Suppression of a broad spectrum of liver autoimmune pathologies by single peptide-MHC-based nanomedicines

Nature Communications

Channakeshava Sokke Umeshappa¹  Roopa Hebbandi Nanjundappa¹  Santiswarup Singha¹  Kun Shao¹  Jun Yamanouchi¹  Yang Yang²  Pere Santamaria³  Pau Serra⁴  Jesus Blanco⁴  Albert Parés⁵ 

[1] 0000 0004 1936 7697, grid.22072.35, Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, T2N 4N1, Calgary, AB, Canada;0000 0004 1936 7697, grid.22072.35, Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, T2N 4N1, Calgary, AB, Canada;0000 0004 1936 7697, grid.22072.35, Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, T2N 4N1, Calgary, AB, Canada;0000 0004 1936 7697, grid.22072.35, Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, T2N 4N1, Calgary, AB, Canada;grid.10403.36, Institut D’Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Spain;grid.10403.36, Institut D’Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Spain;grid.10403.36, Institut D’Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Spain;0000 0004 1937 0247, grid.5841.8, Liver Unit, Hospital Clinic de Barcelona, CIBERehd and University of Barcelona, 08036, Barcelona, Spain;

DOI  :  10.1038/s41467-019-09893-5

来源: publisher

【 摘 要 】

Peptide-major histocompatibility complex class II (pMHCII)-based nanomedicines displaying tissue-specific autoantigenic epitopes can blunt specific autoimmune conditions by re-programming cognate antigen-experienced CD4+ T-cells into disease-suppressing T-regulatory type 1 (TR1) cells. Here, we show that single pMHCII-based nanomedicines displaying epitopes from mitochondrial, endoplasmic reticulum or cytoplasmic antigens associated with primary biliary cholangitis (PBC) or autoimmune hepatitis (AIH) can broadly blunt PBC, AIH and Primary Sclerosing Cholangitis in various murine models in an organ- rather than disease-specific manner, without suppressing general or local immunity against infection or metastatic tumors. Therapeutic activity is associated with cognate TR1 cell formation and expansion, TR1 cell recruitment to the liver and draining lymph nodes, local B-regulatory cell formation and profound suppression of the pro-inflammatory capacity of liver and liver-proximal myeloid dendritic cells and Kupffer cells. Thus, autoreactivity against liver-enriched autoantigens in liver autoimmunity is not disease-specific and can be harnessed to treat various liver autoimmune diseases broadly.

【 授权许可】

CC BY