphocyte subpopulations and proliferation kinetic parameters were measured with flow cytometry, both ex vivo and in vitro. No differences were seen in the proportions of main CD4+ lymphocyte subpopulations (CD4+CD28+, CD4+CD25+, CD4+HLA-DR+, CD4+CD69+, CD4+CD95+) between all examined groups ex vivo. CD4+ T lymphocytes of HD patients exhibited significantly decreased expression of co-stimulatory molecule CD28 and activation markers CD25 and CD69 after stimulation in vitro when compared with PD patients and healthy controls. HD patients showed also decreased percentage of CD4+CD28+ lymphocytes proliferating in vitro; these cells presented decreased numbers of finished divisions after 72 h of stimulation in vitro and had longer G0→G1 time when compared to healthy controls. CD4+ T lymphocytes of PD patients and healthy controls were characterized by similar cell cycle parameters. Our study shows that repeated hemodialysis procedure influences phenotype and proliferation parameters of CD4+ T lymphocytes.

Genomic organisation and biological characterization of the novel human CC chemokine DC-CK-1/PARC/MIP-4/SCYA18

Guan, P.; Burghes, A.; Cunningham, A.; Lira, P.; Brissette, W.; Neote, K.; McColl, S.
Fonte: ACADEMIC PRESS INC Publicador: ACADEMIC PRESS INC
Tipo: Artigo de Revista Científica
Publicado em //1999 Português
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The chemokines are a group of chemotactic molecules that appear to regulate the directed movement of white blood cells in vitro and in vivo and may therefore play important roles in inflammation and immunity. The genes encoding the chemokines are clustered in close physical proximity to each other. A large cluster of human CC chemokine genes resides on chromosome 17. We have used this information in a positional cloning approach to identify novel chemokine genes within this cluster. We constructed a YAC contig encompassing the MIP-1alpha (HGMW-approved symbol SCYA3) gene region and used exon trapping and sequence analysis to isolate novel chemokine genes. Using this approach, a gene encoding a chemokine named MIP-4, based on its homology with MIP-1alpha (49.5% identity at the nucleotide level and 59.6% at the predicted amino acid level), was found. The MIP-4 gene (HGMW-approved symbol SCYA18) consists of three exons spread over 7.1 kb and is separated from the MIP-1alpha gene by 16 kb. The MIP-4 gene encodes a 750-bp mRNA that is expressed in lung and macrophages but not in brain or muscle. The mRNA encodes an 89-amino-acid protein and includes a predicted signal peptide of 21 amino acids. Recombinant or synthetic MIP-4 induced calcium mobilization in naive and activated T lymphocyte subpopulations in vitro. Injection of synthetic MIP-4 into the peritoneal cavity of mice led to the accumulation of both CD4(+) and CD8(+) T lymphocytes...

Compartmentalization of intracellular proinflammatory cytokines in bronchial intraepithelial T cells of stable lung transplant patients

Hodge, G.; Hodge, S.; Reynolds, P.; Holmes, M.
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Publicado em //2006 Português
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Allograft rejection remains a major cause of morbidity and mortality following lung transplantation and is associated with an increased expression of T cell proinflammatory cytokines. We have shown that CD4(+) T cell proinflammatory cytokine production was significantly reduced in peripheral blood and bronchoalveolar lavage (BAL) of stable lung transplant patients, consistent with immunosuppression therapy. However, analysis of inflammatory cytokine profiles of intraepithelial T cells in bronchial brushing (BB) may be more relevant than peripheral blood or BAL T cells for assessing immune graft status. To investigate the immunomodulatory effects of currently used immunosuppressive regimens on bronchial intraepithelial T cell cytokine production, whole blood, BAL and BB from stable lung transplant patients and control volunteers were stimulated in vitro and cytokine production by CD8(+) and CD4(+) T cell subsets determined using multi-parameter flow cytometry. In bronchial intraepithelial T cell subsets in control subjects and transplant patients there was compartmentalization of interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha production, a decrease in interleukin (IL)-2 production by CD4(+) T cells and CD4 : CD8 inversion compared with blood and BAL. Although there was a decrease in T cell proinflammatory cytokine production in blood of transplant patients...

Up-regulation of CCR5 and CCR6 on distinct subpopulations of antigen-activated CD4⁺ T lymphocytes; Up-regulation of CCR5 and CCR6 on distinct subpopulations of antigen-activated CD4(+) T lymphocytes

Ebert, L.; McColl, S.
Fonte: Amer Assoc Immunologists Publicador: Amer Assoc Immunologists
Tipo: Artigo de Revista Científica
Publicado em //2002 Português
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Following infection, naive T cells are activated in the secondary lymphoid tissue, but then need to move to the infected tissue in the periphery to mediate their effector functions. The acquisition of inflammatory chemokine receptors, such as CCR5 and CCR6, may contribute to the efficient relocation of activated T cells to inflamed sites in the periphery. In keeping with this idea, the present study has demonstrated that CCR5 and CCR6 are up-regulated on CD4+ T cells upon activation in the MLR. The observed increase in expression correlated well with the acquisition of an activated/memory phenotype and was largely (CCR5) or completely (CCR6) separated temporally from the initiation of cell division. In contrast, the regulation of two other chemokine receptors, CXCR3 and CXCR4, occurred in close parallel with the cell division process. Increased mRNA levels are likely to contribute to the enhanced surface expression of CCR5 and CCR6, but in the case of CCR6, translocation of intracellular stores of protein to the cell surface may be an additional mechanism of regulation. The up-regulation of CCR5 was more extensive than that of CCR6, as only approximately half the activated CCR5+ T cells coexpressed CCR6. The increased expression of CCR5 resulted in enhanced chemotaxis toward the CCR5 ligand macrophage-inflammatory protein-1/CCL4...

Low CD4 T cell immunity to pneumolysin is associated with nasopharyngeal carriage of pneumococci in children

Zhang, Q.; Bagrade, L.; Bernatoniene, J.; Clarke, E.; Paton, J.; Mitchell, T.; Nunez, D.; Finn, A.
Fonte: Univ Chicago Press Publicador: Univ Chicago Press
Tipo: Artigo de Revista Científica
Publicado em //2007 Português
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BACKGROUND: Recent studies in mice have suggested that T cell immunity may be protective against pneumococcal infection. METHODS: CD4 T cell proliferative responses to the pneumococcal proteins pneumolysin (Ply), Ply toxoid (F433), and choline-binding protein A were investigated in peripheral blood mononuclear cells (PBMCs) and adenoidal mononuclear cells (MNCs) obtained from children undergoing adenoidectomy. RESULTS: Ply and F433 induce significant proliferation of CD4 T cells in both PBMCs and adenoidal MNCs, and both memory and naive phenotypes of CD4 T cells proliferated after stimulation. In PBMCs, CD4 T cell proliferation induced by Ply and F433, which was associated with increased production of interferon (IFN)- gamma and tumor necrosis factor (TNF)- alpha , was significantly lower in children who were culture positive for pneumococcus than in those who were culture negative for pneumococcus (P<.05). Between groups, no such difference was observed in adenoidal MNC CD4 T cell proliferation, which was associated with production of IFN- gamma and interleukin (IL)-10. The CD4 T cell proliferation induced by Ply and F433 was inhibited by antibodies to Toll-like receptor 4. CONCLUSION: These data suggest that Ply induces CD4 T cell proliferative responses with production of IFN- gamma and TNF- alpha in PBMCs or of IFN- gamma and IL-10 in adenoidal MNCs...

Airway infection in stable lung transplant patients is associated with decreased intracellular T-helper type 1 pro-inflammatory cytokines in bronchoalveolar lavage T-cell subsets

Hodge, G.; Hodge, S.; Reynolds, P.; Holmes, M.
Fonte: Wiley-Blackwell Munksgaard Publicador: Wiley-Blackwell Munksgaard
Tipo: Artigo de Revista Científica
Publicado em //2008 Português
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Current immunosuppression protocols to prevent lung transplant rejection reduce pro-inflammatory and T-helper type 1 (Th1) cytokines. However, Th1 T-cell pro-inflammatory cytokine production is important in host defense against bacterial infection in the lungs. Excessive immunosuppression of Th1 T-cell pro-inflammatory cytokines leaves patients susceptible to infection. To investigate whether pulmonary infection in lung transplant recipients is associated with reduced Th1 T-cell pro-inflammatory cytokines, whole blood and bronchoalveolar lavage (BAL) fluid from 13 stable lung transplant patients with ‘culture-negative’ BAL and 13 patients with ‘culture-positive’ BAL was stimulated in vitro, and cytokine production by CD8+ and CD4+ T-cell subsets was determined using multiparameter flow cytometry. In BAL samples, there was a significant decrease in interleukin-2 (IL2) in CD3+ T cells and tumor necrosis factor-α (TNF-α) in CD8+ T cells (but not CD4+) in ‘culture-positive’ compared with ‘culture-negative’ transplant patients. There was no difference in blood Th1 T-cell cytokines between ‘culture-positive’ compared with ‘culture-negative’ transplant patients. A decrease in Th1 cytokines IL-2 and TNF-α in BAL T-cell subsets is associated with isolation of potentially pathogenic organisms in the lungs in stable lung transplant patients. Excessive immunosuppression of these Th1 T-cell pro-inflammatory cytokines in stable transplant patients may leave them susceptible to infection. Modifying immunosuppression by monitoring intracellular Th1 pro-inflammatory cytokines in BAL T cells may help to improve morbidity and infection rates in stable lung transplant patients.; G. Hodge...

Dasatinib inhibits recombinant viral antigen-specific murine CD4+ and CD8+ T-cell responses and NK-cell cytolytic activity in vitro and in vivo

Fraser, C.; Blake, S.; Diener, K.; Lyons, A.; Brown, M.; Hughes, T.; Hayball, J.
Fonte: Elsevier Science Inc Publicador: Elsevier Science Inc
Tipo: Artigo de Revista Científica
Publicado em //2009 Português
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Objective Dasatinib (BMS-354825) is a small molecule Src/Abl tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia. Members of the Src family of kinases are involved in the induction of innate and adaptive immunity. The purpose of this study was to evaluate the inhibitory action of dasatinib on antigen-specific CD8+ and CD4+ T-cell function, as well as natural killer (NK) cell cytotoxicity. Materials and Methods To assess dasatinib-mediated inhibition of antigen-specific T-cell proliferation, transgenic CD4+ and CD8+ T cells specific for ovalbumin were utilized. Endogenous CD4+ and CD8+ T-cell responses were determined following immunization of dasatinib-treated or control mice with a nonreplicating recombinant virus. Clearance of the RMA-S cells, a major histocompatibility complex (MHC) class I–deficient thymoma sensitive to NK-cell lysis, was analyzed in mice undergoing dasatinib treatment. Results Dasatinib inhibited antigen-specific proliferation of murine CD4+ and CD8+ transgenic T cells in vitro and in vivo. Endogenous antigen-specific helper T-cell recall responses and induction of T-cell–mediated cytotoxicity following immunization with a nonreplicating recombinant virus were also inhibited. So to was the ability of NK cells to eliminate MHC class I–deficient cells in vivo. Conclusions These findings suggest that dasatinib has the potential to modulate the host immune response at clinical doses and highlights scope for off target applications...

Autoantigen-specific interactions with CD4(+) thymocytes control mature medullary thymic epithelial cell cellularity

Irla, M.; Hugues, S.; Gill, J.; Nitta, T.; Hikosaka, Y.; Williams, I.; Hubert, F.X.; Scott, H.; Takahama, Y.; Hollander, G.; Reith, W.
Fonte: Cell Press Publicador: Cell Press
Tipo: Artigo de Revista Científica
Publicado em //2008 Português
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Medullary thymic epithelial cells (mTECs) are specialized for inducing central immunological tolerance to self-antigens. To accomplish this, mTECs must adopt a mature phenotype characterized by expression of the autoimmune regulator Aire, which activates the transcription of numerous genes encoding tissue-restricted self-antigens. The mechanisms that control mature Aire(+) mTEC development in the postnatal thymus remain poorly understood. We demonstrate here that, although either CD4(+) or CD8(+) thymocytes are sufficient to sustain formation of a well-defined medulla, expansion of the mature mTEC population requires autoantigen-specific interactions between positively selected CD4(+) thymocytes bearing autoreactive T cell receptor (TCR) and mTECs displaying cognate self-peptide-MHC class II complexes. These interactions also involve the engagement of CD40 on mTECs by CD40L induced on the positively selected CD4(+) thymocytes. This antigen-specific TCR-MHC class II-mediated crosstalk between CD4(+) thymocytes and mTECs defines a unique checkpoint in thymic stromal development that is pivotal for generating a mature mTEC population competent for ensuring central T cell tolerance.; http://www.cell.com/immunity/home; Magali Irla, Stéphanie Hugues...

Myeloma-induced alloreactive T cells arising in myeloma-infiltrated bones include double-positive CD8⁺CD4⁺ T cells: evidence from myeloma-bearing mouse model; Myeloma-induced alloreactive T cells arising in myeloma-infiltrated bones include double-positive CD8(+)CD4(+) T cells: evidence from myeloma-bearing mouse model

Freeman, L.; Lam, A.; Petcu, E.; Smith, R.; Salajegheh, A.; Diamond, P.; Zannettino, A.; Evdokiou, A.; Luff, J.; Wong, P.F.; Khalil, D.; Waterhouse, N.; Vari, F.; Rice, A.; Catley, L.; Hart, D.; Vuckovic, S.
Fonte: Amer Assoc Immunologists Publicador: Amer Assoc Immunologists
Tipo: Artigo de Revista Científica
Publicado em //2011 Português
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The graft-versus-myeloma (GVM) effect represents a powerful form of immune attack exerted by alloreactive T cells against multiple myeloma cells, which leads to clinical responses in multiple myeloma transplant recipients. Whether myeloma cells are themselves able to induce alloreactive T cells capable of the GVM effect is not defined. Using adoptive transfer of T naive cells into myeloma-bearing mice (established by transplantation of human RPMI8226-TGL myeloma cells into CD122+ cell-depleted NOD/SCID hosts), we found that myeloma cells induced alloreactive T cells that suppressed myeloma growth and prolonged survival of T cell recipients. Myeloma-induced alloreactive T cells arising in the myeloma-infiltrated bones exerted cytotoxic activity against resident myeloma cells, but limited activity against control myeloma cells obtained from myeloma-bearing mice that did not receive T naive cells. These myeloma-induced alloreactive T cells were derived through multiple CD8+ T cell divisions and enriched in double-positive (DP) T cells coexpressing the CD8αα and CD4 coreceptors. MHC class I expression on myeloma cells and contact with T cells were required for CD8+ T cell divisions and DP-T cell development. DP-T cells present in myeloma-infiltrated bones contained a higher proportion of cells expressing cytotoxic mediators IFN-γ and/or perforin compared with single-positive CD8+ T cells...

PI3Kγ drives priming and survival of autoreactive CD4⁺ T cells during experimental autoimmune encephalomyelitis; PI3Kgamma drives priming and survival of autoreactive CD4(+) T cells during experimental autoimmune encephalomyelitis

Comerford, I.; Litchfield, W.; Kara, E.; McColl, S.
Fonte: Public Library of Science Publicador: Public Library of Science
Tipo: Artigo de Revista Científica
Publicado em //2012 Português
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The class IB phosphoinositide 3-kinase γ enzyme complex (PI3Kc) functions in multiple signaling pathways involved in leukocyte activation and migration, making it an attractive target in complex human inflammatory diseases including MS. Here, using pik3cg2/2 mice and a selective PI3Kc inhibitor, we show that PI3Kc promotes development of experimental autoimmune encephalomyelitis (EAE). In pik3cg2/2 mice, EAE is markedly suppressed and fewer leukocytes including CD4+ and CD8+ T cells, granulocytes and mononuclear phagocytes infiltrate the CNS. CD4+ T cell priming in secondary lymphoid organs is reduced in pik3cg2/2 mice following immunisation. This is attributable to defects in DC migration concomitant with a failure of full T cell activation following TCR ligation in the absence of p110c. Together, this results in suppressed autoreactive T cell responses in pik3cg2/2 mice, with more CD4+ T cells undergoing apoptosis and fewer cytokineproducing Th1 and Th17 cells in lymphoid organs and the CNS. When administered from onset of EAE, the orally active PI3Kc inhibitor AS605240 caused inhibition and reversal of clinical disease, and demyelination and cellular pathology in the CNS was reduced. These results strongly suggest that inhibitors of PI3Kc may be useful therapeutics for MS.; Iain Comerford...

Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4⁺ T cells infiltrate islets in type 1 diabetes; Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4(+) T cells infiltrate islets in type 1 diabetes

Pathiraja, V.; Kuehlich, J.P.; Campbell, P.D.; Krishnamurthy, B.; Loudovaris, T.; Coates, P.T.H.; Brodnicki, T.C.; O'Connell, P.J.; Kedzierska, K.; Rodda, C.; Bergman, P.; Hill, E.; Purcell, A.W.; Dudek, N.L.; Thomas, H.E.; Kay, T.W.H.; Mannering, S.I.
Fonte: American Diabetes Association Publicador: American Diabetes Association
Tipo: Artigo de Revista Científica
Publicado em //2015 Português
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Type 1 diabetes (T1D) develops when insulin-secreting β-cells, found in the pancreatic islets of Langerhans, are destroyed by infiltrating T cells. How human T cells recognize β-cell-derived antigens remains unclear. Genetic studies have shown that HLA and insulin alleles are the most strongly associated with risk of T1D. These long-standing observations implicate CD4(+) T-cell responses against (pro)insulin in the pathogenesis of T1D. To dissect the autoimmune T-cell response against human β-cells, we isolated and characterized 53 CD4(+) T-cell clones from within the residual pancreatic islets of a deceased organ donor who had T1D. These 53 clones expressed 47 unique clonotypes, 8 of which encoded proinsulin-specific T-cell receptors. On an individual clone basis, 14 of 53 CD4(+) T-cell clones (26%) recognized 6 distinct but overlapping epitopes in the C-peptide of proinsulin. These clones recognized C-peptide epitopes presented by HLA-DQ8 and, notably, HLA-DQ8 transdimers that form in HLA-DQ2/-DQ8 heterozygous individuals. Responses to these epitopes were detected in the peripheral blood mononuclear cells of some people with recent-onset T1D but not in HLA-matched control subjects. Hence, proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4(+) T cells are strongly implicated in the autoimmune pathogenesis of human T1D.; Vimukthi Pathiraja...

Intracellular cytokines in blood T cells in lung transplant patients - a more relevant indicator of immunosuppression than drug levels

Hodge, G.; Hodge, S.; Reynolds, P.; Holmes, M.
Fonte: Blackwell Publishing Ltd Publicador: Blackwell Publishing Ltd
Tipo: Artigo de Revista Científica
Publicado em //2005 Português
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Allograft rejection remains a major cause of morbidity and mortality following lung transplantation and is associated with an increase in T-cell pro-inflammatory cytokine expression. Systemic levels of immunosuppressive drugs used to reduce pro-inflammatory cytokine expression are closely monitored to their 'therapeutic range'. However, it is currently unknown if levels of these drugs correlate with pro-inflammatory cytokine expression in peripheral blood T cells. To investigate the immunomodulatory effects of currently used immunosuppressive regimes on peripheral blood T-cell cytokine production, whole blood from stable lung transplant patients and control volunteers were stimulated in vitro and cytokine production by CD8+ and CD4+ T-cell subsets determined using multiparameter flow cytometry. T-cell IL-2 and TNFalpha production was significantly reduced from lung transplant patients compared to controls. CD4+ T-cell production of IFNgamma was also significantly reduced from lung transplant patients but production of IFNgamma by CD8+ T cells remained unchanged. There was an excellent correlation between the percentage of CD8+ T cells and the percentage of CD8+ T cells producing IFNgamma from transplant patients. T-cell IL-4 and CD8+ T-cell production of TGFbeta was significantly increased from lung transplant patients. We now provide evidence that current immunosuppression protocols have limited effect on peripheral blood IFNgamma production by CD8+ T-cells but do up-regulate T-cell anti-inflammatory cytokines. Drugs that effectively reduce IFNgamma production by CD8+ T cells may improve current protocols for reducing graft rejection in these patients. Intracellular cytokine analysis using flow cytometry may be a more appropriate indicator of immunosuppression than drug levels in these patients. This technique may prove useful in optimizing therapy for individual patients.

Vaccine-induced protection against orthopoxvirus infection Is mediated through the combined functions of CD4 T cell-dependent antibody and CD8 T cell responses

Chaudhri, Geeta; Tahiliani, Vikas; Eldi, Preethi; Karupiah, Gunasegaran
Fonte: American Society for Microbiology Publicador: American Society for Microbiology
Tipo: Artigo de Revista Científica Formato: 11 pages
Português
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Antibody production by B cells in the absence of CD4 T cell help has been shown to be necessary and sufficient for protection against secondary orthopoxvirus (OPV) infections. This conclusion is based on short-term depletion of leukocyte subsets in vaccinated animals, in addition to passive transfer of immune serum to naive hosts that are subsequently protected from lethal orthopoxvirus infection. Here, we show that CD4 T cell help is necessary for neutralizing antibody production and virus control during a secondary ectromelia virus (ECTV) infection. A crucial role for CD4 T cells was revealed when depletion of this subset was extended beyond the acute phase of infection. Sustained depletion of CD4 T cells over several weeks in vaccinated animals during a secondary infection resulted in gradual diminution of B cell responses, including neutralizing antibody, contemporaneous with a corresponding increase in the viral load. Long-term elimination of CD8 T cells alone delayed virus clearance, but prolonged depletion of both CD4 and CD8 T cells resulted in death associated with uncontrolled virus replication. In the absence of CD4 T cells, perforin- and granzyme A- and B-dependent effector functions of CD8 T cells became critical. Our data therefore show that both CD4 T cell help for antibody production and CD8 T cell effector function are critical for protection against secondary OPV infection. These results are consistent with the notion that the effectiveness of the smallpox vaccine is related to its capacity to induce both B and T cell memory. IMPORTANCE Smallpox eradication through vaccination is one of the most successful public health endeavors of modern medicine. The use of various orthopoxvirus (OPV) models to elucidate correlates of vaccine-induced protective immunity showed that antibody is critical for protection against secondary infection...

Aumento de células T CD4+CD69+ e redução de células T reguladoras CD4+CD25+FoxP3+ em camundongos com Lúpus Eritematoso Sistêmico (LES) induzido por pristane; Increase of CD4+CD69+ T cells and reduction of CD4+CD25+FoxP3+ regulatory T cells in pristane-induced mice with systemic lupus erythematosus (SLE)

Peixoto, Tatiana Vasconcelos
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Tese de Doutorado Formato: application/pdf
Publicado em 25/09/2015 Português
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Introdução: O Lúpus Eritematoso Sistêmico (LES) é uma doença autoimune multissistêmica de etiologia complexa que envolve fatores ambientais, genéticos e hormonais. É caracterizada pela produção de autoanticorpos e mediadores inflamatórios, ativação e proliferação de células T autorreativas e perda da autotolerância imunológica. Em pacientes com LES, a expressão do receptor primário de ativação CD69 é aumentada e a de células T supressoras/reguladoras (Treg) CD4+CD25+FoxP3+ é reduzida. O CD69 é essencial para ativação de células T CD4 autorreativas enquanto que as células Treg são importantes na manutenção da autotolerância. Desta forma, células T tem um papel central na patogênese do LES, mas os mecanismos implicados na falência da autotolerância ainda não são elucidados, destacando a importância de estudos em modelos experimentais da doença, como o de LES-induzido por pristane. Objetivo: Quantificar células T CD4+CD69+ ativadas e Treg CD4+CD25+FoxP3+ no sangue, baço e LP de camundongos Balb/c LESinduzido por pristane no sentido de avaliar a falência de autotolerância neste modelo. Métodos: Analisamos 84 camundongos Balb/c fêmeas: 52 receberam por via intraperitoneal uma dose única de 0...

Estilo de vida de pacientes infectados pelo vírus da imunodeficiência humana (HIV) e sua associação com a contagem de linfócitos T CD4+; Lifestyle of HIV seropositives patients and your association with CD4 positive t-lymphocytes counts

de Lima Eidam, Cristiane; Mestre em Educação Física - UFSC; da Silva Lopes, Adair; Doutor do Departamento de Educação Física/UFSC, Florianópolis, SC, Brasil.; Crosland Guimarães, Mark Drew; Departamento de Medicina da Universidade Federal de Minas
Fonte: Universidade Federal de Santa Catarina. Florianópolis, SC. Brasil Publicador: Universidade Federal de Santa Catarina. Florianópolis, SC. Brasil
Tipo: info:eu-repo/semantics/article; info:eu-repo/semantics/publishedVersion; "Avaliado por Pares",; Avaliado por Pares; Descritiva Formato: application/pdf; application/pdf
Publicado em 19/11/2006 Português
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Este estudo pretendeu avaliar o estilo de vida de pacientes infectados pelo vírus da imunodeficiência humana (HIV) e associá-lo à contagem de linfócitos T CD4+. A amostra, selecionada por conveniência, foi constituída de 111 indivíduos (68 homens e 43 mulheres, com idade média de 37 anos). Os dados para avaliação do estilo de vida (hábitos alimentares, atividade física, comportamento preventivo, relacionamentos e controle do estresse), foram obtidos por meio de entrevista. Para a contagem do número de linfócitos T CD4+, considerou-se o resultado do último exame laboratorial apresentado na ficha do paciente. Foram realizadas análises descritivas, análise de variância (ANOVA) one-way, com o teste post hoc de Tukey e o teste qui–quadrado. Os resultados evidenciaram que a contagem média de linfócitos T CD4+ foi de 345 cel/mm3 e a mediana de 296 cel/mm3. A maioria dos pacientes realizava os exames de rotina e seguia as recomendações médicas (92,8%), usava preservativos durante as relações sexuais (80,2%), estava satisfeita com os relacionamentos (80,2%) e reservava tempo, todos os dias, para relaxar (82%). O perfil do estilo de vida, nos componentes hábitos alimentares e de atividade física habitual, foi classificado como insatisfatório. O comportamento preventivo foi a variável do estilo de vida com resultado médio significativamente superior aos demais (6...

Restauración de la inmunidad innata en pacientes con infección por VIH/SIDA después de inicio de terapia antirretroviral

Afani S,Alejandro; Jiusán L,Lorena; Raby A,Pablo; Sitia,Giovanni; Puente P,Javier; Sepúlveda C,Cecilia; Miranda W,Dante; Cabrera C,Roy; Guidotti,Luca; Lanza,Paola
Fonte: Sociedad Médica de Santiago Publicador: Sociedad Médica de Santiago
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/06/2006 Português
Relevância na Pesquisa
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Background: Highly active antiretroviral therapy (HAART) in HIV/AIDS infection induces an important reduction of the viral load (VL) and an immune system reconstitution. CD4+ T lymphocyte count is the immunological measurement commonly used for the follow up of HIV/AIDS patients. Aim: To study prospectively the restoration of the innate immune system in patients with HIV/AIDS infection during their first year on HAART. Patients and Methods: 25 naive HIV/AIDS patients, from San José Hospital and University of Chile Clinical Hospital, Santiago, Chile, were studied between years 2002-2003. Every 4 months after HAART initiation, CD3+, CD4+, CD8+ T lymphocytes and CD16/56+ natural killer (NK) cells were quantified by flow cytometry. NK cell cytotoxicity was measured using radioactive chrome liberation (Cr51). Tumor necrosis factor alpha (TNF-a) and interleukin-10 (IL-10) were measured in peripheral blood mononuclear cells and viral load was determined using Amplicor HIV-1 from Roche Diagnostics Systems. Results: Thirteen of the 25 patients continued in the study. They were all males, average age 35 years old (23-50). At baseline average CD4+ count was 146 cells/µL (31-362) and average viral load was 82.000 copies/mL (4.000-290.000). A raise in CD3+...