Novel Immunotherapies for Autoimmune Hepatitis

Abstract

Autoimmune hepatitis (AIH) is a multifactorial autoimmune disease of unknown pathogenesis, characterized by a loss of immunological tolerance against liver autoantigens resulting in the progressive destruction of the hepatic parenchyma. Current treatments are based on non-specific immunosuppressive drugs. Although tremendous progress has been made using specific biological agents in other inflammatory diseases, progress has been slow to come for AIH patients. While current treatments are successful in the majority of patients, treatment discontinuation is difficult to achieve, and relapses are frequent. Lifelong immunosuppression is not without risks, especially in the pediatric population; 4% of patient with type 1 AIH will eventually develop hepatocellular carcinoma with a 2.9% probability after 10 years of treatment. Therefore, future treatments should aim to restore tolerance to hepatic autoantigens and induce long-term remission. Promising new immunotherapies have been tested in experimental models of AIH including T and B cell depletion and regulatory CD4+ T cells infusion. Clinical studies on limited numbers of patients have also shown encouraging results using B-cell-depleting (rituximab) and anti-TNF-α (infliximab) antibodies. A better understanding of key molecular targets in AIH combined with effective site-specific immunotherapies could lead to long-term remission without blanket immunosuppression and with minimal deleterious side effects.

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach

“…In these cases, progressive fibrosis of the liver leads to the liver failure, when the only remaining treatment option is the organ transplantation. TNF-α is considered as one of the crucial mediators of liver damage in AIH, thus, anti-TNF-α biological drugs have been used in difficult-totreat patients suffering from this disorder (11). PDE inhibitors have been earlier successfully tested in the ConA-induced hepatitis model in mice.…”

“…In contrast, a reduction of cAMP concentrations may exert an immunostimulatory effect (10). TNF-α is considered a key cytokine in the development and course of RA, AIH, as well as sepsis (11)(12)(13). Thus, anti-TNF-α therapies are gaining a growing interest as a treatment option of these diseases.…”

Rapamycin alleviates experimental autoimmune hepatitis by immunoregulation of Th1 and Th17 cells

“…All mice were randomly divided into three groups after 1 week of adaptive feeding as follows: NS (normal saline) group (n=6), AIH+NS group (n=6) and AIH+RAP group (n=6). The AIH mouse model was established as previously reported [1][2][3] by intraperitoneal administration of 0.5 ml fresh S-100 antigen emulsi ed in an equal volume of complete Freund's adjuvant (CFA, Sigma, Cat No. :F5881, USA) (the concentration of S-100 antigen is 1 mg/mL) on 1st and 7th day.…”

“…Histological features of AIH include mild to severe interface hepatitis with in ammatorycell in ltration, bridging necrosis, increased hepatocyte apoptosis, multilobular collapse, and bile duct injury or loss [2]. AIH patients require lifelong immunosuppression, which does not always prevent progression to end-stage liver damage [3].…”

Regulatory T Lymphocytes (Treg): Modulation and Clinical Application

“…This fact supports the hypothesis of treating patients with autologous Tregs expanded ex vivo and may lead to tolerance to hepatic antigens during the development of chronic disease, with remission of the clinical signs and symptoms of AIH. The use of IL-2 for Treg expansion in vivo is an option for treatment in patients with reduced Treg numbers [82][83][84].…”