Grant: Project Grant

Demyelinating autoimmune diseases, such as multiple sclerosis (MS), result from dysfunctions of the immune system that cause it to destroy myelin in the nervous system. As B cells (a type of immune cells) play key roles in these diseases, B cell-depleting drugs have proven remarkably effective and are now part of the first-line therapeutic arsenal. A PROBLEM is that these drugs deplete most B cells, including beneficial ones, increasing the risk of infection. Moreover, they are not curative, possibly because they spare a subset of B cells that secrete disease-promoting antibodies known as autoantibodies. Our GENERAL GOALS are to clarify the nature of autoantibodies and antibody-producing cells in an improved mouse model of autoimmune demyelination, while testing new therapeutics. CRUCIAL QUESTIONS to address are: 1) how these cells develop and migrate; 2) what is their importance and therefore their value as potential therapeutic targets? Our HYPOTHESES are: 1) the fate of these cells depends on proteins such as BCMA and CCR10; and 2) disease can be mitigated by blocking the antibody response either genetically or pharmaceutically. To test this, our SPECIFIC AIMS will be to examine how our mouse model is affected by: 1) genetic deletion of BCMA or CCR10; 2) interventions aimed at eliminating anti-myelin antibodies; and 3) administration of an inert anti-myelin antibody capable of interfering with endogenous autoantibodies. To this end, we will take benefit of cutting-edge technologies and ongoing collaborations with antibody manufacturers. This project will provide not only BASIC KNOWLEDGE on autoantibodies and antibody-producing cells, which may help to understand how autoimmunity can develop, but also TRANSLATIONAL KNOWLEDGE on two prospective treatments: plasmablast depletion and administration of a protective interfering antibody.