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

Abstract

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.

Suppression of Autoimmune Rheumatoid Arthritis with Hybrid Nanoparticles That Induce B and T Cell Tolerance to Self-Antigen

“…Many if not most autoimmune diseases involve antibodies to self-antigens that mediate disease pathology. − Some of the most promising strategies for treating the cause of these diseases directly or indirectly target either B cells or T cells involved in the production of autoimmune antibodies. ,− B cell depletion via CD20-targeting monoclonal antibody rituximab has been FDA approved to treat rheumatoid arthritis and pemphigus and is being evaluated for treatment of many other autoimmune diseases such as SLE. ,− While remission of symptoms in pemphigus is achieved in most patients, relapses occur when B cells are replenished, requiring additional rounds of treatment. , T cell directed therapies include depletion of T cells at the induction/expansion of tolerogenic Tregs that suppress immune responses. ,, For example, administration of low doses of interleukin 2 to expand Tregs has shown promise in the treatment of systemic lupus erythematosus (SLE) and type I diabetes . Cellular therapies using CD19-CAR T cells to deplete B cells or administering expanded Tregs are also beginning to show promise in clinical trials. − …”

Targeted modulation of gut microbiota by traditional Chinese medicine and natural products for liver disease therapy

“…It is generally believed that multiple factors, such as heredity, immunity, inflammation, infection, and dysbacteriosis, contribute to the progression of AILD. However, as the complex etiology and pathogenesis of the disease have not yet been fully elucidated, there is currently a lack of specific diagnostic criteria and safe and effective drugs ( 68 ). Such a situation urgently requires researchers to conduct in-depth exploration to elucidate the pathogenesis of AILD, identify promising therapeutic targets, and provide a powerful impetus for screening ideal drugs and formulating effective therapeutic strategies.…”

Strategies to enhance CAR-T persistence

“…As a type of immunosuppressive cell, Tregs are critical for immune system tolerance and hyperimmune response avoidance [ 72 , 73 ]. Therefore, unlike other CAR cells for anticancer treatment, CAR-Tregs maintain the Treg phenotype and function.…”