Emerging Opportunities for Site-Specific Molecular and Cellular Interventions in Autoimmune Hepatitis

Abstract

Current corticosteroid-based treatments of autoimmune hepatitis frequently have incomplete or unsatisfactory outcomes, side effects, and excessive immune suppression. The goal of this review is to describe the advances in developing animal models of autoimmune hepatitis and in treating diverse immune-mediated diseases that make pursuit of site-specific molecular and cellular inventions in autoimmune hepatitis feasible. Prime source and review articles in English were selected by a Medline search through October 2009. A murine model infected with an adenovirus expressing human CYP2D6 is a resource for evaluating new therapies because of its histological and serological features, persistence, and progressive hepatic fibrosis. Synthetic analog peptides that block autoantigen expression, a dimeric recombinant human fusion protein of cytotoxic T lymphocyte antigen-4, monoclonal antibodies against tumor necrosis factor-alpha, recombinant interleukin 10, tolerization techniques for disease-triggering autoantigens, T regulatory cell transfer, vaccination against antigen-specific cytotoxic CD8+ T cells, and gene silencing methods using small inhibitory RNAs are feasible interventions to explore. Treatments directed at dampening immunocyte activation with soluble cytotoxic T lymphocyte antigen-4, inhibiting immunocyte differentiation with recombinant interleukin 10, and improving immunosuppressive activity with regulatory T cell modulation have the most immediate promise. Progress in the development of an animal model of autoimmune hepatitis and experiences in other immune-mediated diseases justify the evaluation of site-specific molecular and cellular interventions in this disease.

Review article: the prevention and reversal of hepatic fibrosis in autoimmune hepatitis

“…As autoimmune hepatitis is characterised by hepatic inflammation and the proliferation of liver-infiltrating cytotoxic lymphocytes that differentiate and proliferate along a type 1 cytokine pathway, 227 agents that neutralise pro-inflammatory cytokines, such as tumour necrosis factor-alpha (TNF-a), have a strong rationale as anti-fibrotic therapies. 228 Such agents, however, including etanercept, 229,230 infliximab, 47,230 and pentoxifylline, 231 have either not improved mortality, had serious side effects, or exhibited no anti-fibrotic activity in diverse non-autoimmune liver diseases. Infliximab did rescue 7 of 11 patients with steroid-refractory autoimmune hepatitis, 47 but concerns about infectious complications 47,228 and drug-induced autoreactivity 230,[232][233][234] have justified a cautious interest in this agent.…”

Management of autoimmune hepatitis: Focus on pharmacologic treatments beyond corticosteroids

“…Cyclosporine and FK506 have each been used in AIH patients, primarily as salvage therapies for steroid-refractory disease [22,54] . regimen normalized serum AST and alanine aminotransferase (ALT).…”

“…These non-standard treatments application is not widespread and they are not included into any standard management algorithm [15] . Only recently has the emergence of powerful immunosuppressive agents, mainly from liver transplantation, challenged the supremacy of the corticosteroid regimens [22,54] . Drugs outside of the standard repertoire now promise greater immune suppression than conventional medications, offer site-specific actions and satisfactory patient tolerance [22,54] .…”

“…Only recently has the emergence of powerful immunosuppressive agents, mainly from liver transplantation, challenged the supremacy of the corticosteroid regimens [22,54] . Drugs outside of the standard repertoire now promise greater immune suppression than conventional medications, offer site-specific actions and satisfactory patient tolerance [22,54] . Site-specific molecular treatments are also possible because of improved understanding of the central pathogenic disease pathways and technological advances that now enable modulation of these pathways [22,54] .…”

“…Drugs outside of the standard repertoire now promise greater immune suppression than conventional medications, offer site-specific actions and satisfactory patient tolerance [22,54] . Site-specific molecular treatments are also possible because of improved understanding of the central pathogenic disease pathways and technological advances that now enable modulation of these pathways [22,54] . Furthermore, successes in experimental models and in other autoimmune diseases have primed these molecular interventions for study in AIH [22,54] .…”