IMMUNE TOLERANCE

Mechanisms that underlie loss of antigen tolerance in HLA-associated autoimmune diseases

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 Obiettivo del progetto (Objective)

'An estimated 3-7% of Europe's population (80% females) suffer from autoimmune diseases (AID) that affect the body's various organs. In healthy people, harmless proteins from self, bacterial flora or food do not elicit a destructive inflammatory response due to antigen tolerance. Central to antigen tolerance is the function of regulatory T cells, a population of lymphocytes key to the prevention of excessive inflammatory tissue damage by immune effector cells. Unfortunately, the mechanisms that safeguard a balanced interaction of HLA class II-restricted regulatory and effector CD4 T cells are incompletely understood. This explains why the current treatment of AID remains inadequate. Towards the priority research areas for chronic inflammatory diseases identified in the Innovative Medicines Initiative's Research Agenda 2008, we suggest the following original approaches: 1.) Identification of the functional roles of HLA class II-restricted CD4 T cells in the induction/prevention of AID using a HLA-DR*0405 transgenic mouse model of autoimmune pancreatitis (AIP); 2.) identification of humoral autoantigens that can aid in the diagnosis of AIP; 3.) enhancement of a novel mouse model of human celiac disease (CD) by introduction of the CD-associated HLA-DQ8 (class II) allele; and 4.) pre-clinical testing of oral enzyme therapy, currently the most promising alternative treatment approach to CD, comparing efficacy in the existing CD mouse model of a 2-enzyme-glutenase (prolyl endopeptidase and endoprotease B2) vs. an extract of germinating wheat enzymes. This project will lead to insight into pathomechanisms that underlie loss of antigen tolerance in HLA-associated AID, development of a diagnostic serum test for AIP, analysis of the HLA-dependency of CD-specific autoantibodies and proof-of-efficacy in vivo for oral enzyme therapy of CD.'

Introduzione (Teaser)

European researchers dissected the arm of the immune system that is responsible for autoimmune diseases (AID). They concentrated on specific receptors on antigen presenting cells and their role in inducing and regulating autoimmunity.

Descrizione progetto (Article)

In AID, our body recognises 'self' antigens as foreign thereby leading to destructive inflammatory responses in various organs. Normally our regulatory T cells counteract effector T cells through a phenomenon called antigenic tolerance, which prevents such adverse effects. To maintain or induce such tolerance, antigen presentation on specialised receptors called major histocompatibility (MHC) or human leukocyte antigen (HLA) class II receptors is required.

The precise mechanisms underlying antigen tolerance are poorly understood. The EU-funded 'Mechanisms that underlie loss of antigen tolerance in HLA-associated autoimmune diseases' (IMMUNE TOLERANCE) project worked on elucidating these mechanisms as well as AID. To achieve their goal, scientists used a mouse model of human autoimmune pancreatitis (AIP) to study the role of risk HLA type-restricted T cells in disease induction.

They observed that upon adoptive transfer of risk HLA type-restricted T cells animals did not develop AIP, demonstrating that these T cells are not directly causing the disease. Instead, cytotoxic T cells were causing AIP upon adoptive transfer. These results suggested a defect in regulatory T cells restricted by the risk HLA type, underscoring the importance of HLA class II in the predisposition to autoimmunity.

Additionally, researchers studied the role of HLA receptors in coeliac disease and evaluated the effectiveness of oral enzyme therapy in a pre-clinical mouse model.

Overall, the IMMUNE TOLERANCE study provided invaluable insight into the mechanism of interaction between regulatory and effector T cells in health and disease. Importantly, the work entailed an important translational component by testing the therapeutic potential of enzyme therapy in coeliac disease.