Peptide-MHC-based nanovaccines for the treatment of autoimmunity: a “one size fits all” approach?

Abstract

Nanotechnology offers enormous potential in drug delivery and in vivo imaging. Nanoparticles (NPs), for example, are being extensively tested as scaffolds to deliver anti-cancer therapeutics or imaging tags. Our recent work, discussed herein, indicates that an opportunity exists to use NPs to deliver ligands for, and trigger, cognate receptors on T lymphocytes as a way to induce therapeutic immune responses in vivo. Specifically, systemic delivery of NPs coated with Type 1 diabetes (T1D)-relevant peptide-major histocompatibility complex molecules triggered the expansion of cognate memory autoregulatory (disease-suppressing) T cells, suppressed the progression of autoimmune attack against insulin-producing beta cells, and restored glucose homeostasis. This therapeutic avenue exploits a new paradigm in the progression of chronic autoimmune responses that enables the rational design of disease-specific "nanovaccines" capable of blunting autoimmunity without impairing systemic immunity, a long sought-after goal in the therapy of these disorders. Here, we discuss the research paths that led to the discovery of this therapeutic avenue and highlight the features that make it an attractive approach for the treatment, in an antigen-specific manner, of a whole host of autoimmune diseases.

Nanoparticles and Antigen-Specific T-Cell Therapeutics: A Comprehensive Study on Uptake and Release

“…Additional surface coating with an HLA-peptide multimer would allow the exclusive targeting of T cells carrying the compatible antigenspecific T-cell receptor. This technology could be further developed to a clinical strategy, where NPs can be used for manipulation of T cells not only in vitro but also in vivo [37]. Besides surface functionalization, particle uptake was altered by other factors, mainly depending on the activation state of the cell.…”

Peptide–MHC-based nanomedicines for autoimmunity function as T-cell receptor microclustering devices

“…PEG molecules were used as an in situ surface-coating agent. In a typical reaction, 3 g PEG (2 kDa) was melted in a 50 ml round bottom flask at 100°C and then mixed with 7 ml of benzyl ether and 2 mmol Fe(acac) 3 . The reaction was stirred for 1 h and heated to 260°C with reflux for 2 h. The mixture was cooled to room temperature and mixed with 30 ml water.…”

“…In agreement with this, the 20 disease-relevant pMHC-NPs tested so far have shown similar efficacy, regardless of disease model, prevalence, or role in the disease. The NP component is an essential ingredient of the final drug product, rather than a vehicle for antigen delivery [1][2][3] .…”

Antigen-Specific Therapeutic Approaches in Type 1 Diabetes

“…Different outcomes and mechanisms of action have been reported, depending on the structure that was used for therapy (monomers versus dimers or multimers coupled to nanoparticles) (reviewed in Clemente- Casares et al 2011). Whereas pMHC class I monomers cannot activate T cells efficiently, higher-order structures can do so in a manner that is proportional to the valency, hence avidity, of the pMHC -TCR interaction (Herrmann and Mescher 1986;McCluskey et al 1989;Abastado et al 1995).…”

“…Nonautoantigen-loaded APCs are spared. A more in-depth discussion of the significance of this new immunological paradigm and therapeutic approach can be found in the work of Clemente- Casares et al (2011).…”