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

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.

Ubiquitous antigen-specific T regulatory type 1 cells variably suppress hepatic and extrahepatic autoimmunity

“…We reasoned that bile duct or hepatocyte damage in PBC and PSC or AIH, respectively, would trigger the release of not only the PBC-relevant autoantigen PDC, but also the AIH-relevant autoantigens cytochrome P450 (CYP2D6) and formimidoyltransferase cyclodeaminase (FTCD), leading to the priming of autoreactive CD4 + T cells capable of responding to the corresponding pMHC-NPs. This was indeed the case (5). Remarkably, these therapeutic effects were dissociated from impairment of normal immunity (5).…”

“…This was indeed the case (5). Remarkably, these therapeutic effects were dissociated from impairment of normal immunity (5).…”

“…A growing body of evidence has established the feasibility of using antigen-specific approaches for the treatment of autoimmunity (1). We have shown that nanoparticles (NPs) coated with disease-relevant peptide MHC (pMHC) molecules (2) can resolve inflammation in various organ-specific autoimmune disease models in a disease-specific manner without impairing normal immunity (3)(4)(5). In all these models, pMHC class II-NP (pMHCII-NP) therapy functions by reprogramming cognate antigen-experienced CD4 + T cells into FoxP3 -CD25 -T regulatory type 1-like (TR1-like) cells, followed by systemic expansion.…”

“…Like human PBC, PBC in NOD.c3c4 mice is associated with spontaneous T and B cell responses against the mitochondrial pyruvate dehydrogenase (PDC) complex (7). Treatment of NOD.c3c4 mice with NPs displaying IA g7 presenting mPDC-E2 epitopes blunted the progression of, and reversed overt, PBC (5). In contrast, treatment with NPs coated with the pancreatic β cell-specific BDC 2.5mi /IA g7 pMHC triggered neither TR1 cell expansion nor disease reversal.…”

Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route

“…Immunomodulation followed by infusion of antigen-specific Tregs has been shown to control autoimmunity in the pancreatic islets [33]. It has also been possible to decrease destructive CD8+cells in the pancreas by giving plasmid-encoding proinsulin [34]. Thus, whereas different techniques are being developed in animal experiments, studies in experimental animals do not prove that the treatment works in humans.…”