New test system for drugs to treat rheumatoid arthritis

A humanized murine arthritis model for the development of innovative immunotherapeutics for rheumatoid arthritis

Rheumatoid arthritis (RA) is the most common inflammatory rheumatic joint disease. Via an immune-mediated chronic inflammatory process it can lead to joint destruction and systemic inflammatory effects. In Germany, an estimated 440,000 people suffer from this disease.

Current therapies are based on unspecific suppression of the immune system, which implies the risk of serious infections. Despite frequent improvements in the patient’s condition, a reduction in disease activity can rarely be achieved. Thus, despite improved therapy options, there is still a medical need for personalized, sustainably effective and well tolerated treatment strategies.

Recently, pharmaceutical therapies for established rheumatoid arthritis have experienced a significant improvement due to the inhibition of effector pathways by neutralizing critical inflammatory mediators such as TNF, IL-6 and others using blocking antibodies or synthetic inhibitors of receptor-associated signaling molecules (JAK inhibitors).

Establishment of a humanized mouse model

© Fraunhofer IME

This project aims to establish a new humanized mouse model of rheumatoid arthritis (RA) as an essential tool for the development of innovative therapeutic strategies. Mouse models are used in early drug development to test the efficacy of targeted pharmacological manipulation of a target structure in the complex interplay of a variety of mechanisms involved in disease initiation prior to the start of clinical trials in humans. In order to improve the transferability of animal experimental results to the therapeutic situation in humans, the new model uses mice in which genetic modification replaces disease-relevant murine proteins with human structures.

Initially, the new RA model will be used to characterize the molecular mechanisms of action of a new therapeutic strategy for modulation of T cells. These results can then be used to advance drug candidates into a clinical proof-of-concept trial.

The Cluster of Excellence CIMD enables an interdisciplinary research approach

Areas of expertise of the two core institutes Fraunhofer IME and IZI will be pooled in this project:

  • Animal models: established collagen type II-induced arthritis (CIA) as a standard model in the development of innovative antirheumatic drugs (Fraunhofer IME)

  • Drug discovery and validation: recombinant production of therapeutic MHC/peptide complexes (Fraunhofer IME) and modified exosomes from mesenchymal stem cells (Fraunhofer IZI)

Outlook

In cooperation with the research group of Prof. Holmdahl at the Swedish Karolinska Institute, knock-in mouse lines are established, which instead of murine antigen-presenting molecules express analogous human variants. These molecules are expressed not only on the antigen-presenting cells in the circulation, peripheral tissues and secondary immunological organs (e.g. lymph nodes), but also in the thymus critical which is for the imprinting of immunological self-tolerance during the maturation processes of the immune system. The influence of human MHCII molecules (molecules that are important for immune recognition) on the activation and development of individual cell types of the innate and adaptive immune system (e.g. T cells, B cells, macrophages, dendritic cells) can therefore be investigated in these mouse lines. The testing of new drugs in a humanized mouse model (i.e. in a mouse with human antigen-presenting molecules) therefore allows the researchers to experimentally test drugs in vivo for their effects under more meaningful conditions for their intended later use in humans.

The mouse lines are used to identify new antigenic determinants which are to be recognized in the context of arthritogenic immune responses and used as potential target structures for the drug development of immunomodulatory antirheumatic drugs.