Peptide-MHC-Based Nanomedicines for the Treatment of Autoimmunity: Engineering, Mechanisms, and Diseases

Abstract

The development of autoimmunity results from a breakdown of immunoregulation and involves cellularly complex immune responses against broad repertoires of epitope specificities. As a result, selective targeting of specific effector autoreactive T- or B-cells is not a realistic therapeutic option for most autoimmune diseases. Induction of autoantigen-specific regulatory T-cells capable of effecting bystander (dominant), yet tissue-specific, immunoregulation has thus emerged as a preferred therapeutic alternative. We have shown that peptide-major histocompatibility complex (pMHC)-based nanomedicines can re-program cognate autoantigen-experienced T-cells into disease-suppressing regulatory T-cells, which in turn elicit the formation of complex regulatory cell networks capable of comprehensively suppressing organ-specific autoimmunity without impairing normal immunity. Here, we summarize the various pMHC-based nanomedicines and disease models tested to date, the engineering principles underpinning the pharmacodynamic and therapeutic potency of these compounds, and the underlying mechanisms of action.

Preclinical evaluation of a precision medicine approach to DNA vaccination in Type 1 diabetes

“…Treatment with a single InsB9-23 (R22E) mimotope (p8E, also present in our Endotope construct) in soluble form also significantly prevented the onset of disease in NOD mice (38). Presentation of a few selected epitopes on MHC molecules displayed on nanoparticles in Pere Santamaria's successful studies also leads to tolerance that spread to other epitopes of the same antigen or others (16,39). Collectively, these studies illustrate the fact that ASITs are progressively shifting their focus from antigens to epitopes.…”

Preclinical evaluation of a precision medicine approach to DNA vaccination in type 1 diabetes

“…More recently, we showed that two peptides in combination (p79 mimotope and hybrid insulin peptide [2.5HIP]) delivered by soluble antigen array starting later, at 8 wk of age, protected 70% of mice ( 5 ). Presentation of a few selected epitopes on MHC molecules displayed on nanoparticles in Pere Santamaria’s successful studies on stage 2 disease also leads to tolerance that spread to other epitopes of the same antigen or others ( 16 , 36 ). Collectively, these studies illustrate the successful transition of ASITs from antigens to a few epitopes.…”

Peptide-HLA-based immunotherapeutics platforms for direct modulation of antigen-specific T cells

“…AgS cytotoxic CD8 T cell responses have previously been achieved via heterologous expression of membrane pMHC complexes, for example, by DNA vaccination 18 . Alternatively, nanoparticle display of pMHC can stimulate or inhibit AgS T cell responses depending on the presence and nature of costimulatory and co-inhibitory ligands 19 , 20 . In contrast, soluble pMHC complexes, including streptavidin-based tetramers, largely suppress T cell responses 21 , 22 .…”