Abstract
Induction of antigen-specific immune tolerance has emerged as the next frontier in treating autoimmune disorders, including atherosclerosis and graft-vs-host reactions during transplantation. Nanostructures are under investigation as a platform for the coordinated delivery of critical components, i.e., the antigen epitope combined with tolerogenic agents, to the target immune cells and subsequently induce tolerance. In the present study, the utility of supramolecular peptide nanofibers to induce antigen-specific immune tolerance was explored. To study the influence of surface charges of the nanofibers towards the extent of the induced immune response, the flanking charge residues at both ends of the amphipathic fibrillization peptide sequences were varied. Dexamethasone, an immunosuppressive glucocorticoid drug, and the ovalbumin-derived OVA323-339 peptide that binds to I-A(d) MHC Class II were covalently linked at either end of the peptide sequences. It was shown that the functional extensions did not alter the structural integrity of the supramolecular nanofibers. Furthermore, the surface charges of the nanofibers were modulated by the inclusion of charged residues. Dendritic cell culture assays suggested that nanofiber of less negative ζ-potential can augment the antigen-specific tolerogenic response. Our findings illustrate a molecular approach to calibrate the tolerogenic response induced by peptide nanofibers, which pave the way for better design of future tolerogenic immunotherapies.
Highlights
Autoimmune disorders are rising in developed and rapidly developing countries[1]
This study investigated the effect of surface charge on the peptide nanofibers towards eliciting antigenspecific immunotolerance
To systematically investigate the effect of linker-charged residues on the formation of supramolecular nanofibers and antigen-specific tolerance induction, a library of Multidomain peptides (MDPs) with either K or E flanking residues appended to both ends of the fibrillization domain was designed (Figure 1a)
Summary
Autoimmune disorders (e.g., atherosclerosis and graft-vs-host reactions during transplantation) are rising in developed and rapidly developing countries[1]. Nanoparticles are extensively explored as a platform for induction of antigen-specific immune tolerance, either through delivering antigen to APCs present in natural tolerogenic environments (e.g., liver)[5, 6], or co-delivery of tolerogenic pharmacological agents (e.g., dexamethasone) and antigens to the APCs. Nanoparticles are extensively explored as a platform for induction of antigen-specific immune tolerance, either through delivering antigen to APCs present in natural tolerogenic environments (e.g., liver)[5, 6], or co-delivery of tolerogenic pharmacological agents (e.g., dexamethasone) and antigens to the APCs The latter approach can steer the recipient APCs toward a tolerogenic phenotype, thereby avoiding the "off-target" induction of proinflammatory responses in the former approach[7,8,9] as well as limiting the side effects of long-term systemic immunosuppression, e.g., cancer promotion[10]. Usage of conventional nanoparticles still encounters challenges in large-scale production[11] and stability and transport[12, 13]
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