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dc.contributor.authorLeon, Martin A.
dc.contributor.authorFite, Rebuma Firdessa
dc.contributor.authorRuffalo, Justin Kristopher
dc.contributor.authorPickens, Chad J.
dc.contributor.authorSestak, Joshua Orion
dc.contributor.authorCreusot, Remi J.
dc.contributor.authorBerkland, Cory
dc.date.accessioned2020-10-20T20:49:03Z
dc.date.available2020-10-20T20:49:03Z
dc.date.issued2019-06-17
dc.identifier.citationLeon, 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.9b00090en_US
dc.identifier.urihttp://hdl.handle.net/1808/30789
dc.descriptionThis 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.abstractType 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.sponsorshipNIH T32 GM008545en_US
dc.description.sponsorshipJuvenile Diabetes Research Foundation (2-SRA-2017-312-S-B)en_US
dc.description.sponsorshipNIH Shared Instrumentation Grant # S10RR024664en_US
dc.description.sponsorshipNSF Major Research Instrumentation Award # 1625923en_US
dc.description.sponsorshipNIH S10OD020056en_US
dc.description.sponsorshipDiabetes Research Center grant P30DK063608en_US
dc.description.sponsorshipNIH HHSN272201300006Cen_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsCopyright © 2019 American Chemical Societyen_US
dc.titleSoluble Antigen Arrays Displaying Mimotopes Direct the Response of Diabetogenic T Cellsen_US
dc.typeArticleen_US
kusw.kuauthorLeon, Martin A.
kusw.kuauthorRuffalo, Justin Kristopher
kusw.kuauthorPickens, Chad J.
kusw.kuauthorBerkland, Cory
kusw.kudepartmentChemistryen_US
kusw.kudepartmentChemical and Petroleum Engineeringen_US
kusw.kudepartmentPharmaceutical Chemistryen_US
kusw.kudepartmentBioengineering Research Centeren_US
dc.identifier.doi10.1021/acschembio.9b00090en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-8992-6306en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-9346-938Xen_US
kusw.oaversionScholarly/refereed, author accepted manuscripten_US
kusw.oapolicyThis item meets KU Open Access policy criteria.en_US
dc.identifier.pmidPMC7402076en_US
dc.rights.accessrightsopenAccessen_US


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