Functionalization-dependent effects of cellulose nanofibrils on tolerogenic mechanisms of human dendritic cells

Abstract

Sergej Tomić,1,2 Nataša Ilić,1 Vanja Kokol,3 Alisa Gruden-Movsesijan,1 Dušan Mihajlović,2 Marina Bekić,1 Ljiljana Sofronić-Milosavljević,1 Miodrag Čolić,1,2,4 Dragana Vučević2 1Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia; 2Institute for Medical Research, Medical Faculty of the Military Medical Academy, University of Defense, Belgrade, Serbia; 3Institute of Engineering Materials and Design, University of Maribor, Maribor, Slovenia; 4Medical Faculty Foča, University of East Sarajevo, Foča, Bosnia and Herzegovina Background: Cellulose nanofibrils (CNF) are attractive nanomaterials for various biomedical applications due to their excellent biocompatibility and biomimetic properties. However, their immunoregulatory properties are insufficiently investigated, especially in relation to their functionalization, which could cause problems during their clinical application. Methods: Using a model of human dendritic cells (DC), which have a central role in the regulation of immune response, we investigated how differentially functionalized CNF, ie, native (n) CNF, 2,2,6,6-tetramethylpiperidine 1-oxyl radical-oxidized (c) CNF, and 3-aminopropylphosphoric acid-functionalized (APAc) CNF, affect DC properties, their viability, morphology, differentiation and maturation potential, and the capacity to regulate T cell-mediated immune response. Results: Nontoxic doses of APAcCNF displayed the strongest inhibitory effects on DC differentiation, maturation, and T helper (Th) 1 and Th17 polarization capacity, followed by cCNF and nCNF, respectively. These results correlated with a specific pattern of regulatory cytokines production by APAcCNF-DC and their increased capacity to induce suppressive CD8+CD25+IL-10+ regulatory T cells in immunoglobulin-like transcript (ILT)-3- and ILT-4-dependent manner. In contrast, nCNF-DC induced predominantly suppressive CD4+CD25hiFoxP3hi regulatory T cells in indolamine 2,3-dioxygenase-1-dependent manner. Different tolerogenic properties of CNF correlated with their size and APA functionalization, as well as with different expression of CD209 and actin bundles at the place of contact with CNF. Conclusion: The capacity to induce different types of DC-mediated tolerogenic immune responses by functionalized CNF opens new perspectives for their application as well-tolerated nanomaterials in tissue engineering and novel platforms for the therapy of inflammatory T cell-mediated pathologies. Keywords: cellulose nanofibrils, biocompatibility, tolerogenic dendritic cells, regulatory T-cell subsets, immunomodulation

Keywords

• Cellulose Nanofibrils
• Biocompatibility
• Tolerogenic Dendritic Cells
• Regulatory T cell subsets
• Immunomodulation