Our research group is interested in antigen-specific immune tolerance induction and its development as a curative therapy for HLA-associated autoimmune diseases (AID). Our main hypothesis is that the dysregulated immune system in AID can be reprogrammed. The existence of autoreactive T and B cells, frequently demonstrated in AID, does not preclude this possibility. Instead, the key questions are how a state of unresponsiveness of the immune system to relevant (auto-)antigens can be (re-)established in AID, and what regulatory cell population(s) may perform this task.
Therapeutic immune tolerance induction is emerging as a promising treatment concept for AID because "a short course of immunotherapy (would translate) into long-term benefit while maintaining immune competency" (Bluestone JA, Tang Q; Sci Transl Med 2015). However, we still lack a clear understanding of the cellular components and tissue compartments most conductive to therapeutic tolerance induction. To address these questions, we test and compare different nanoscale vehicles and peptide/protein delivery methods in mouse models of AID.
Celiac disease (CD) has been identified as the AID most suitable for the exploration of tolerogenic immunomodulatory approaches, because key components of CD pathogenesis -including the environmental antigen gluten/gliadin as disease driver- have been identified. Our findings have provided proof-of-efficacy for gliadin nanoparticles in vivo (Freitag TL et al.; Gastroenterology 2020) and encouraged a phase 2a study now successfully completed in CD patients. Original results from transcriptomic studies have provided us with tolerogenic signatures in different experimental settings, identifying gene targets regulating gliadin memory responses. The regulated genes directly point towards B and T cell differentiation, APC function, costimulation and MHC II peptide loading.
Our research is also focused on epitope discovery, i.e. the identification of suitable environmental or (auto-)antigen targets for immunomodulation in other human AID. Based on recent findings, we plan to elucidate mechanisms of immune tolerance induction, providing the opportunity to develop antigen-specific immunotherapy of CD and other AID, e.g. type 1 diabetes, multiple sclerosis and narcolepsy type 1.