Adoptive cell transfer in autoimmune hepatitis

Abstract

Adoptive cell transfer is an intervention in which autologous immune cells that have been expanded ex vivo are re-introduced to mitigate a pathological process. Tregs, mesenchymal stromal cells, dendritic cells, macrophages and myeloid-derived suppressor cells have been transferred in diverse immune-mediated diseases, and Tregs have been the focus of investigations in autoimmune hepatitis. Transferred Tregs have improved histological findings in animal models of autoimmune hepatitis and autoimmune cholangitis. Key challenges relate to discrepant findings among studies, phenotypic instability of the transferred population, uncertain side effects and possible need for staged therapy involving anti-inflammatory drugs. Future investigations must resolve issues about the purification, durability and safety of these cells and consider alternative populations if necessary.

Keywords:

• adoptive transfer
• autoimmune hepatitis
• Tregs
• treatment

Financial & competing interests disclosure

AJ Czaja researched, designed and wrote this article. The tables are original, constructed by Czaja, fully referenced and developed solely for this review. The review article is original, current and comprehensive, and it has not been published previously. This review did not receive financial support from a funding agency or institution, and AJ Czaja has no conflict of interests to declare. The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Adoptive transfer of autologous immune cells (Tregs, mesenchymal stromal cells, dendritic cells, macrophages and myeloid-derived suppressor cells) that have been modified, expanded or induced ex vivo have been used in animal models and humans to treat various immune-mediated diseases, including autoimmune hepatitis.

• The principal candidates for adoptive cell therapy in autoimmune hepatitis are Tregs because they have broad immunosuppressive actions and correctable defects in autoimmune hepatitis.

• Tregs can be rendered antigen-specific, induce antigen tolerance and yield a durable protection by generating secondary Tregs (‘infectious tolerance’) and suppressing the accumulation and maturation of dendritic cells.

• Tregs that have been induced from CD4⁺CD25^– T lymphocytes after stimulation with TGF-β have greater immunosuppressive effects and functional stability in an inflammatory milieu than natural, thymic-derived Tregs, and they are the preferred Treg subset for adoptive cell therapy in autoimmune hepatitis.

• Adoptive transfer of Tregs in murine models of autoimmune hepatitis have prevented the occurrence of fatal disease, reduced inflammatory activity in liver tissue, restored peripheral tolerance to a liver autoantigen (formiminotransferase cyclodeaminase) and maintained immunological tolerance for at least 1 month.

• Uncertainties exist in the occurrence and nature of Treg abnormalities in autoimmune hepatitis, and studies that have indicated abnormalities in the number and function of Tregs have been challenged.

• Key difficulties in developing the adoptive transfer of Tregs for autoimmune hepatitis are the phenotypic instability of these cells in an inflammatory milieu, their uncertain safety profile and the lack of standardized methodologies to ensure identity, purity, potency and sterility of cell preparations.

• Combination or sequential therapies using pharmacological agents (corticosteroids, mycophenolate mofetil, rapamycin or proteasome inhibitors) to suppress inflammatory activity, expand the Treg population and protect the phenotype of the induced Tregs may be necessary to optimize adoptive cell therapy.

• Prime alternative cell populations to be considered for adoptive transfer in autoimmune hepatitis are mesenchymal stromal cells and dendritic cells.

• Multi-center collaboration will be necessary to develop, refine, evaluate, establish and distribute a treatment that is highly individualized, labor intensive, expensive and restricted to specialized centers.