Targeting auto-reactive B-cells by vaccination to cure human auto-immune disease

Currently, most human autoimmune diseases are chronic conditions without a prospect of cure.

My aim in this proposal is to meet the next major challenge, achieving cure in autoimmune disease.Many autoimmune diseases are characterized by autoantibodies and are remarkably responsive to B-cell targeted therapies, demonstrating that the autoreactive B-cell is central to disease pathogenesis.

Nonetheless, the selective and permanent elimination of the autoreactive B-cell, both memory and plasma cells alike, is not presently feasible due to a lack of specific markers and treatments.

My aim is to develop a vaccine that will allow the specific and long-lasting depletion of autoreactive B-cells, thereby inducing cure.

Using the unique mutated sequences of autoreactive B-cell receptors (BCR), cytotoxic T-cells that specifically eradicate autoreactive B-cells will be induced.

This concept extends the remit of vaccines beyond infectious diseases and cancer, into the sphere of autoimmune disease.Using the well-defined autoimmune disease rheumatoid arthritis (RA) as prototype, I will study the RA-specific autoimmune response. Our recent findings show that RA is characterized by a restricted, oligoclonally-expanded autoreactive B-cell pool.

Using recently developed technologies, my team will identify autoreactive B-cells and the BCR repertoire at several (pre)disease stages.

We will then determine the potency of the many non-germline-encoded mutations in BCRs as neoantigens amenable to T-cell recognition and vaccination.

Incorporating these neoantigens into multiple long peptides covering the autoreactive B-cell repertoire, we will design patient-tailored vaccines and perform a phase I trial to determine the feasibility of specifically depleting disease-causing B-cells.This research will create the possibility for patient-tailored vaccines that can permanently eradicate auto-reactive B-cells in B-cell driven auto-immune diseases; diseases that are still incurable to date.