Scientific Abstract

Currently there are >100,000 patients who are refractory to first-line treatments for inflammatory bowel disease and even more for other self-reactive diseases. We will determine if mesenchymal stem cell (MSC) transplantation is an antigen-specific therapy for inflammatory bowel disease. The rationale driving this project is that there are natural cells in the body that are known to express peripheral tissue antigens (pTAs) and induce tolerance to self-reactive lymphocytes in vivo. We have discovered that MSCs also express these pTAs and can maintain this expression during ex vivo processing unlike other pTA-expressing cells. Since MSCs can expand rapidly and be stored for point-of-care delivery they are a practical cell type for manufacturing to clinical scale and therapeutic use. We hypothesize that the expression of self antigens by MSCs is essential for the therapeutic efficacy of cell transplants in models of autoimmune disease, and therefore may be amenable to ex vivo monitoring/optimization to create a tailored cell therapy. The objectives of this project are to evalutate the relevance of pTA expression in the immune response to MSCs, both in vitro and in vivo, and utilize these cell grafts for the treatment of an antigen-specific model of intestinal autoimmunity. Our approach is innovative for several reasons: (i) the discovery that MSCs express pTAs has never been considered or described and is the primary focus of this proposal; (ii) cellular/molecular imaging of MSCs at the mesoscopic and microscopic scale in immunological disease has never been performed; (iii) we have created an antigen-specific system, whereby MSCs expressing a unique antigen driven by a pTA promoter will be used to test whether MSCs can prevent autoimmune attack targeted at this antigen; and (iv) extensive follow-up of cell grafts will be performed to assess maldifferentiation and cancerous growth, which has yet to be studied in the context of MSC transplants in IBD. The long-term goal is to evaluate this use of a unique form of antigen presentation by MSCs as a therapeutic mode of action and essentially create a new drug class based on antigen-specific stem cell grafts.