Efecto modulador ex vivo de los fármacos biológicos para la enfermedad inflamatoria intestinal sobre las células mononucleares de sangre periférica y la mucosa intestinal

Abstract

Inflammatory bowel disease comprises a group of chronic disorders of the gastrointestinal tract mainly classified into Crohn's disease and ulcerative colitis. It is a serious condition that affects millions of people worldwide and which precise etiology remains unknown. Despite the variety of pharmacological treatments available, such us the new biological drugs, there is no effective treatment to cure this pathology and the current goal is to induce and maintain remission to improve the quality of life of these patients. Biological drugs can act on different targets that have a key role in the disease, however their mechanisms of action are partly understood. This work aims to evaluate the ex vivo modulatory effect of biological drugs with different targets –infliximab, inflectra and adalimumab (anti-TNF-α), and vedolizumab (antiintegrin α4β7)– on the migration of peripheral blood mononuclear cells (PBMCs) to the intestinal mucosa in healthy patients. To this end, PBMCs were obtained and cultured in the absence/presence of biological drugs. Afterwards, migratory surface markers (beta7, CCR2, CCR5, CCR6 and CCR9) of the subpopulations of antigen presenting cells (APCs) were characterized by flow cytometry, as well as their capacity to migrate towards different intestinal chemoattractants (CCL2, CCL25 and MAdCAM1) on a transwell culture model. This study demonstrates the blockade that vedolizumab exerts on integrin α4β7, reducing the expression of beta7 on the surface of APCs. In contrast, anti-TNF-α drugs seem to increase the expression of this integrin in monocytes. Functional assays on transwell model show that ligand CCL2 induces the most potent effect over the spontaneous migration of APCs. Moreover, after culture with biological drugs, this study suggests that the ex vivo modulatory effect of biological drugs over the recruitment of APCs might be preferentially mediated through ligand CCL2. This work highlights the role of biological drugs over the migratory capacity of circulating APCs towards the intestinal mucosa in healthy individuals, setting the basis to further explore this mechanism of action in inflammatory bowel disease patients.