Soluble Antigen Arrays Displaying Mimotopes Direct the Response of Diabetogenic T Cells
| Autor: | Rebuma Firdessa-Fite, Cory Berkland, Remi J. Creusot, Joshua O Sestak, Chad J. Pickens, Martin A. Leon, Justin K Ruffalo |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
T-Lymphocytes medicine.medical_treatment Antigen presentation Protein Array Analysis Mice Transgenic Immunotherapy Adoptive 01 natural sciences Biochemistry Article Immune tolerance Epitopes 03 medical and health sciences Immune system Antigen Mice Inbred NOD medicine Animals Cells Cultured Antigen Presentation Peptide modification 010405 organic chemistry Chemistry Mimotope Experimental autoimmune encephalomyelitis General Medicine Immunotherapy medicine.disease 0104 chemical sciences Diabetes Mellitus Type 1 030104 developmental biology Immunology Molecular Medicine Female Spleen |
| Zdroj: | ACS Chem Biol |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/acschembio.9b00090 |
| Popis: | 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 (SAgA(p79)) or using copper-catalyzed alkyne-azide cycloaddition (cSAgA(p79)) chemistry. SAgAs constructed using the hydrolyzable aminooxy linkage, thus capable of releasing p79, exhibited physicochemical properties similar to the triazole linkage. Both SAgA(p79) 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. cSAgA(p79) was more stimulatory than SAgA(p79) 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. |
| Databáze: | OpenAIRE |
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