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We previously showed that Ag-specific tolerance targeting single \u03b2 cell protein epitopes is effective in preventing T1D induced by transfer of monospecific diabetogenic CD4 and CD8 transgenic T cells to NOD.scid mice. However, tolerance induction to individual diabetogenic proteins, for example, GAD65 (glutamic acid decarboxylase 65) or insulin, has failed to ameliorate T1D both in wild-type NOD mice and in the clinic. Initiation and progression of T1D is likely due to activation of T cells specific for multiple diabetogenic epitopes. To test this hypothesis, recombinant insulin, GAD65, and chromogranin A proteins were encapsulated within poly(d,l-lactic-co-glycolic acid) (PLGA) nanoparticles (COUR CNPs) to assess regulatory T cell induction, inhibition of Ag-specific T cell responses, and blockade of T1D induction\/progression in NOD mice. Whereas treatment of NOD mice with CNPs containing a single protein inhibited the corresponding Ag-specific T cell response, inhibition of overt T1D development only occurred when all three diabetogenic proteins were included within the CNPs (CNP-T1D). Blockade of T1D following CNP-T1D tolerization was characterized by regulatory T cell induction and a significant decrease in both peri-insulitis and immune cell infiltration into pancreatic islets. As we have recently published that CNP treatment is both safe and induced Ag-specific tolerance in a phase 1\/2a celiac disease clinical trial, Ag-specific tolerance induced by nanoparticles encapsulating multiple diabetogenic proteins is a promising approach to T1D treatment.<\/jats:p>","DOI":"10.4049\/jimmunol.2200208","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T15:16:41Z","timestamp":1657811801000},"page":"465-475","source":"Crossref","is-referenced-by-count":37,"title":["Tolerogenic Immune-Modifying Nanoparticles Encapsulating Multiple Recombinant Pancreatic \u03b2 Cell Proteins Prevent Onset and Progression of Type 1 Diabetes in Nonobese Diabetic Mice"],"prefix":"10.1093","volume":"209","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5818-8515","authenticated-orcid":false,"given":"Joseph R","family":"Podojil","sequence":"first","affiliation":[{"name":"Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University , Chicago, IL"},{"name":"COUR Pharmaceutical Development Company, Inc. , Northbrook, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3133-5236","authenticated-orcid":false,"given":"Samantha","family":"Genardi","sequence":"additional","affiliation":[{"name":"COUR Pharmaceutical Development Company, Inc. , Northbrook, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Yi","family":"Chiang","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University , Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6619-0386","authenticated-orcid":false,"given":"Sandeep","family":"Kakade","sequence":"additional","affiliation":[{"name":"COUR Pharmaceutical Development Company, Inc. , Northbrook, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Neef","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University , Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tushar","family":"Murthy","sequence":"additional","affiliation":[{"name":"COUR Pharmaceutical Development Company, Inc. , Northbrook, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"II","given":"Michael T","family":"Boyne","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University , Chicago, IL"},{"name":"COUR Pharmaceutical Development Company, Inc. , Northbrook, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3060-7829","authenticated-orcid":false,"given":"Adam","family":"Elhofy","sequence":"additional","affiliation":[{"name":"COUR Pharmaceutical Development Company, Inc. , Northbrook, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9556-0718","authenticated-orcid":false,"given":"Stephen D","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University , Chicago, IL"},{"name":"Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University , Chicago, IL"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,8,1]]},"reference":[{"key":"2025021008233630900_r1","volume-title":"National Diabetes Statistics Report, 2020","author":"Centers for Disease Control and Prevention","year":"2020"},{"key":"2025021008233630900_r2","doi-asserted-by":"crossref","first-page":"98","DOI":"10.34172\/hpp.2020.18","article-title":"Prevalence and incidence of type 1 diabetes in the world: a systematic review and meta-analysis","volume":"10","author":"Mobasseri","year":"2020","journal-title":"Health Promot. 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