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

• Published in: Nature communications Vol. 10; no. 1; pp. 2150 - 17
• Main Authors: Umeshappa, Channakeshava Sokke, Singha, Santiswarup, Blanco, Jesus, Shao, Kun, Nanjundappa, Roopa Hebbandi, Yamanouchi, Jun, Parés, Albert, Serra, Pau, Yang, Yang, Santamaria, Pere
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 14.05.2019; Nature Publishing Group UK; Nature Portfolio
• Subjects: Aged; Animal models; Animals; Antigens; Autoantigens; Autoantigens - immunology; Autoimmune diseases; Autoimmune Diseases - drug therapy; Autoimmune Diseases - immunology; CD4 antigen; Cell Line; Cholangitis; Dendritic cells; Disease; Disease Models, Animal; Drainage; Endoplasmic reticulum; Epitopes; Epitopes - immunology; Female; Hepatitis; Hepatocytes; Histocompatibility Antigens Class II - chemistry; Histocompatibility Antigens Class II - immunology; Humans; Immunity; Inflammation; Kupffer cells; Liver; Liver - drug effects; Liver - immunology; Liver diseases; Liver Diseases - drug therapy; Liver Diseases - immunology; Lymph nodes; Lymphocytes B; Lymphocytes T; Major histocompatibility complex; Male; Manufacturing cells; Metastases; Mice; Middle Aged; Mitochondria; Nanomedicine - methods; Nanoparticles - administration & dosage; Nanoparticles - chemistry; Peptides; Peptides - administration & dosage; Peptides - chemistry; Peptides - immunology; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Tumors
• DOI: 10.1038/s41467-019-09893-5
• ISSN: 2041-1723

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.