Nonstandard drugs and feasible new interventions for autoimmune hepatitis: part II.

Molecular, cellular, and genetic interventions are now feasible for autoimmune hepatitis because of improved understanding of pathogenic mechanisms, advances in recombinant technology, and previous successes in animal models and humans with other immune-mediated inflammatory diseases. Non-mitogenic monoclonal antibodies to CD3 promote apoptosis of cytotoxic T lymphocytes, inhibit production of pro-inflammatory cytokines, improve the function of regulatory T cells, and induce a durable remission in mouse models and humans with autoimmune diabetes. Monoclonal antibodies to CD20 deplete B lymphocytes, modify antibody-dependent and cell-mediated cytotoxic pathways, enhance regulatory T cell function, and improve isolated cases of autoimmune hepatitis with B-cell disorders. Recombinant cytotoxic T lymphocyte antigen-4 fused with immunoglobulin can block the second co-stimulatory signal required for lymphocyte activation, and it has been licensed for use in rheumatoid arthritis but not tried in autoimmune hepatitis. Other considerations on the distant horizon are monoclonal antibodies against inhibitory receptors on regulatory T cells, adoptive transfer of fresh regulatory T cells, tailored glycolipids that strengthen the immunosuppressive activity of natural killer T cells, small inhibitory ribonucleic acid molecules that silence promoter genes supporting disease activity, and mesenchymal stem cell transplantation to re-constitute immune homeostasis and support the damaged liver. Development of these feasible new interventions for autoimmune hepatitis requires therapeutic animal models, societal support, and a collaborative network of investigators to conduct rigorous clinical trials.