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Targeting Enclysis in Liver Autoimmunity, Transplantation, Viral Infection and Cancer
Yara O Aghabi1, Alia Yasin1, James I Kennedy1
1College of Medical and Dental Sciences, Institute for Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
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.
Insights
New research reveals hepatocytes engulf regulatory T cells (Tregs) via enclysis. Inhibiting this process may enhance Treg therapies for liver diseases and transplants, while promoting it could boost anti-cancer immunity.
Area of Science:
- Hepatology
- Immunology
- Cell Biology
Background:
- Persistent liver inflammation contributes to cirrhosis, a leading cause of morbidity and mortality.
- Current treatments for end-stage liver disease are limited, with transplantation requiring lifelong immunosuppression.
- Regulatory T cell (Treg) therapies show promise for autoimmune diseases and transplant tolerance.
Purpose of the Study:
- To investigate the role of hepatocyte-mediated engulfment and deletion of Tregs (enclysis) in liver immune regulation.
- To propose enclysis as a therapeutic target to modulate Treg cell function in liver diseases.
- To explore the potential of manipulating enclysis to enhance Treg-based therapies or anti-tumor/antiviral immunity.
Main Methods:
- Discovery of hepatocyte engulfment and deletion of Tregs through a process termed enclysis.
- Hypothesizing the therapeutic potential of modulating enclysis in liver disease contexts.
- Reviewing existing Treg cell expansion strategies and their potential synergy with enclysis modulation.
Main Results:
- Hepatocytes naturally engulf and delete Treg cells via enclysis.
- Inhibition of enclysis may enhance the efficacy of Treg cell therapies in autoimmune liver diseases and transplantation.
- Enhancement of enclysis could transiently reduce Treg cells, potentially improving anti-viral and anti-tumor immunity.
Conclusions:
- Enclysis is a novel mechanism of liver immune regulation involving Treg cell clearance by hepatocytes.
- Targeting enclysis offers a new therapeutic strategy to potentiate Treg cell-based treatments for liver diseases.
- Modulating enclysis presents a dual therapeutic opportunity: enhancing Treg therapy or boosting beneficial immunity by reducing Treg abundance.
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