Loading...
Soluble Antigen Arrays Displaying Mimotopes Direct the Response of Diabetogenic T Cells
Leon, Martin A. Fite, Rebuma Firdessa Ruffalo, Justin Kristopher Pickens, Chad J. Sestak, Joshua Orion Creusot, Remi J. Berkland, Cory
Leon, Martin A.
Fite, Rebuma Firdessa
Ruffalo, Justin Kristopher
Pickens, Chad J.
Sestak, Joshua Orion
Creusot, Remi J.
Berkland, Cory
Citations
Altmetric:
Abstract
Type 1 diabetes (T1D) is an autoimmune disorder which develops when insulin-producing, pancreatic beta cells are destroyed by an aberrant immune response. Current therapies for T1D either treat symptoms or cause global immunosuppression, which leave patients at risk of developing long-term complications or vulnerable to foreign pathogens. Antigen-specific immunotherapies have emerged as a selective approach for autoimmune diseases by inducing tolerance while mitigating global immunosuppression. We previously reported SAgAs with multiple copies of a multiple sclerosis (MS) autoantigen grafted onto hyaluronic acid (HA) as an efficacious therapy in experimental autoimmune encephalomyelitis. While the immune response of MS is distinct from T1D, the mechanism of SAgAs was hypothesized to be similar and via induction of immune tolerance to diabetes antigens. We synthesized SAgAs composed of HA polymer backbone conjugated with multiple copies of the T1D autoantigen mimotope p79 using aminooxy chemistry (SAgAp79) or using copper-catalyzed alkyne-azide cycloaddition (cSAgAp79) chemistry. SAgAs constructed using the hydrolyzable aminooxy linkage, thus capable of releasing p79, exhibited physicochemical properties similar to the triazole linkage. Both SAgAp79 versions showed high specificity and efficacy in stimulating epitope-specific T cells. SAgAs can be taken up by most immune cell populations but do not induce their maturation, and conventional dendritic cells are responsible for the brunt of antigen presentation within splenocytes. cSAgAp79 was more stimulatory than SAgAp79 both in vitro and in vivo, an effect that was ascribed to the peptide modification rather than the type of linkage. In summary, we provide here the first proof-of-principle that SAgA therapy could also be applicable to T1D.
Description
This document is the Accepted Manuscript version of a Published Work that appeared in final form in
ACS Chemical Biology, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://doi.org/10.1021/acschembio.9b00090.
Date
2019-06-17
Journal Title
Journal ISSN
Volume Title
Publisher
American Chemical Society
Research Projects
Organizational Units
Journal Issue
Keywords
Citation
Leon, M. A., Firdessa-Fite, R., Ruffalo, J. K., Pickens, C. J., Sestak, J. O., Creusot, R. J., & Berkland, C. (2019). Soluble Antigen Arrays Displaying Mimotopes Direct the Response of Diabetogenic T Cells. ACS chemical biology, 14(7), 1436–1448. https://doi.org/10.1021/acschembio.9b00090