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1.
Nature ; 582(7810): 104-108, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32427965

RESUMO

Malaria caused by Plasmodium falciparum remains the leading single-agent cause of mortality in children1, yet the promise of an effective vaccine has not been fulfilled. Here, using our previously described differential screening method to analyse the proteome of blood-stage P. falciparum parasites2, we identify P. falciparum glutamic-acid-rich protein (PfGARP) as a parasite antigen that is recognized by antibodies in the plasma of children who are relatively resistant-but not those who are susceptible-to malaria caused by P. falciparum. PfGARP is a parasite antigen of 80 kDa that is expressed on the exofacial surface of erythrocytes infected by early-to-late-trophozoite-stage parasites. We demonstrate that antibodies against PfGARP kill trophozoite-infected erythrocytes in culture by inducing programmed cell death in the parasites, and that vaccinating non-human primates with PfGARP partially protects against a challenge with P. falciparum. Furthermore, our longitudinal cohort studies showed that, compared to individuals who had naturally occurring anti-PfGARP antibodies, Tanzanian children without anti-PfGARP antibodies had a 2.5-fold-higher risk of severe malaria and Kenyan adolescents and adults without these antibodies had a twofold-higher parasite density. By killing trophozoite-infected erythrocytes, PfGARP could synergize with other vaccines that target parasite invasion of hepatocytes or the invasion of and egress from erythrocytes.


Assuntos
Apoptose/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Malária Falciparum/imunologia , Malária Falciparum/prevenção & controle , Parasitos/imunologia , Plasmodium falciparum/citologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Adolescente , Adulto , Animais , Anticorpos Antiprotozoários/imunologia , Antígenos de Protozoários/química , Antígenos de Protozoários/imunologia , Aotidae/imunologia , Aotidae/parasitologia , Caspases/metabolismo , Criança , Estudos de Coortes , DNA de Protozoário/química , DNA de Protozoário/metabolismo , Ativação Enzimática , Eritrócitos/parasitologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/química , Quênia , Vacinas Antimaláricas/imunologia , Malária Falciparum/parasitologia , Masculino , Camundongos , Parasitos/citologia , Parasitos/crescimento & desenvolvimento , Plasmodium falciparum/crescimento & desenvolvimento , Proteínas de Protozoários/química , Tanzânia , Trofozoítos/citologia , Trofozoítos/crescimento & desenvolvimento , Trofozoítos/imunologia , Vacúolos/imunologia
2.
Cancer Immunol Immunother ; 67(9): 1449-1459, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30030558

RESUMO

Dendritic cells play a critical role in initiating T-cell responses. In spite of this recognition, they have not been used widely as adjuvants, nor is the mechanism of their adjuvanticity fully understood. Here, using a mutated neoepitope of a mouse fibrosarcoma as the antigen, and tumor rejection as the end point, we show that dendritic cells but not macrophages possess superior adjuvanticity. Several types of dendritic cells, such as bone marrow-derived dendritic cells (GM-CSF cultured or FLT3-ligand induced) or monocyte-derived ones, are powerful adjuvants, although GM-CSF-cultured cells show the highest activity. Among these, the CD11c+ MHCIIlo sub-set, distinguishable by a distinct transcriptional profile including a higher expression of heat shock protein receptors CD91 and LOX1, mannose receptors and TLRs, is significantly superior to the CD11c+ MHCIIhi sub-set. Finally, dendritic cells exert their adjuvanticity by acting as both antigen donor cells (i.e., antigen reservoirs) as well as antigen presenting cells.


Assuntos
Antígeno CD11c/imunologia , Células Dendríticas/imunologia , Células Dendríticas/transplante , Fibrossarcoma/terapia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Antígenos de Histocompatibilidade Classe II/imunologia , Imunoterapia Adotiva/métodos , Animais , Antígenos de Neoplasias/imunologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Células Dendríticas/efeitos dos fármacos , Epitopos/imunologia , Feminino , Fibrossarcoma/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T/imunologia
3.
J Infect Dis ; 210(7): 1133-44, 2014 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-24737802

RESUMO

BACKGROUND: Apoptosis of several host cells induced by parasites/parasite products has been investigated in human filariasis to understand immune hyporesponsiveness. However, apoptosis of monocytes-one of the major antigen presenting cells in peripheral circulation, which are chronically exposed to filarial antigens in infected subjects-is yet to be understood. METHODS: Apoptosis of human monocytes with Brugia pahangi antigen (BpA) was demonstrated by scoring several apoptotic markers using flow cytometry. Ability of BpA and plasma of infected subjects to suppress lymphocyte proliferation was demonstrated by (3)H thymidine incorporation assay and carboxyfluorescein succinimidyl ester dilution assay. RESULTS: BpA induced significant apoptosis of normal human monocytes, primarily through Toll-like receptor 4 (TLR4), and suppressed phytohemagglutinin (PHA)-mediated proliferation of normal human T lymphocytes. However, monocytes of Wuchereria bancrofti-infected subjects were resistant to BpA-induced apoptosis. Plasma of infected subjects also mediated apoptosis of normal monocytes, presumably due to circulating filarial antigens, and resulted in inhibition of PHA-induced proliferation. CONCLUSION: Normal human monocytes were found to be qualitatively different from those of filariasis-infected subjects; whereas filarial antigens mediate apoptosis of normal human monocytes through TLR4, those of infected subjects were found to be resistant.


Assuntos
Antígenos de Helmintos/imunologia , Apoptose , Brugia pahangi/imunologia , Filariose/imunologia , Monócitos/imunologia , Receptor 4 Toll-Like/imunologia , Wuchereria bancrofti/imunologia , Animais , Antígenos de Helmintos/metabolismo , Proliferação de Células , Estudos de Coortes , Citometria de Fluxo , Humanos , Tolerância Imunológica , Monócitos/fisiologia , Linfócitos T/imunologia , Receptor 4 Toll-Like/metabolismo
4.
Cancer Immunol Res ; 8(10): 1287-1299, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32759362

RESUMO

Live cells are the most abundant sources of antigen in a tumor-bearing host. Here, we used live tumor cells as source of antigens to investigate the mechanism underlying their immunogenicity in murine tumor models. The live tumor cells were significantly more immunogenic than irradiated or apoptotic tumor cells. We examined the interaction of live and apoptotic tumor cells with major subsets of antigen-presenting cells, i.e., CD8α+ dendritic cells (DC), CD8α- DCs, plasmacytoid DCs, and CD169+ macrophages at skin draining lymph nodes. The CD8α+ DCs captured cell-associated antigens from both live and apoptotic tumor cells, whereas CD169+ macrophages picked up cell-associated antigens mostly from apoptotic tumor cells. Trogocytosis and cross-dressing of membrane-associated antigenic material from live tumor cells to CD8α+ DCs was the primary mechanism for cross-priming of tumor antigens upon immunization with live cells. Phagocytosis of apoptotic tumor cells was the primary mechanism for cross-priming of tumor antigens upon immunization with apoptotic or irradiated cells. These findings clarify the mechanism of cross-priming of cancer antigens by DCs, allowing for a greater understanding of antitumor immune responses.


Assuntos
Apresentação Cruzada/imunologia , Células Dendríticas/imunologia , Animais , Antígenos CD8/imunologia , Proliferação de Células/fisiologia , Feminino , Humanos , Camundongos
5.
Int J Biochem Cell Biol ; 45(8): 1568-76, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23665236

RESUMO

Several lines of evidence suggest that specific transcriptional events are involved in cell cycle, proliferation and differentiation processes; however, their deregulation by proto-oncogenes are involved in the development of leukemia and tumors. One such proto-oncogene is ecotropic viral integration site I which can differentially effect cell cycle progression and proliferation, in cell types of different origin. Our data for the first time shows that ecotropic viral integration site I binds to ΔNp63 promoter element directly and down regulates its expression. Down regulation of ΔNp63 induces the expression of p21 in HT-29 cells and also in colon carcinoma cells that do not express p53 including patient samples expressing low level of p53, that eventually delay cell cycle progression at G0/G1 phase. Concomitant silencing of ecotropic viral integration site I from the cells or introduction of ΔNp63 to the cells significantly rescued this phenotype, indicating the growth defect induced by ΔNp63 deficiency to be, at least in part, attributable to ecotropic viral integration site I function. The mutual regulation between ecotropic viral integration site I and ΔNp63 may constitute a novel axis which might affect the downstream pathways in cells that do not express functional p53.


Assuntos
Ciclo Celular , Neoplasias do Colo/patologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima/genética , Sequência de Bases , Proliferação de Células , Neoplasias do Colo/genética , Proteínas de Ligação a DNA/química , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Células HCT116 , Células HEK293 , Células HT29 , Humanos , Proteína do Locus do Complexo MDS1 e EVI1 , Dados de Sequência Molecular , Regiões Promotoras Genéticas/genética , Ligação Proteica/genética , Estrutura Terciária de Proteína , Proto-Oncogene Mas , Proto-Oncogenes , Fatores de Transcrição/química , Transcrição Gênica , Proteína Supressora de Tumor p53/deficiência , Dedos de Zinco
6.
PLoS One ; 6(6): e20861, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21687737

RESUMO

BACKGROUND: Thyroid hormones regulate cell proliferation, differentiation as well as apoptosis. However molecular mechanism underlying apoptosis as a result of thyroid hormone signaling is poorly understood. The antiapoptotic role of Senescence Marker Protein-30 (SMP30) has been characterized in response to varieties of stimuli as well as in knock out model. Our earlier data suggest that thyroid hormone 3, 3'5 Triiodo L Thyronine (T(3)), represses SMP30 in rat liver. METHODOLOGY/PRINCIPAL FINDINGS: In highly metastatic MCF-7, human breast cancer cell line T3 treatment repressed SMP30 expression leading to enhanced apoptosis. Analysis by flow cytometry and other techniques revealed that overexpression and silencing of SMP30 in MCF-7 resulted in decelerated and accelerated apoptosis respectively. In order to identify the cis-acting elements involved in this regulation, we have analyzed hormone responsiveness of transiently transfected hSMP30 promoter deletion reporter vectors in MCF-7 cells. As opposed to the expected epigenetic outcome, thyroid hormone down regulated hSMP30 promoter activity despite enhanced recruitment of acetylated H3 on thyroid response elements (TREs). From the stand point of established epigenetic concept we have categorised these two TREs as negative response elements. Our attempt of siRNA mediated silencing of TRß, reduced the fold of repression of SMP30 gene expression. In presence of thyroid hormone, Trichostatin- A (TSA), which is a Histone deacetylase (HDAC) inhibitor further inhibited SMP30 promoter activity. The above findings are in support of categorisation of both the thyroid response element as negative response elements as usually TSA should have reversed the repressions. CONCLUSION: This is the first report of novel mechanistic insights into the remarkable downregulation of SMP30 gene expression by thyroid hormone which in turn induces apoptosis in MCF-7 human breast cancer cells. We believe that our study represents a good ground for future effort to develop new therapeutic approaches to challenge the progression of breast cancer.


Assuntos
Apoptose/efeitos dos fármacos , Neoplasias da Mama/patologia , Proteínas de Ligação ao Cálcio/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Elementos de Resposta/genética , Glândula Tireoide/metabolismo , Tri-Iodotironina Reversa/farmacologia , Apoptose/genética , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/genética , Células HEK293 , Histona Acetiltransferases/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Humanos , Ácidos Hidroxâmicos/farmacologia , Metástase Neoplásica , Regiões Promotoras Genéticas/genética , Moduladores Seletivos de Receptor Estrogênico/metabolismo , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Glândula Tireoide/efeitos dos fármacos , Receptores beta dos Hormônios Tireóideos/metabolismo , Transcrição Gênica/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos
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