dc.contributor.author | Leon, Martin A. | |
dc.contributor.author | Fite, Rebuma Firdessa | |
dc.contributor.author | Ruffalo, Justin Kristopher | |
dc.contributor.author | Pickens, Chad J. | |
dc.contributor.author | Sestak, Joshua Orion | |
dc.contributor.author | Creusot, Remi J. | |
dc.contributor.author | Berkland, Cory | |
dc.date.accessioned | 2020-10-20T20:49:03Z | |
dc.date.available | 2020-10-20T20:49:03Z | |
dc.date.issued | 2019-06-17 | |
dc.identifier.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 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/30789 | |
dc.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. | en_US |
dc.description.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. | en_US |
dc.description.sponsorship | NIH T32 GM008545 | en_US |
dc.description.sponsorship | Juvenile Diabetes Research Foundation (2-SRA-2017-312-S-B) | en_US |
dc.description.sponsorship | NIH Shared Instrumentation Grant # S10RR024664 | en_US |
dc.description.sponsorship | NSF Major Research Instrumentation Award # 1625923 | en_US |
dc.description.sponsorship | NIH S10OD020056 | en_US |
dc.description.sponsorship | Diabetes Research Center grant P30DK063608 | en_US |
dc.description.sponsorship | NIH HHSN272201300006C | en_US |
dc.publisher | American Chemical Society | en_US |
dc.rights | Copyright © 2019 American Chemical Society | en_US |
dc.title | Soluble Antigen Arrays Displaying Mimotopes Direct the Response of Diabetogenic T Cells | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Leon, Martin A. | |
kusw.kuauthor | Ruffalo, Justin Kristopher | |
kusw.kuauthor | Pickens, Chad J. | |
kusw.kuauthor | Berkland, Cory | |
kusw.kudepartment | Chemistry | en_US |
kusw.kudepartment | Chemical and Petroleum Engineering | en_US |
kusw.kudepartment | Pharmaceutical Chemistry | en_US |
kusw.kudepartment | Bioengineering Research Center | en_US |
dc.identifier.doi | 10.1021/acschembio.9b00090 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-8992-6306 | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-9346-938X | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC7402076 | en_US |
dc.rights.accessrights | openAccess | en_US |