RESUMO
BACKGROUND/AIM: The aim of the current study was to investigate the synergistic efficacy of Robo1 bichimeric antigen receptor-natural killer cell (BiCAR-NK) immunotherapy and 125I seed brachytherapy in an orthotopic pancreatic cancer mouse model. MATERIALS AND METHODS: The orthotopic pancreatic tumor model was established with human pancreatic cancer BxPC-3 cells expressing red fluorescent protein. The mice were treated with 125I seed implantation alone or the combination of 125I seeds with Robo1-specific CAR-NK cells. To assess tumor inhibition, in vivo fluorescence imaging was conducted. 7 Tesla magnetic resonance (7T-MR) scanning was applied to measure the changes in the metabolic profiles of tumor tissues. RESULTS: Tumor size was significantly reduced in the 125I and 125I +CAR-NK treated group compared to the untreated group (p<0.05). The 125I seed +CAR-NK treated group showed significantly higher tumor reduction than 125I seed treatment alone (p<0.05). T1 diffusion weighted imaging (T1DWI) sequence showed that the tumors of the 125I +BiCAR-NK treated group had a significantly higher grey scale value than the tumors from the untreated control and the group treated with 125I seed alone (p<0.05). CONCLUSION: Robo1 specific CAR-NK immunotherapy enhances efficacy of 125I seed brachytherapy in an orthotopic pancreatic cancer mouse model.
Assuntos
Braquiterapia/métodos , Imunoterapia , Radioisótopos do Iodo/uso terapêutico , Células Matadoras Naturais/imunologia , Proteínas do Tecido Nervoso/imunologia , Neoplasias Pancreáticas/terapia , Receptores de Antígenos/imunologia , Receptores Imunológicos/imunologia , Animais , Apoptose , Proliferação de Células , Citotoxicidade Imunológica/imunologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas RoundaboutRESUMO
Early Growth Response (EGR) zinc finger transcription factors are induced under diverse mitogenic signals on different cell types such as lymphocytes. Their genetic expression does not require de novo protein synthesis, which suggests its role as immediate response mediators between cell surface receptor signaling and gene expression regulation. EGR factors are involved in modulating the immune response, by means of the induction of differentiation of lymphocyte precursors, activation of T and B cells, as well as their involvement in central and peripheral tolerance. The maturation state, particularly for B cells, and signaling through the T or B cell receptors seems to be quite relevant for the induction of the expression of these transcription factors. EGR-1 functions as a positive regulatory factor for B and T cells mediated by transcriptional regulation of key cytokines and costimulatory molecules, and its interaction with NFAT. On the opposite, EGR-2 and 3 act as negative regulators involved in anergy induction and apoptosis. EGR-2 and 3 deficiency has been related to the development of lupus like disease in murine models. The deficiency of these transcription factors has been associated to deficient Cbl-b expression, a resistant to anergy phenotype, and expansion of effector and activated T cells.
Assuntos
Fatores de Transcrição de Resposta de Crescimento Precoce/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Ativação Linfocitária/imunologia , Receptores de Antígenos/imunologia , Animais , Apoptose , Autoimunidade , Diferenciação Celular , Humanos , Tolerância Imunológica , Imunomodulação , Lúpus Eritematoso Sistêmico/genética , Camundongos , Transdução de Sinais , Dedos de Zinco/genéticaRESUMO
Dendritic cells (DCs) are the most efficient antigen-presenting cells. They are activated in the periphery by conserved pathogen molecules and by inflammatory mediators produced by a variety of cell types in response to danger signals. It is widely appreciated that inflammatory responses in peripheral tissues are usually associated with the development of acidic microenvironments. Surprisingly, there are relatively few studies directed to analyze the effect of extracellular acidosis on the immune response. We focus on the influence of extracellular acidosis on the function of immature DCs. The results presented here show that acidosis activates DCs. It increases the acquisition of extracellular antigens for MHC class I-restricted presentation and the ability of antigen-pulsed DCs to induce both specific CD8+ CTL and B-cell responses. These findings may have important implications to our understanding of the mechanisms through which DCs sense the presence of infection or inflammation in nonlymphoid tissues.
Assuntos
Acidose/metabolismo , Células Dendríticas/metabolismo , Animais , Apresentação de Antígeno/imunologia , Antígenos/imunologia , Movimento Celular/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Humanos , Inflamação/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Proteínas de Membrana/imunologia , Neoplasias/metabolismo , Pinocitose/imunologia , Receptores de Antígenos/imunologiaRESUMO
El sistema inmune es una red intrincada en la que participan diferentes tipos de células y de moléculas. La acción coordinada de todos sus elementos permite que se desarrolle una respuesta eficaz contra la célula tumoral. Sin embargo, los tumores presentan diversos mecanismos de evasión que permiten el desarrollo del mismo. En esta revisión se presentan eventos celulares y moleculares que participan en la regulación de la respuesta inmune contra tumores. Se discute la interacción de distintas moléculas como las del complejo principal de histocompatibilidad, receptor de antígenos de linfocitos T, moléculas de adhesión, antígenos tumorales y citocinas, así como lo más reciente sobre los mecanismos de escape tumoral e inmunoterapia
The immune system is a tight network of different types of cells and molecules. The coordinated action of these elements mounts a precise immune response against tumor cells. However, these cells present several escape mechanisms, leading to tumor progression. This paper shows several cellular and molecular events involved in the regulation of the immune response against tumor cells. The interaction of several molecules such as MHC, TcR, adhesins, tumor antigens and cytokines are discussed, as well as the most recent knowledge about escape mechanisms and immunotherapy.
Assuntos
Humanos , Linfócitos T/imunologia , Adesão Celular , Imunoterapia Ativa , Interleucinas/imunologia , Interferons/imunologia , Interferons/líquido cefalorraquidiano , Fator de Necrose Tumoral alfa/imunologia , Imunoterapia , Complexo Principal de Histocompatibilidade/imunologia , Antígenos de Neoplasias/imunologia , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias/terapia , Receptores de Antígenos/imunologiaRESUMO
The immune system is a tight network of different types of cells and molecules. The coordinated action of these elements mounts a precise immune response against tumor cells. However, these cells present several escape mechanisms, leading to tumor progression. This paper shows several cellular and molecular events involved in the regulation of the immune response against tumor cells. The interaction of several molecules such as MHC, TcR, adhesins, tumor antigens and cytokines are discussed, as well as the most recent knowledge about escape mechanisms and immunotherapy.
Assuntos
Neoplasias/imunologia , Antígenos de Neoplasias/imunologia , Adesão Celular , Fatores Estimuladores de Colônias/imunologia , Humanos , Imunoterapia , Imunoterapia Ativa , Interferons/imunologia , Interleucinas/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Neoplasias/patologia , Neoplasias/terapia , Receptores de Antígenos/imunologia , Linfócitos T/imunologia , Evasão Tumoral , Fator de Necrose Tumoral alfa/imunologiaRESUMO
We have introduced some modifications in the technique called "cell decoration" in order to increase the amount of lipid-conjugated antibodies which can be incorporated into the membrane of B cells. As shown by FACS analysis, we have obtained an approximately 4-fold increment in the amount of specific antibodies incorporated into the cell membrane. The procedure, which consists of successive changes of the medium that contains the lipid-conjugated antibodies, avoided changes on parameters that interfere with cell viability. The proposed modification resulted in an approximately 2-fold enhancement of the ability of decorated B cells to act as antigen presenting cells for specific T hybridomas.