The old dogma in the field of Biomaterials was to avoid as much as possible recognition by the immune system as “foreign”. Less than a decade ago, there has been a boon in technologies and strategies designed to appropriately engage with the immune system using defined components. Self-assembly allows the development of multi-subunit materials with facile synthesis and preparation methods, that are practical from an engineering perspective but also from a basic immunological standpoint, as it allows higher control over how individual parts affect a particular immune response outcome. In this thesis, we used peptide self-assembly to design the first anti-TNF immunotherapy in which the content of T cell and B cell epitopes was individually adjusted. In the past, peptide assemblies have been developed with the aim to target foreign antigens. Here, we show that peptide nanofibers in particular can be designed to target autologous or self-derived molecules, such as cytokines. Peptide assemblies consisting of TNF-derived B cell epitopes and foreign or non-TNF-derived T cell epitopes were designed to enable a TNF-specific autoantibody response without breaking T cell tolerance to the cytokine, which resulted in unique combinations of T cell and B cell responses, and protection in mouse models of TNF-mediated inflammation. Our results further indicate that peptide nanofibers represent a highly robust self-assembly platform capable of maintaining the fibrillization capacity despite co-presentation of high density, relatively hydrophobic, CD4 T helper cell epitopes. Collectively, the work presented in this thesis suggests a new peptide-based technology with immense potential for diverse immunotherapy applications.




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