Antigen-specific immunotherapies (ASITs) address important clinical needs in treating autoimmune diseases. However, Type 1 diabetes is a heterogeneous disease wherein patient characteristics influence responsiveness to ASITs. Targeting not only disease-relevant T cell populations, but also specific groups of patients using precision medicine is a new goal toward achieving effective treatment. HLA-restricted peptides provide advantages over protein as antigens, however, methods for profiling antigen-specific T cells need to improve in sensitivity, depth, and throughput to facilitate epitope selection. Delivery approaches are highly diverse, illustrating the many ways relevant antigen-presenting cell populations and anatomical locations can be targeted for tolerance induction. The role of persistence of antigen presentation in promoting durable antigen-specific tolerance requires further investigation. Based on the outcome of ASIT trials, the field is moving toward using patient-specific variations to improve efficacy, but challenges still lie on the path to delivering more effective and safer treatment to the T1D patient population.
Autoantigen-specific immunotherapy using peptides offers a more targeted approach to treat autoimmune diseases, but the limited in vivo stability and uptake of peptides impedes clinical implementation. We previously showed that multivalent delivery of peptides as soluble antigen arrays (SAgAs) efficiently protects against spontaneous autoimmune diabetes in the non-obese diabetic (NOD) mouse model. Here, we compared the efficacy, safety, and mechanisms of action of SAgAs versus free peptides. SAgAs, but not their corresponding free peptides at equivalent doses, efficiently prevented the development of diabetes. SAgAs increased the frequency of regulatory T cells among peptide-specific T cells or induce their anergy/exhaustion or deletion, depending on the type of SAgA (hydrolysable (hSAgA) and non-hydrolysable "click" SAgA (cSAgA)) and duration of treatment, whereas their corresponding free peptides induced a more effector phenotype following delayed clonal expansion. Moreover, the N-terminal modification of peptides with aminooxy or alkyne linkers, which was needed for grafting onto hyaluronic acid to make hSAgA or cSAgA variants, respectively, influenced their stimulatory potency and safety, with alkyne-functionalized peptides being more potent and less anaphylactogenic than aminooxy-functionalized peptides. Both SAgA variants significantly delayed anaphylaxis compared to their respective free peptides. The anaphylaxis, which occurred in NOD mice but not in C57BL/6 mice, was dose-dependent but did not correlate with the production of IgG1 or IgE against the peptides. We provide evidence that SAgAs significantly improve the efficacy and safety of peptide-based immunotherapy.
Type 1 diabetes (T1D) is a complex autoimmune disease characterized by heterogeneity in genetic risk factors and immune profiles of patients and for which a cure or approved treatment is not yet available. Antigen-specific immunotherapy (ASIT) offers a targeted treatment of T1D that selectively inhibits autoreactive T cells. So far, ASIT trials showed limited efficacy, as only a subset of patients is responsive. Thus, approaches that consider the genetic and immunological heterogeneity of T1D patients to provide more tailored treatments are needed. Using mRNA encoding multiple epitopes tailored to the NOD mouse (model of T1D), we engineered bone marrow-derived dendritic cells (DCs) by mRNA electroporation (mRNA-DCs). The mRNA is designed to enable optimal presentation of epitopes to both CD4 and CD8 T cells. Antigen presentation persisted at least three days in vivo. Markers of anergy as well as IL-10 expression were found to be upregulated in antigen-specific CD4 and CD8 T cells after treating NOD mice with mRNA-DCs. T1D development was significantly suppressed with 3 biweekly treatments with 106 DCs containing 2 µg of antigen mRNA. Moreover, efficacy of the mRNA-DCs was enhanced when mRNAs encoding antigens and IL-27 were co-delivered into DCs by electroporation or when DCs were treated with rapamycin during differentiation. Endogenous expression of antigens may enable post-translational modifications and more prolonged presentation. Thus, we developed a promising and customizable ASIT platform to deliver multiple epitopes to exogenous tolerogenic DCs (or to endogenous APCs using a nanoparticle-based platform not covered here) that will consider the patient’s immune profile for a precision medicine treatment of T1D. Disclosure R. Fite: None. R. J. Creusot: None. Funding American Diabetes Association (1-19-PMF-022 to R.F.F.)
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