Developing a CAR T Cell Based Therapy for Graves’ Disease

Overview

Graves’ disease is an autoimmune thyroid disorder that results in elevated plasma levels of the thyroid hormones T3 and T4. Thyroid hormone overproduction is caused by pathogenic B cells producing IgG antibodies that bind to and stimulate the thyrotropin receptor (TSHr). These anti-TSHr B cells are activated and maintained by helper T cells that bind to linear epitopes of TSHr. Without these anti-TSHr helper T cells, the pathogenic B cells would remain inactive and normally die by apoptosis. Therefore, the elimination of anti-TSHr helper T cells could be a treatment method for Graves’ disease. Chimeric antigen receptor (CAR) T cell therapy offers a highly specific and effective method for targeting and eliminating pathogenic immune cells in autoimmune diseases. CAR T cell therapy works by engineering T cells to target a given region, or epitope, that it would come across in the body. Here, we designed a plasmid for an extracellular CAR domain that could target the pathogenic anti-TSHr helper T cells found in Graves’ disease. This extracellular domain is based off of an MHC class II molecule presenting a linear epitope of TSHr in order to mimic the complex formed between anti-TSHr T helper cell receptors and the MHC class II molecules found on professional antigen presenting cells. The ten most cited linear epitopes for TSHr in Graves’ disease were selected from the Immune Epitope Database as candidates for the plasmid. HLA-DR3 and HLA-DR5 were selected as the MHC class II molecules for presenting the epitopes. Five additional epitopes with high binding affinities to the selected HLAs were generated using the NetMHCIIPan server. We reasoned that the fifteen selected epitopes would provide a broad coverage of the disease associated epitopes in Graves’ disease. To mimic the natural structure of the HLAs, the sequence for the epitope was inserted between the two subunits of the HLA and tested in silico for correct protein folding. Future work will include assessment of the binding affinities of the various constructs to anti-TSHr T helper cells and selection of internal domains for therapeutic CAR T cells.

Competition history

• AJAS 2020 Category not listed

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