Promising Pharmacological, Molecular and Cellular Treatments of Autoimmune Hepatitis

Albert      J. Czaja

Abstract

Current corticosteroid regimens are effective in autoimmune hepatitis, but therapy can be complicated by side effects, disease progression, incomplete response, and relapse after drug withdrawal. The aims of this review are to describe the promising pharmacological, molecular and cellular interventions for autoimmune hepatitis and to stimulate further investigations that can refresh or replace current treatments. Murine models that introduce pertinent human disease-related antigens by vaccination or viral infection promise a resource by which to evaluate new treatments. Promising new drug therapies include the calcineurin-inhibitors (cyclosporine, tacrolimus), next generation purine antagonists (mycophenolate mofetil, 6-thioguanine nucleotides), next generation glucocorticoids (budesonide, deflazacort), and inhibitors of the mammalian target of rapamycin (rapamycin). Feasible molecular interventions are recombinant molecules that affect immune regulatory pathways (cytotoxic T lymphocyte antigen 4, recombinant interleukin 10), monoclonal antibodies that disrupt activation pathways (antibodies to CD3, CD28, CD 20, or tumor necrosis factor-α), and synthetic peptides that block antigen display or promote antigen desensitization (oral tolerance). New methods to stimulate or replenish regulatory T cell populations (adoptive transfer, mesenchymal stem cell or autologous bone marrow transplantation) are feasible as are genetic manipulations (gene silencing) and gene supplementations (gene replacement therapy). The emergence of new therapies for autoimmune hepatitis requires a standardized and universalized animal model of the human disease, consensus regarding the most promising modality to be tested, and formation of a cooperative international network of committed clinical investigators to evaluate new therapies in a pre-designed rigorous yet expeditious fashion.

Keywords: Site-specific drugs, monoclonal antibodies, recombinant molecules, immune cell manipulations, genetic engineering, autoimmune hepatitis, azathioprine, corticosteroid therapy, cytokines, apoptosis