Christen / Hintermann Lab

Type 1 Diabetes

Type 1 diabetes (T1D) is a severe autoimmune disease affecting the insulin producing β-cells in the pancreatic islets of Langerhans. In 2019 an estimated 463 million people worldwide,and about 9,5 million individuals in Germany suffer from diabetes. Thereof about 10% have T1D and require daily insulin substitution in order to survive. Over the last 30 years, the annual incidence of T1D is increasing in almost every region that has been analyzed.

Currently, treatment of T1D is largely restricted to a symptomatic insulin-replacement therapy. Due to the effectiveness of insulin and the possible side effect of general immunosuppressive drugs, almost no therapies targeting the autoreactive immune system is being used in clinical practice. Nevertheless, many patients with T1D suffer from long-term adverse effects, such as cardiovascular diseases, retinopathy, neuropathy, diabetic nephropathy, and foot-disease. In addition, patients with T1D live with the constant danger of encountering hypoglycemic events that especially when occurring at night pose a very serious threat to life. Thus, the medical need for a novel immunotherapy of T1D is huge.

During the pathogenesis of T1D, cells of the innate followed by cells of the adaptive immune system infiltrate the pancreas and cluster around and in the islets of Langerhans (insulitis). β-cell autoantigen-specific T cells are activated by antigen-presenting cells (APC) in the pancreatic lymph nodes and/or the tertiary lymphoid structures arising around the islets and subsequently destroy the β-cells resulting in T1D. 

Autoimmune liver diseases

There are three major autoimmune liver diseases (ALD), namely autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). They all have in common that an aggressive autoimmune reaction results in destruction of liver tissue and development of severe hepatic fibrosis. 
 

Autoimmune Hepatitis - AIH
AIH is an often life-threatening disease resulting in the progressive destruction of the liver parenchyma and chronic fibrosis. AIH has a female predominance (sex ratio, 3.6:1), occurs in children and adults of all ages and affects different ethnic groups with an overall prevalence of ~20 cases per million persons in Northern Europe. The histological hallmark of AIH is the presence of interface hepatitis, characterized by piecemeal necrosis affecting patches of hepatocytes. One of the core diagnostic criteria of AIH and its subtypes is the presence of specific antibodies to particular liver autoantigens.

The current standard therapy of AIH is a glucocorticoid treatment with prednisone or prednisolone alone or in combination with azathioprine. Recently alternative treatments have been successfully introduced, in particular for patients suffering from AIH relapses after corticosteroid withdrawal. However, during standard therapy, adults rarely achieve resolution of their laboratory and liver tissue abnormalities in less than 12 months and withdrawal of therapy after two years leads to relapse in 85% of cases. Moreover, these long-term therapies carry the risk of significant steroid-specific and azathioprine-related side effects.

Primary Biliary Cholangitis -  PBC
PBC has an incidence ranging from 0.3 to 5.8 in 100.000 and has clear female dominance (F:M 9:1). PBC is an autoimmune liver disease characterized by a chronic cholestasis, destruction of the intrahepatic small bile ducts and the presence of anti-mitochondrial antibodies (AMA) in over 95% of patients. The target structure are cholangiocytes / biliary epithelial cells (BEC) that are attacked by an aggressive autoimmune response occurring due to a loss of tolerance against several liver autoantigens including the E2-subunits of the 2-keto acid dehydrogenase family.

Although alternative treatments are being evaluated, current therapy is still largely restricted to the administration of ursodeoxycholic acid (UDCA). However, almost 40% of patients are unresponsive to UDCA treatment. Recently, obeticholic acid (OCA) in combination with UDCA has been approved as the first new drug in almost 20 years for treatment of PBC, especially of patient refractory to UDCA single treatment.

Primary Sclerosing Cholangitis - PSC

PSC is a chronic cholangiopathy characterized by progressive inflammation of the bile duct region resulting in the development of biliary fibrosis and possibly cirrhosis and malignancy. PSC has an annual incidence of approximately 1 in 100.000, is typically diagnosed between 30 and 40 years of age, and has a male predominance (M:F 2:1). Most PSC patients display damage of the large bile ducts (90-95%) with characteristic strictures and dilatations of the biliary tree as well as onion skin fibrosis surrounding the damaged ducts. Strikingly, approximately 70-80% of PSC patients also present with inflammatory bowel  disease (IBD) and are associated with a higher risk for malignancies. A significant proportion of patients generate perinuclear anti-neutrophilic cytoplasmic antibodies (pANCA). However, such antibodies are not considered for diagnostic purposes. 

In contrast to PBC, the administration of UDCA is controversial for the therapy of PSC. A meta-analysis of several clinical trials revealed no beneficial role of UDCA in slowing the progression of PSC. Alternative treatments including the UDCA derivative NorUDCA and several nuclear receptor agonists are under current investigation in pre-clinical models.