Antigenic targets and animal model in immune necrotizing myopathies – CAMANAI

Introduction: The auto-immune diseases are a major cause of morbidity. Usually, long time duration of immunosuppressant are needed to maintain the remission. Treatments are frequently associated with numerous side effects and the relapses frequently occur especially when the treatment is stop. Definitive remission with short treatment duration is now conceivable using antigen-specific immunosuppression.

Objectives: To define the T and B cells targets in an autoimmune muscle disease and to develop a mouse model of the disease to test innovative targeted treatment.

Rational and working hypothesis: We will focus on necrotizing auto-immune myopathies specifically associated with anti-3-hydroxy-3-méthyl-glutaryl-coenzyme A réductase (HMGCR) antibody (Ab). It is rare chronic muscle disease. This disabling setting justifies immunosuppressant for many years, permitting in the best case to stop the muscle damages. There is a strong genetic background since more than 70% of the patients harbor the HLA-DR11 haplotype. Recently, we have published data strongly suggesting that anti-HMGCR Ab maybe pathogenic, even if their cognate antigen is supposed to be intra-cytoplasmic. We hypothesize that this an Ab mediated disease and that immune anti-HMGCR response is crucial.


Project and methods: (Part 1) We will test the presence of anti-HMGCR specific CD4+ T cells. The strong genetic background is a rare opportunity to identify this population. First, in vitro, different HMGCR peptides will be tested for their affinity to HLA-DR11 molecule. Next, we will synthetize the HLA-DR11 specific tetramer corresponding to the previously identified peptides. Using an innovative multidimensional encoding of MHC multimers, we will test the blood samples from the patients and identify the peptides involved in the immune response.

(Part 2) We will identify the specific anti-HMGCR B cells. In blood samples from patients, using FACS analysis and fluorescent HMGCR proteins, we will identify and single cell sort this population. Base on this collection we will produce human specific monoclonal anti-HMGCR Ab.

(Partie 3) We will develop a mouse model of the disease. Two different approaches will be tested. HLA-DR11 transgenic mice will be immunized against the previously identified HMGCR peptide. We will also test a passive transfer of human monoclonal anti-HMGCR Ab.

People involved in the project and leader of the project: The leader of the project and the team he belongs to are known experts in the field of auto-immune muscle diseases. They are reference center for patients suffering from auto-immune myopathies and have prospectively collected blood samples from patients. They have published numerous clinical and scientific studies (eg: development of experimental auto-immune myositis) on auto-immunes myopathies and recently published a study on the pathogenic role of anti-HMGCR Ab. The team is in the myology center. Concerning the identification of specific HMGCR-T cells, the leader will collaborate with an expert of identification of self-reactive T cells in human (Dr R. Mallone). For this project a PhD student as well as Post-Doc will be involved.

Schedule and budget : 3 years and 250 KEuros.

Impact: The identification of T and B cells epitopes involved in the auto-immune anti-HMGCR myopathies will help to further clarify the pathogenesis of the disease as well as the development of a mouse model. In addition the mouse model we permit to develop new targeted innovative strategy.