Imunoterapia com células t-car: bioengenharia contra a leucemia linfoblástica aguda car-t cells / Immunotherapy: bioengineering against acute lymphoblastic leukemia

Introdução: Uma atual abordagem da imunoterapia do câncer baseia-se na modifi cação genética de linfócitos T, através da expressão deuma molécula de superfície capaz de atuar como um receptor específi co. Tal molécula foi intitulada Receptor Antigênico Quimérico (CAR)e tem a função de reconhecer antígenos presentes em células tumorais para redirecionar o ataque linfocitário. Desenvolvido como umtratamento para a Leucemia Linfoblástica Aguda (LLA) do tipo B, o receptor CAR expresso pela célula modifi cada atua especifi camente noreconhecimento do CD19, principal cluster de diferenciação da linhagem linfoide B. Ao reconhecer o antígeno, o sítio interno da moléculatransmite um sinal de ativação do ataque citolítico, o qual atinge apenas a célula-alvo e promove sua eliminação com baixa toxicidade.Objetivo: Descrever a manipulação e funcionamento da imunoterapia com Células T-CAR no tratamento da LLA do tipo B e destacar osbenefícios desta técnica para os pacientes. Método: Estudo de revisão bibliográfi ca a partir de artigos de bases de dados online PubMede do Portal Capes, no período de 2011 a 2017 e livros acadêmicos correlacionados. Conclusão: Com as técnicas de engenharia genética,a imunoterapia com Células T-CAR proporcionou melhora signifi cativa na qualidade de vida dos pacientes de ensaios clínicos devido àbaixa agressividade do tratamento e alta especifi cidade contra a célula tumoral, atingindo taxas próximas de 95% de remissão completada doença. Os resultados indicam novas oportunidades de avanço no tratamento da LLA e outras neoplasias.

Introduction: A current approach to cancer immunotherapy is based on the genetic modifi cation of T-lymphocytes by the expression ofa cell surface molecule able to act as a specifi c receptor. Such molecule has been called Chimeric Antigen Receptor (CAR) and has thefunction of recognizing antigens in tumor cells to redirect the lymphocyte attack. Developed as a treatment for Acute LymphoblasticLeukemia (ALL) type B, the CAR-receptor expressed by the modifi ed cell acts specifi cally on the recognition of CD19, the majordifferentiation cluster of lymphoid B lineage. After antigen recognition, the molecule internal site transmits a signal of cytolytic attackactivation, which reaches only the target cell, therefore promoting its elimination with low toxicity. Objective: To describe manipulationand functioning of immunotherapy with CAR-T cells on the treatment of type B ALL and to highlight the benefi ts of this technique forthe patients. Method: Bibliographic review study based on articles from online databases PubMed and Capes Portal from 2011 through2017 and correlated academic books. Conclusion: With genetic engineering techniques, CAR-T Cells immunotherapy provided signifi cantimprovement in life quality of clinical trials patients, due to low treatment aggressiveness, as well as high specifi city against tumor cells,with disease complete remission rates near to 95%. The results point out new opportunities for advancement in the treatment of ALLand other neoplasms.

Introducción: Actualmente, uno de los enfoques en inmunoterapia para cáncer es la modifi cación genética de linfocitos T a través dela expresión de moléculas de superfi cie capaces de actuar como receptor específi co. Estas moléculas se llaman Receptor AntigénicoQuimérico (CAR) y su función es reconocer antígenos presentes en las células tumorales direccionando el ataque linfocitario. El receptorCAR fue desarrollado para el tratamiento de Leucemia Linfoblástica Aguda (LLA) tipo B y se expresa en la célula modifi cada para actúarespecífi camente en el reconocimiento de CD19, principal marcador de diferenciación del linaje de linfocitos B. Cuando es reconocido elantígeno, el sitio interno de la molécula trasmite una señal de activación para iniciar el ataque citolítico, atacando de forma específi ca alas células cancerígenas y promoviendo la eliminación de éstas con baja toxicidad. Objetivo: Describir la manipulación y funcionamientode la inmunoterapia con células T-CAR en el tratamiento de LLA tipo B y mostrar los benefi cios de la técnica en los pacientes. Método:Estudio de revisión bibliográfi ca de artículos científi cos de los años 2011-2017 en bases de datos on-line y libros académicos relacionados.Conclusión: Gracias a las técnicas de ingeniería genética, la inmunoterapia con células T-CAR proporcionó una mejora signifi cativa en lacalidad de vida de los pacientes participantes de ensayos clínicos, debido a la baja agresividad del tratamiento y a la alta especifi cad delmismo contra las células tumorales. Siendo la tasa de remisión completa de la enfermedad de aproximadamente un 95%. Los resultadosmuestran nuevas oportunidades de avances en el tratamiento de la LLA y en otras neoplasias.

Relaxation of the mouse pubic symphysis during late pregnancy is not accompanied by the influx of granulocytes.

In some animals, such as mice and guinea pigs, a hormonally controlled mechanism increases the flexibility of the pubic symphysis and enhances the cervical remodeling necessary for safe delivery. Cervical ripening during pregnancy is associated with a paradoxical influx of leukocytes. However, the changes in cell metabolism during relaxation of the mouse pubic symphysis for delivery have not been extensively studied. In this work, we used light microscopy and transmission and scanning electron microcopy, as well as immunohistochemistry and Western blotting for MMP-8, to investigate the involvement of granulocytes or resident stromal cells in the relaxation of the virgin pubic symphysis during late pregnancy (days 18 and 19, before delivery) in vivo and in explanted joints. MMP-8 was studied because this collagenase is a hallmark for cervical ripening associated with the influx of granulocytes during late pregnancy. Extensive dissolution and disorganization of the extracellular matrix was seen around fibroblastic-like cells in late pregnancy. In contrast to the cervix (positive control), morphological and immunohistochemical analyses revealed that there was no characteristic cellular inflammatory response in the interpubic tissue. Staining for MMP-8 was observed in chondroid and fibroblastic-like cells of virgin and relaxed interpubic ligament, respectively. However, no granulocytes were seen during the extensive remodeling of the pubic joint in late pregnancy. These results indicate that constitutive stromal cells may have an important role in tissue relaxation during remodeling of the pubic symphysis in pregnancy.

Hepatic morphological alterations, glycogen content and cytochrome P450 activities in rats treated chronically with N(omega)-nitro-L-arginine methyl ester (L-NAME).

Chronic treatment of rats with N(omega)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) biosynthesis, results in hypertension mediated partly by enhanced angiotensin-I-converting enzyme (ACE) activity. We examined the influence of L-NAME on rat liver morphology, on hepatic glycogen, cholesterol, and triglyceride content, and on the activities of the cytochrome P450 isoforms CYP1A1/2, CYP2B1/2, CYP2C11, and CYP2E1. Male Wistar rats were treated with L-NAME (20 mg/rat per day via drinking water) for 2, 4, and 8 weeks, and their livers were then removed for analysis. Enzymatic induction was produced by treating rats with phenobarbital (to induce CYP2B1/2), beta-naphthoflavone (to induce CYP1A1/2), or pyrazole (to induce CYP2E1). L-NAME significantly elevated blood pressure; this was reversed by concomitant treatment with enalapril (ACE inhibitor) or losartan (angiotensin II AT(1) receptor antagonist). L-NAME caused vascular hypertrophy in hepatic arteries, with perivascular and interstitial fibrosis involving collagen deposition. Hepatic glycogen content also significantly increased. L-NAME did not affect fasting glucose levels but significantly reduced insulin levels and increased the insulin sensitivity of rats, based on an intraperitoneal glucose tolerance test. Immunoblotting experiments indicated enhanced phosphorylation of protein kinase B and of glycogen synthase kinase 3. All these changes were reversed by concomitant treatment with enalapril or losartan. L-NAME had no effect on hepatic cholesterol or triglyceride content or on the basal or drug-induced activities and protein expression of the cytochrome P450 isoforms. Thus, the chronic inhibition of NO biosynthesis produced hepatic morphological alterations and changes in glycogen metabolism mediated by the renin-angiotensin system. The increase in hepatic glycogen content probably resulted from enhanced glycogen synthase activity following the inhibition of glycogen synthase kinase 3 by phosphorylation.