The SAgA of Antigen-Specific Immunotherapy for Type 1 Diabetes.

Abstract

Islet antigen-specific strategies are the holy grail of immunotherapy for type 1 diabetes (T1D) (1), as they selectively target the autoimmune responses involved in β-cell destruction (2). The idea is to induce a response opposite to that of a conventional vaccine. The administration of antigen(s) in the absence of inflammation (e.g., adjuvants) should potentiate the outcomes of physiological immune homeostasis, i.e., anergy, regulatory polarization, and, to a lesser extent, deletion. Such antigens can be delivered as proteins, peptides, bacteria engineered to secrete these products, DNA plasmids, or nanoparticles coated with antigens (either alone or preloaded on MHC molecules). Peptides are easy to synthesize by amino acid chemistry, but they are variably water-soluble and short-lived in vivo (in the order of minutes), which makes it difficult to achieve the steady concentrations more suitable for tolerance induction. Nonetheless, peptide-based immunotherapies have proven safe and, in some cases, documented encouraging immune and clinical outcomes (3). In this issue of Diabetes , Firdessa-Fite et al. (4) give peptides a boost by mounting them on a hyaluronan backbone to obtain a soluble antigen array (SAgA). First, this backbone accounts for their superior solubility. The linker used was either stable (“click” chemistry, cSAgA) or hydrolysable (hSAgA), to facilitate peptide release upon uptake by antigen-presenting cells (APCs). Second, SAgAs deliver multiple peptide copies to individual APCs, thus providing a multivalent (high avidity) engagement of T cells that is more efficient for signal transduction. This may be …