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

Channakeshava Sokke Umeshappa,Jesus Blanco,Santiswarup Singha,Yang Yang,Albert Parés,Jun Yamanouchi,Kun Shao,Pere Santamaria,Pau Serra,Roopa Hebbandi Nanjundappa

doi:10.1038/s41467-019-09893-5

Abstract

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.

Highlights

Peptide-major histocompatibility complex class II-based nanomedicines displaying tissue-specific autoantigenic epitopes can blunt specific autoimmune conditions by reprogramming cognate antigen-experienced CD4+ T-cells into disease-suppressing T-regulatory type 1 (TR1) cells
As was the case for the TR1-like CD4+ T-cells induced by type 1 diabetes (T1D)-relevant pMHC class II-NPs in NOD mice[1], the PDC-E2166–181/IAg7 tetramer+ T-cells that expanded in response to PDC-E2166–181/IAg7-NP treatment were CD25–/ FoxP3– and expressed the TR1 markers lymphocyte-activation gene-3 (LAG-3), CD49b, LAP
We have used mice undergoing primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), or autoimmune hepatitis (AIH), as well as NSG mice humanized with PBMCs from PBC patients to investigate whether hepatocyte and/or cholangiocyte destruction in autoimmunity results in the stimulation of autoreactive T-cells capable of responding to disease-relevant and irrelevant pMHCIIbased nanomedicines

Summary

Introduction

Peptide-major histocompatibility complex class II (pMHCII)-based nanomedicines displaying tissue-specific autoantigenic epitopes can blunt specific autoimmune conditions by reprogramming cognate antigen-experienced CD4+ T-cells into disease-suppressing T-regulatory type 1 (TR1) cells. 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. We find that pMHCII-based nanomedicines displaying epitopes from various liver-autoimmune disease-relevant antigens can blunt the relevant liver autoimmune disease (i.e. PDCbased nanomedicines blunt PBC) and their irrelevant counterparts (i.e. PSC and AIH in addition to PBC) They do so without impairing the ability of the host to mount antibody responses against exogenous antigens, to clear viral or bacterial infections or to kill metastatic allogeneic tumors. Hepatocyte and cholangiocyte autoimmune insults can readily trigger the stimulation of peripheral T-cells recognizing liver-prevalent selfantigens, and such T-cell responses can be harnessed by pMHCIIbased nanomedicines to treat liver autoimmunity broadly

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Results

Conclusion