Emerging treatments for autoimmune hepatitis.
Prednisone alone or a lower dose of prednisone in combination with azathioprine induces remission and enhances survival in autoimmune hepatitis. Treatment failure, incomplete response, drug-induced side effects, and relapse after drug withdrawal are unsatisfactory outcomes that justify the search for new therapies. Potent new drugs promise greater blanket immunosuppression than current regimens, and insights into the pathogenic mechanisms of the disease make site-specific interventions possible. Cyclosporine and tacrolimus are calcineurin inhibitors that impair the transcription of interleukin 2, reduce the expression of cytokines, and diminish T lymphocyte proliferation. Mycophenolate mofetil antagonizes the synthesis of purines and depletes stores of guanine nucleotides necessary for DNA synthesis and expansion of T cell clones. Controlled clinical trials are warranted to establish the role of these new drugs in the treatment of autoimmune hepatitis. Promising site-specific therapies include peptides that competitively block autoantigen presentation, agents such as cytotoxic T lymphocyte antigen 4 that inhibit the second co-stimulatory signal of immunocyte activation, T cell vaccination, oral tolerance therapy, and cytokine manipulation with monoclonal antibodies and recombinant supplements. Confident animal models of experimental autoimmune hepatitis are necessary to mature these interventions. In conclusion, promising immunosuppressive agents that alter cytokine expression and T lymphocyte proliferation may be of value in the treatment of autoimmune hepatitis. Critical mechanisms of immunocyte activation, cytotoxic T cell expansion, and cytokine modulation are the targets of site-specific interventions.
Czaja
Albert J
AJ
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA. czaja.albert@mayo.edu
D001379:Azathioprine / Q000378:metabolism / Q000627:therapeutic use; D065095:Calcineurin Inhibitors; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D019693:Hepatitis, Autoimmune / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D011241:Prednisone / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology
D065095:Calcineurin Inhibitors; D016207:Cytokines; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D001379:Azathioprine; D011241:Prednisone