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

Molecular Therapy: Methods & Clinical Development

Shamael R. Dastagir¹  Rémi J. Creusot¹  Rebuma Firdessa-Fite¹  Jorge Postigo-Fernandez¹  Chunliang Xu¹  James H. Stoeckle¹ 

[1]Columbia Center for Translational Immunology and Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA

关键词: type 1 diabetes;    T cells;    tolerance;    antigen targeting;    antigen presentation;    epitope;    mimotope;    diabetogenic;    dendritic cell;    stromal cell;   

DOI  :  10.1016/j.omtm.2016.12.002

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown