Abstract
Persistent liver inflammation can lead to cirrhosis, which associates with significant morbidity and mortality worldwide. There are no curative treatments beyond transplantation, followed by long-term immunosuppression. The global burden of end stage liver disease has been increasing and there is a shortage of donor organs, therefore new therapies are desperately needed. Harnessing the power of the immune system has shown promise in certain autoimmunity and cancer settings. In the context of the liver, regulatory T cell (Treg) therapies are in development. The hypothesis is that these specialized lymphocytes that dampen inflammation may reduce liver injury in patients with chronic, progressive diseases, and promote transplant tolerance. Various strategies including intrinsic and extracorporeal expansion of Treg cells, aim to increase their abundance to suppress immune responses. We recently discovered that hepatocytes engulf and delete Treg cells by enclysis. Herein, we propose that inhibition of enclysis may potentiate existing regulatory T cell therapeutic approaches in patients with autoimmune liver diseases and in patients receiving a transplant. Moreover, in settings where the abundance of Treg cells could hinder beneficial immunity, such us in chronic viral infection or liver cancer, enhancement of enclysis could result in transient, localized reduction of Treg cell numbers and tip the balance towards antiviral and anti-tumor immunity. We describe enclysis as is a natural process of liver immune regulation that lends itself to therapeutic targeting, particularly in combination with current Treg cell approaches.
Highlights
The liver has a critical role in detoxification and it often becomes the site of cellular damage
Loss of tolerance in the liver is observed in autoimmune family disorders such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), where immune-mediated injury affects hepatocytes, small and large bile ducts respectively
We noted no differences between FOXP3+ Treg cell numbers in liver tissue sections from AIH patients compared to other end stage diseases, we found that more FOXP3+ cells were engulfed by hepatocytes in AIH [19]
Summary
The liver has a critical role in detoxification and it often becomes the site of cellular damage. The WHO estimates that in 2015, HBV resulted in 887,000 deaths [4] and in 2016, HCV resulted in 339,000 deaths worldwide [5] Of these diseases that cause chronic liver inflammation, HCV is the only one where a curative treatment for the majority of patients is available. The outcome of liver inflammation is determined by the balance of effector and regulatory immune cells activities: chronic hepatitis arises when effector cells persist, causing liver injury. Despite their prevalence, effector cells in chronic disease fail to control hepatocellular carcinoma, one of the two cancers with mortality projected to rise by 38% by 2035 [1]. The clinical goal is to increase the abundance of functional Treg cells in autoimmunity [14,15,16] and eliminate Tregs in early infection [16, 17] in order to clear the virus and potentiate immunotherapy [12, 18]
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