Efficient Presentation of Multiple Endogenous Epitopes to Both CD4 + and CD8 + Diabetogenic T Cells for Tolerance

Abstract

Antigen-specific immunotherapy of type 1 diabetes, typically via delivery of a single native β cell antigen, has had little clinical benefit to date. With increasing evidence that diabetogenic T cells react against multiple β cell antigens, including previously unappreciated neo-antigens that can be emulated by mimotopes, a shift from protein- to epitope-based therapy is warranted. To this end, we aimed to achieve efficient co-presentation of multiple major epitopes targeting both CD4+ and CD8+ diabetogenic T cells. We have compared native epitopes versus mimotopes as well as various targeting signals in an effort to optimize recognition by both types of T cells in vitro. Optimal engagement of all T cells was achieved with segregation of CD8 and CD4 epitopes, the latter containing mimotopes and driven by endosome-targeting signals, after delivery into either dendritic or stromal cells. The CD4+ T cell responses elicited by the endogenously delivered epitopes were comparable with high concentrations of soluble peptide and included functional regulatory T cells. This work has important implications for the improvement of antigen-specific therapies using an epitope-based approach to restore tolerance in type 1 diabetes and in a variety of other diseases requiring concomitant targeting of CD4+ and CD8+ T cells.

Promising non-viral vector for efficient and versatile delivery of mRNA for antigen-specific immunotherapy

“…When administered intravenously, DCs were primarily retained in lungs, while the nanoparticles efficiently targeted lymphoid tissues such as the spleen. These studies took advantage of a new platform (Endotope) that enables optimal engagement of CD4 + and CD8 + T cells with multiple antigenic peptides encoded by DNA or mRNA [8].…”

Antigen-specific peptide immunotherapy for treatment and prevention of type 1 diabetes

“…As with other ASI therapies where a single antigen is used, the issue of epitope spreading is not being addressed and therefore restricts successful therapy outcomes. Dastagir, et al have recently described the use of a DNA construct expressing epitopes from a range of b cell antigens and its ability to successfully and efficiently stimulate different antigen-specific CD4 + and CD8 + T cells [339]. The use of mimotopes with a superior antigen-specific T cell engagement ability compared to native sequences, as well as intracellular differential MHC targeting were utilised to ensure high-affinity antigen presentation [365][366][367].…”

“…The use of mimotopes with a superior antigen-specific T cell engagement ability compared to native sequences, as well as intracellular differential MHC targeting were utilised to ensure high-affinity antigen presentation [365][366][367]. This group's work further investigated the effects of DNA construct delivering multiple epitopes and demonstrated a broader involvement of antigen-specific CD4 + and CD8 + T cells resulting in protection from T1D in NOD mice [339]. Similar to my investigation of the effects of Dual liposomes, they found did not observe a significant increase in antigen-specific Foxp3+ Tregs.…”

“…Similar to my investigation of the effects of Dual liposomes, they found did not observe a significant increase in antigen-specific Foxp3+ Tregs. However, CD73 and PD-1 expressions were upregulated suggesting that tolerance may be achieved through anergy [339]. Another recent peptide immunotherapy study MultiPepT1De investigated the safety profile intradermal delivery of multiple b-cell antigens in subjects with recent onset of T1D and an HLA-DRB1*0401 genotype.…”

“…It is likely that in humans a longer peptide containing both CD4 and CD8 epitopes will be used in order to both inactivate pathogenic CTL responses as well as induce regulatory populations [339]. Therefore, this study can contribute to better understanding of mechanisms of tolerance induction when different antigenic peptides are administered together.…”