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1.
Sci Adv ; 8(7): eabj7002, 2022 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-35179953

RESUMO

Effectiveness of checkpoint immunotherapy in cancer can be undermined by immunosuppressive tumor-associated macrophages (TAMs) with an M2 phenotype. Reprogramming TAMs toward a proinflammatory M1 phenotype is a novel approach to induce antitumor immunity. The M2 phenotype is controlled by key transcription factors such as signal transducer and activator of transcription 6 (STAT6), which have been "undruggable" selectively in TAMs. We describe an engineered exosome therapeutic candidate delivering an antisense oligonucleotide (ASO) targeting STAT6 (exoASO-STAT6), which selectively silences STAT6 expression in TAMs. In syngeneic models of colorectal cancer and hepatocellular carcinoma, exoASO-STAT6 monotherapy results in >90% tumor growth inhibition and 50 to 80% complete remissions. Administration of exoASO-STAT6 leads to induction of nitric oxide synthase 2 (NOS2), an M1 macrophage marker, resulting in remodeling of the tumor microenvironment and generation of a CD8 T cell-mediated adaptive immune response. Collectively, exoASO-STAT6 represents the first platform targeting transcription factors in TAMs in a highly selective manner.


Assuntos
Exossomos , Neoplasias , Exossomos/genética , Exossomos/metabolismo , Humanos , Macrófagos/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/terapia , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/metabolismo , Microambiente Tumoral/genética , Macrófagos Associados a Tumor
2.
BMC Bioinformatics ; 17: 171, 2016 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-27089880

RESUMO

BACKGROUND: The immune system is multifaceted, structured by diverse components that interconnect using multilayered dynamic cellular processes. Genomic technologies provide a means for investigating, at the molecular level, the adaptations of the immune system in host defense and its dysregulation in pathological conditions. A critical aspect of intersecting and investigating complex datasets is determining how to best integrate genomic data from diverse platforms and heterogeneous sample populations to capture immunological signatures in health and disease. RESULT: We focus on gene signatures, representing highly enriched genes of immune cell subsets from both diseased and healthy tissues. From these, we construct a series of biomaps that illustrate the molecular linkages between cell subsets from different lineages, the connectivity between different immunological diseases, and the enrichment of cell subset signatures in diseased tissues. Finally, we overlay the downstream genes of drug targets with disease gene signatures to display the potential therapeutic applications for these approaches. CONCLUSION: An in silico approach has been developed to characterize immune cell subsets and diseases based on the gene signatures that most differentiate them from other biological states. This modular 'biomap' reveals the linkages between different diseases and immune subtypes, and provides evidence for the presence of specific immunocyte subsets in mixed tissues. The over-represented genes in disease signatures of interest can be further investigated for their functions in both host defense and disease.


Assuntos
Mapeamento Cromossômico , Doenças do Sistema Imunitário/genética , Sistema Imunitário , Transcriptoma , Animais , Perfilação da Expressão Gênica , Marcação de Genes , Genômica/métodos , Humanos , Camundongos
3.
J Immunol ; 193(4): 1622-35, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25009205

RESUMO

Human monocyte-derived dendritic cell (MoDC) have been used in the clinic with moderately encouraging results. Mouse XCR1(+) DC excel at cross-presentation, can be targeted in vivo to induce protective immunity, and share characteristics with XCR1(+) human DC. Assessment of the immunoactivation potential of XCR1(+) human DC is hindered by their paucity in vivo and by their lack of a well-defined in vitro counterpart. We report in this study a protocol generating both XCR1(+) and XCR1(-) human DC in CD34(+) progenitor cultures (CD34-DC). Gene expression profiling, phenotypic characterization, and functional studies demonstrated that XCR1(-) CD34-DC are similar to canonical MoDC, whereas XCR1(+) CD34-DC resemble XCR1(+) blood DC (bDC). XCR1(+) DC were strongly activated by polyinosinic-polycytidylic acid but not LPS, and conversely for MoDC. XCR1(+) DC and MoDC expressed strikingly different patterns of molecules involved in inflammation and in cross-talk with NK or T cells. XCR1(+) CD34-DC but not MoDC efficiently cross-presented a cell-associated Ag upon stimulation by polyinosinic-polycytidylic acid or R848, likewise to what was reported for XCR1(+) bDC. Hence, it is feasible to generate high numbers of bona fide XCR1(+) human DC in vitro as a model to decipher the functions of XCR1(+) bDC and as a potential source of XCR1(+) DC for clinical use.


Assuntos
Antígenos CD34/imunologia , Células Sanguíneas/imunologia , Células Dendríticas/imunologia , Monócitos/imunologia , Receptores Acoplados a Proteínas G/imunologia , Adjuvantes Imunológicos/farmacologia , Apresentação de Antígeno/imunologia , Técnicas de Cultura de Células , Diferenciação Celular/imunologia , Linhagem Celular , Apresentação Cruzada/imunologia , Perfilação da Expressão Gênica , Proteínas de Fluorescência Verde , Humanos , Imidazóis/imunologia , Células Matadoras Naturais/imunologia , Lipopolissacarídeos/imunologia , Fenótipo , Poli I-C/imunologia , Linfócitos T/imunologia , Receptor 3 Toll-Like , Receptor 4 Toll-Like
4.
Front Neurol ; 4: 169, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24198809

RESUMO

Teriflunomide is an oral disease-modifying therapy recently approved in several locations for relapsing-remitting multiple sclerosis. To gain insight into the effects of teriflunomide, immunocyte population changes were measured during progression of experimental autoimmune encephalomyelitis in Dark Agouti rats. Treatment with teriflunomide attenuated levels of spinal cord-infiltrating T cells, natural killer cells, macrophages, and neutrophils. Teriflunomide also mitigated the disease-induced changes in immune cell populations in the blood and spleen suggesting an inhibitory effect on pathogenic immune responses.

5.
Cell ; 129(4): 773-85, 2007 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-17512410

RESUMO

The immunological synapse (IS) is a junction between the T cell and antigen-presenting cell and is composed of supramolecular activation clusters (SMACs). No studies have been published on naive T cell IS dynamics. Here, we find that IS formation during antigen recognition comprises cycles of stable IS formation and autonomous naive T cell migration. The migration phase is driven by PKCtheta, which is localized to the F-actin-dependent peripheral (p)SMAC. PKCtheta(-/-) T cells formed hyperstable IS in vitro and in vivo and, like WT cells, displayed fast oscillations in the distal SMAC, but they showed reduced slow oscillations in pSMAC integrity. IS reformation is driven by the Wiscott Aldrich Syndrome protein (WASp). WASp(-/-) T cells displayed normal IS formation but were unable to reform IS after migration unless PKCtheta was inhibited. Thus, opposing effects of PKCtheta and WASp control IS stability through pSMAC symmetry breaking and reformation.


Assuntos
Apresentação de Antígeno/fisiologia , Células Apresentadoras de Antígenos/metabolismo , Junções Intercelulares/metabolismo , Isoenzimas/metabolismo , Proteína Quinase C/metabolismo , Linfócitos T/metabolismo , Proteína da Síndrome de Wiskott-Aldrich/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Comunicação Celular/fisiologia , Movimento Celular/fisiologia , Ativação Enzimática/fisiologia , Inibidores Enzimáticos/farmacologia , Repressão Enzimática/efeitos dos fármacos , Repressão Enzimática/fisiologia , Junções Intercelulares/genética , Junções Intercelulares/imunologia , Isoenzimas/genética , Ativação Linfocitária/fisiologia , Lipídeos de Membrana/metabolismo , Camundongos , Camundongos Knockout , Proteína Quinase C/genética , Proteína Quinase C-theta , Linfócitos T/imunologia , Proteína da Síndrome de Wiskott-Aldrich/genética
6.
Drug News Perspect ; 19(6): 325-8, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16971968

RESUMO

Proliferation of specific renal cell types leads to the development of many types of kidney disease. Given the central role that both cyclin-dependent kinases (CDKs) and glycogen synthase kinase-3 (GSK-3) play in promoting aberrant proliferation within the kidney, these paralogous serine/threonine kinases are being explored as therapeutic molecular targets in proliferative renal diseases. CDK/GSK-3 inhibitors have now demonstrated efficacy in preclinical models of mesangial proliferative glomerulonephritis, crescentic glomerulonephritis, proliferative lupus nephritis and collapsing glomerulopathy. Moreover, they have recently entered human clinical trials in IgA nephropathy. Since the pathogenesis of most proliferative renal diseases is multifactorial, there is the belief that CDK/GSK-3 inhibitors, as inherently promiscuous drugs, may have several modes of action. This is supported by recent studies in systems research delineating the antiinflammatory profile of CDK/GSK-3 inhibitors compared with other immunomodulators. Thus, CDK/GSK-3 inhibitors may emerge as effective drugs for proliferative renal diseases due to their integrative properties across several aspects of disease pathogenesis. This brief mini-review will highlight these issues.


Assuntos
Proliferação de Células/efeitos dos fármacos , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Nefropatias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Biomarcadores/metabolismo , Quinases Ciclina-Dependentes/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Nefropatias/metabolismo , Nefropatias/patologia , Inibidores de Proteínas Quinases/uso terapêutico
7.
J Am Soc Nephrol ; 17(10): 2854-63, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16914539

RESUMO

Collapsing glomerulopathy (CG) has become an important cause of ESRD. First delineated from other proteinuric glomerular lesions in the 1980s, CG is now recognized as a common, distinct pattern of proliferative parenchymal injury that portends a rapid loss of renal function and poor responses to empiric therapy. Notwithstanding, the rise in disorders that are associated with CG, the identification of the first susceptibility genes for CG, the remarkable increase in murine modeling of CG, and promising preclinical testing of new therapeutic strategies suggest that the outlook for CG as a poorly understood and therapeutically resistant renal disease is set to change in the future. This focused review highlights recent advances in research into the pathogenesis and treatment of CG.


Assuntos
Glomerulonefrite , Glomerulonefrite/etnologia , Glomerulonefrite/etiologia , Glomerulonefrite/terapia , Humanos
8.
J Virol ; 80(4): 1850-62, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16439541

RESUMO

Human immunodeficiency virus type 1 (HIV-1)-encoded Tat provides transcriptional activation critical for efficient HIV-1 replication by interacting with cyclin T1 and recruiting P-TEFb to efficiently elongate the nascent HIV transcript. Tat-mediated transcriptional activation in mice is precluded by species-specific structural differences that prevent Tat interaction with mouse cyclin T1 and severely compromise HIV-1 replication in mouse cells. We investigated whether transgenic mice expressing human cyclin T1 under the control of a murine CD4 promoter/enhancer cassette that directs gene expression to CD4(+) T lymphocytes and monocytes/macrophages (hu-cycT1 mice) would display Tat responsiveness in their CD4-expressing mouse cells and selectively increase HIV-1 production in this cellular population, which is infected primarily in HIV-1-positive individuals. To this end, we crossed hu-cycT1 mice with JR-CSF transgenic mice carrying the full-length HIV-1(JR-CSF) provirus under the control of the endogenous HIV-1 long terminal repeat and demonstrated that human cyclin T1 expression is sufficient to support Tat-mediated transactivation in primary mouse CD4 T lymphocytes and monocytes/macrophages and increases in vitro and in vivo HIV-1 production by these stimulated cells. Increased HIV-1 production by CD4(+) T lymphocytes was paralleled with their specific depletion in the peripheral blood of the JR-CSF/hu-cycT1 mice, which increased over time. In addition, increased HIV-1 transgene expression due to human cyclin T1 expression was associated with increased lipopolysaccharide-stimulated monocyte chemoattractant protein 1 production by JR-CSF mouse monocytes/macrophages in vitro. Therefore, the JR-CSF/hu-cycT1 mice should provide an improved mouse system for investigating the pathogenesis of various aspects of HIV-1-mediated disease and the efficacies of therapeutic interventions.


Assuntos
Linfócitos T CD4-Positivos/virologia , Ciclinas/metabolismo , Infecções por HIV/virologia , HIV-1/fisiologia , Células Mieloides/virologia , Animais , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/metabolismo , Ciclina T , Ciclinas/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Proteína do Núcleo p24 do HIV/análise , Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Imuno-Histoquímica , Lipopolissacarídeos/imunologia , Camundongos , Camundongos Transgênicos , Microscopia Confocal , Células Mieloides/metabolismo , Provírus/genética , Baço/virologia
9.
J Clin Invest ; 114(6): 823-7, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15372106

RESUMO

Insulin resistance plays a primary role in the development of type 2 diabetes and may be related to alterations in fat metabolism. Recent studies have suggested that local accumulation of fat metabolites inside skeletal muscle may activate a serine kinase cascade involving protein kinase C-theta (PKC-theta), leading to defects in insulin signaling and glucose transport in skeletal muscle. To test this hypothesis, we examined whether mice with inactivation of PKC-theta are protected from fat-induced insulin resistance in skeletal muscle. Skeletal muscle and hepatic insulin action as assessed during hyperinsulinemic-euglycemic clamps did not differ between WT and PKC-theta KO mice following saline infusion. A 5-hour lipid infusion decreased insulin-stimulated skeletal muscle glucose uptake in the WT mice that was associated with 40-50% decreases in insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated PI3K activity. In contrast, PKC-theta inactivation prevented fat-induced defects in insulin signaling and glucose transport in skeletal muscle. In conclusion, our findings demonstrate that PKC-theta is a crucial component mediating fat-induced insulin resistance in skeletal muscle and suggest that PKC-theta is a potential therapeutic target for the treatment of type 2 diabetes.


Assuntos
Tecido Adiposo/fisiologia , Resistência à Insulina/genética , Isoenzimas/deficiência , Isoenzimas/genética , Proteína Quinase C/deficiência , Proteína Quinase C/genética , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/terapia , Ácidos Graxos não Esterificados/sangue , Infusões Intravenosas , Insulina/sangue , Insulina/fisiologia , Proteínas Substratos do Receptor de Insulina , Isoenzimas/uso terapêutico , Lipídeos/administração & dosagem , Lipídeos/farmacologia , Camundongos , Camundongos Knockout , Músculo Esquelético/fisiologia , Fosfoproteínas/metabolismo , Fosforilação , Proteína Quinase C/uso terapêutico , Proteína Quinase C-theta , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
10.
J Biol Chem ; 279(44): 45304-7, 2004 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-15364919

RESUMO

Obesity and stress inhibit insulin action by activating protein kinases that enhance serine phosphorylation of IRS1 and have been thus associated to insulin resistance and the development of type II diabetes. The protein kinase C (PKC) is activated by free-fatty acids, and its activity is higher in muscle from obese diabetic patients. However, a molecular link between PKC and insulin resistance has not been defined yet. Here we show that PKC phosphorylates IRS1 at serine 1101 blocking IRS1 tyrosine phosphorylation and downstream activation of the Akt pathway. Mutation of Ser(1101) to alanine makes IRS1 insensitive to the effect of PKC and restores insulin signaling in culture cells. These results provide a novel mechanism linking the activation of PKC to the inhibition of insulin signaling.


Assuntos
Insulina/farmacologia , Isoenzimas/fisiologia , Fosfoproteínas/metabolismo , Proteína Quinase C/fisiologia , Transdução de Sinais , Células 3T3-L1 , Animais , Células CHO , Cricetinae , Proteínas Substratos do Receptor de Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Proteína Quinase C-theta , Serina/metabolismo
11.
J Exp Med ; 200(2): 181-9, 2004 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-15263025

RESUMO

The serine/threonine-specific protein kinase C (PKC)-theta is predominantly expressed in T cells and localizes to the center of the immunological synapse upon T cell receptor (TCR) and CD28 signaling. T cells deficient in PKC-theta exhibit reduced interleukin (IL)-2 production and proliferative responses in vitro, however, its significance in vivo remains unclear. We found that pkc-theta(-/-) mice were protected from pulmonary allergic hypersensitivity responses such as airway hyperresponsiveness, eosinophilia, and immunoglobulin E production to inhaled allergen. Furthermore, T helper (Th)2 cell immune responses against Nippostrongylus brasiliensis were severely impaired in pkc-theta(-/-) mice. In striking contrast, pkc-theta(-/-) mice on both the C57BL/6 background and the normally susceptible BALB/c background mounted protective Th1 immune responses and were resistant against infection with Leishmania major. Using in vitro TCR transgenic T cell-dendritic cell coculture systems and antigen concentration-dependent Th polarization, PKC-theta-deficient T cells were found to differentiate into Th1 cells after activation with high concentrations of specific peptide, but to have compromised Th2 development at low antigen concentration. The addition of IL-2 partially reconstituted Th2 development in pkc-theta(-/-) T cells, consistent with an important role for this cytokine in Th2 polarization. Taken together, our results reveal a central role for PKC-theta signaling during Th2 responses.


Assuntos
Isoenzimas/fisiologia , Proteína Quinase C/fisiologia , Células Th1/metabolismo , Células Th2/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Antígenos CD28/biossíntese , Diferenciação Celular , Divisão Celular , Separação Celular , Técnicas de Cocultura , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Interferon gama/metabolismo , Interleucina-2/metabolismo , Interleucina-4/metabolismo , Isoenzimas/metabolismo , Leishmania major/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Peptídeos/química , Proteína Quinase C/metabolismo , Proteína Quinase C-theta , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Transgenes
12.
Curr Opin Immunol ; 14(3): 323-30, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-11973130

RESUMO

The hypothesis that protein kinase C (PKC)-theta; plays an important role in T-lymphocyte activation, as indicated by numerous studies in cell lines, was recently confirmed in mice deficient in the expression of this enzyme. In response to TCR stimulation, peripheral T cells lacking PKC-theta; failed to activate NF-kappaB and AP-1, and to express IL-2. This revealed a critical function for this PKC family member in linking membrane-proximal activation cascades to transcriptional responses governing T-cell activation. Although the molecular interactions in which PKC-theta; engages have not been fully delineated, insights from a variety of recent studies have permitted new models to be formulated regarding the mechanisms through which it achieves its unique effector functions.


Assuntos
Isoenzimas/fisiologia , Proteína Quinase C/fisiologia , Sinapses/fisiologia , Linfócitos T/imunologia , Animais , Membrana Celular/enzimologia , Ativação Enzimática , Humanos , Integrinas/fisiologia , Camundongos , NF-kappa B/metabolismo , Proteína Quinase C-theta , Fator de Transcrição AP-1/metabolismo
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