Challenges and opportunities in achieving effective regulatory T cell therapy in autoimmune liver disease

Challenges and opportunities in achieving effective regulatory T cell therapy in autoimmune liver disease

Autoimmune liver diseases (AILD) include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). These immune-mediated liver diseases involve a break down in peripheral self-tolerance with largely unknown aetiology. Regulatory T cells (Treg) are crucia...

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Bibliographic Details
Published in:Seminars in immunopathology Vol. 44; no. 4; pp. 461 - 474
Main Authors: Richardson, N., Wootton, G. E., Bozward, A. G., Oo, Y. H.
Format: Journal Article
Language:English
Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-07-2022
Springer Nature B.V
Subjects:
Bile acids
Biomedical and Life Sciences
Biomedicine
Cell therapy
Chimeric antigen receptors
Cholangitis
Clinical trials
Dosage
Epithelium
Good Manufacturing Practice
Hepatitis
Hepatocytes
Immunological tolerance
Immunology
Immunoregulation
Immunosuppression
Immunotherapy
Inflammation
Interleukin 2
Internal Medicine
Liver diseases
Longevity
Lymphocytes T
Microenvironments
Pathology
Patients
Phenotypes
Precision medicine
Review
T cell receptors
Liver microenvironment
Cell therapy
Autoimmune liver
Regulatory T cell
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Summary:Autoimmune liver diseases (AILD) include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). These immune-mediated liver diseases involve a break down in peripheral self-tolerance with largely unknown aetiology. Regulatory T cells (Treg) are crucial in maintaining immunological tolerance. Hence, Treg immunotherapy is an attractive therapeutic option in AILD. Currently, AILD do not have a curative treatment option and patients take life-long immunosuppression or bile acids to control hepatic or biliary inflammation. Clinical investigations using good manufacturing practice (GMP) Treg in autoimmune liver disease have thus far demonstrated that Treg therapy is safe and that Treg migrate to inflamed liver tissue. For Treg immunotherapy to achieve efficacy in AILD, Treg must be retained within the liver and maintain their suppressive phenotype to dampen ongoing immune responses to hepatocytes and biliary epithelium. Therefore, therapeutic Treg subsets should be selected for tissue residency markers and maximal functionality. Optimisation of dosing regime and understanding longevity of Treg in vivo are critical to successful Treg therapy. It is also essential to consider combination therapy options to complement infused Treg, for instance low-dose interleukin-2 (IL-2) to support pre-existing and infused Treg survival and suppressive function. Understanding the hepatic microenvironment in both early- and late-stage AILD presents significant opportunity to better tailor Treg therapy in different patient groups. Modification of a hostile microenvironment to a more favourable one either prior to or during Treg therapy could enhance the efficacy and longevity of infused GMP-Treg. Applying recent technology to discovery of autoantigen responses in AILD, T cell receptor (TCR) sequencing and use of chimeric antigen receptor (CAR) technology represents the next frontier for disease-specific CAR-Treg therapies. Consideration of all these aspects in future trials and discovery research would position GMP Treg immunotherapy as a viable personalised-medicine treatment option for effective control of autoimmune liver diseases.
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ISSN:1863-2297
1863-2300
DOI:10.1007/s00281-022-00940-w