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Frontiers of Medicine ; (4): 1170-1185, 2023.
Article in English | WPRIM | ID: wpr-1010819


OX40 is a costimulatory receptor that is expressed primarily on activated CD4+, CD8+, and regulatory T cells. The ligation of OX40 to its sole ligand OX40L potentiates T cell expansion, differentiation, and activation and also promotes dendritic cells to mature to enhance their cytokine production. Therefore, the use of agonistic anti-OX40 antibodies for cancer immunotherapy has gained great interest. However, most of the agonistic anti-OX40 antibodies in the clinic are OX40L-competitive and show limited efficacy. Here, we discovered that BGB-A445, a non-ligand-competitive agonistic anti-OX40 antibody currently under clinical investigation, induced optimal T cell activation without impairing dendritic cell function. In addition, BGB-A445 dose-dependently and significantly depleted regulatory T cells in vitro and in vivo via antibody-dependent cellular cytotoxicity. In the MC38 syngeneic model established in humanized OX40 knock-in mice, BGB-A445 demonstrated robust and dose-dependent antitumor efficacy, whereas the ligand-competitive anti-OX40 antibody showed antitumor efficacy characterized by a hook effect. Furthermore, BGB-A445 demonstrated a strong combination antitumor effect with an anti-PD-1 antibody. Taken together, our findings show that BGB-A445, which does not block OX40-OX40L interaction in contrast to clinical-stage anti-OX40 antibodies, shows superior immune-stimulating effects and antitumor efficacy and thus warrants further clinical investigation.

Mice , Animals , Receptors, Tumor Necrosis Factor/physiology , Receptors, OX40 , Membrane Glycoproteins , Ligands , Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology
Acta gastroenterol. latinoam ; 36(4): 211-217, dic. 2006. ilus
Article in Spanish | LILACS | ID: lil-459135


Apoptosis es un término griego que significa “caída de las hojas viejas de los árboles en otoño”. Esta palabra describe el proceso por el cual células indeseables, dañadas o senescentes son eliminadas de los organismos multicelulares. La muerte cellular patológica en el hígado fue siempre referida como necrosis, pero procesos fisiopatológicos en este órgano pueden conducir a injuria celular tanto por apoptosis como por necrosis. Apoptosis difiere de necrosis porque la primera es controlada activamente y la membrana celular es mantenida, evitando la extravasación de material intracelular con la consecuente respuesta inflamatoria. El proceso de apoptosis puede ocurrir por dos mecanismos: el de receptor de muerte (DR) o extrínseco o por el mecanismo mitochondrial llamado también intrínseco. Las células hepaticas expresan diferentes receptores de muerte: Fas, TNF-R1, TRAIL-R1 y TRAIL-R2. Las células estelares expresan Fas y TRAIL cuando están activadas y transformadas fenotípicamente en miofibroblastos, y éstas también sufren apoptosis durante la resolución de la injuria hepática. Los colangiocitos parecen ser células tipo II (en éstas el mecanismo de apoptosis mitochondrial parece ser esencial). Apoptosis mediada por estos receptors juega un rol importante en una variedad de procesos biológicos tales como el daño tisular, protección contra microorganismos patógenos, y su papel central en la injuria hepática y posterior progresión a la fibrosis ha sido bien establecido en diferentes enfermedades hepáticas. Un factor importante en apoptosis cellular es que puede ocurrir en ausencia de elevación sérica de transaminasas hepáticas como ocurre en la necrosis celular. Este artículo es una revisión de este proceso.

Apoptosis is a Greek term that means "the fall of the old leaves of the autumn trees". This term describes the process by which undesirable, damaged or old cells are eliminated from the multicellular organisms. Pathologic cell death in the liver has traditionally been referred to as necrosis, but pathophysiologic process in the liver can lead to cell injury and death by apoptosis as well by necrosis. The first differs from the second, because it is actively controlled and the membrane integrity is maintained, avoiding extravasations of intracellular mate rial and inflammatory response. Apoptosis can occur by two mechanisms: death receptor (DR) or extrinsic mechanism and mitochondrial or intrinsic mechanism. Liver cells express different death receptors: hepatocytes express Fas, TNF-R1, TRAIL-R1, TRAIL-R2; Stellate Cell (HCS) express Fas and TRAIL when is activated into myofibroblast-like phenotype and undergo apoptosis during resolution of liver injury in vivo. Cholangiocytes seem to be type II cells (in which the mitochondrial mechanism to apoptotic is essential) regarding signaling of Fas endothelial cells from rat livers express Fas, and their activation may lead to apoptosis of endothelial cells from hepatic sinusoids. Apoptosis mediated by these receptors have a major role in a variety of biological processes as tissue injury, protection against pathogenic microorganisms, and the role on hepatic injury and posterior progression to fibrosis has been well established in different hepatic diseases. Apoptosis may occur in the absence of significant transaminase elevations as happen in cellular necrosis. This paper is a review of this process.

Humans , Animals , Apoptosis/physiology , Hepatocytes/pathology , Liver Diseases/pathology , Liver Diseases/physiopathology , Disease Progression , Fibrosis/pathology , Fibrosis/physiopathology , Receptors, TNF-Related Apoptosis-Inducing Ligand/physiology , Receptors, Tumor Necrosis Factor/physiology
Article in English | WPRIM | ID: wpr-77003


Current therapies for autoimmune diseases are not cures but merely palliatives, aimed at reducing symptoms. For the most part, these treatments provide nonspecific suppression of the immune system and thus do not distinguish between a pathogenic autoimmune response and a protective immune response. Recently emerging evidence not only has indicated the involvement of members of the TNF receptor/ligand superfamilies but also has revealed exciting innovative strategies for the treatment of autoimmune diseases and other chronic inflammatory diseases without depressing the immune response in general. In this review, we will discuss the regulatory mechanisms of TNF receptor/ligand family members, such as HVEM/ LIGHT, 4-1BB/4-1BBL, and GITR/GITRL that regulate T and B cell functions and participate in the process of inflammatory diseases. We will also discuss how intervening in the costimulatory pathways mediated by these molecules might have some potential as a therapeutic approach to immune disorders.

Animals , Humans , Apoptosis , Autoimmune Diseases/immunology , B-Lymphocytes/immunology , Dendritic Cells/physiology , Inflammation/immunology , Lymphocyte Activation/immunology , Models, Biological , Receptors, Tumor Necrosis Factor/physiology , T-Lymphocytes/immunology , Tumor Necrosis Factor-alpha/immunology