20.500.12556/DKUM-85047 Phosphonate-modified cellulose nanocrystals potentiate the Th1 polarising capacity of monocyte-derived dendritic cells via GABA-B receptor Purpose: Phosphonates, like 3-AminoPropylphosphonic Acid (ApA), possess a great potential for the therapy of bone tumours, and their delivery via cellulose nanocrystals (CNCs) seems a promising approach for their increased efficacy in target tissues. However, the immunological effects of CNC-phosphonates have not been investigated thoroughly. The main aim was to examine how the modification of CNCs with phosphonate affects their immunomodulatory properties in human cells. Methods: Wood-based native (n) CNCs were modified via oxidation (ox-CNCs) and subsequent conjugation with ApA (ApA-CNCs). CNCs were characterised by atomic force microscopy (AFM) and nanoindentation. Cytotoxicity and immunomodulatory potential of CNCs were investigated in cultures of human peripheral blood mononuclear cells (PBMCs) and monocyte-derived dendritic cells (MoDCs)/T cells co-cultures by monitoring phenotype, cytokines production, allostimulatory and Th/Treg polarisation capacity. Results: AFM showed an increase in CNCs’ thickens, elasticity modulus and hardness during the modification with ApA. When applied at non-toxic doses, nCNCs showed a tolerogenic potential upon internalisation by MoDCs, as judged by their increased capacity to up-regulate tolerogenic markers and induce regulatory T cells (Treg), especially when present during the differentiation of MoDCs. In contrast, ox- and ApA-CNCs induced oxidative stress and autophagy in MoDCs, which correlated with their stimulatory effect on the maturation of MoDCs, but also inhibition of MoDCs differentiation. ApA-CNC-treated MoDCs displayed the highest allostimulatory and Th1/CTL polarising activity in co-cultures with T cells. These effects of ApA-CNCs were mediated via GABA-B receptor-induced lowering of cAMP levels in MoDCs, and they could be blocked by GABA-B receptor inhibitor. Moreover, the Th1 polarising and allostimulatory capacity of MoDCs differentiated with ApA-CNC were largely preserved upon the maturation of MoDCs, whereas nCNC- and ox-CNC-differentiated MoDCs displayed an increased tolerogenic potential. Conclusion: The delivery of ApA via CNCs induces potent DC-mediated Th1 polarisation, which could be beneficial in their potential application in tumour therapy. cellulose nanocrystals phosphonates dendritic cells regulatory T-cell subsets immunomodulation GABA-B receptor celuloza celulozni nanokristali fosfonati dendritične celice imunomodulacija GABA-B receptorji true false true Angleški jezik Slovenski jezik Znanstveno delo 2023-08-17 08:47:16 2023-08-17 08:52:03 2023-08-18 03:09:53 0000-00-00 00:00:00 2022 0 0 str. 3191-3216 Vol. 17 July 2022 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 2022-07-01 677.46:620.3 117195779 10.2147/IJN.S362038 1178-2013 Phosphonate-Modified_Cellulose_Nano-Bekic-2022.pdf Phosphonate-Modified_Cellulose_Nano-Bekic-2022.pdf 1 0F56665CACF1D1C3095B3DF75E843C90 897869eb0fec89747a48ee422e2dcea15b1a37f9af432dba14fb2a8ce65ef4a4 962daba8-3ccb-11ee-af21-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=169628 https://www.dovepress.com/phosphonate-modified-cellulose-nanocrystals-potentiate-the-th1-polaris-peer-reviewed-fulltext-article-IJN 0 9cbaff01-3ccb-11ee-af21-00155d000105 https://dk.um.si/Dokument.php?lang=slv&id=169629 Fakulteta za strojništvo 0 0 0