Our aim is to develop a bench-to-bedside protocol to treat autoimmune inflammatory bowel diseases (IBD) with a novel cell therapy approach using a tolerogenic, interferon-¿ stimulated, monocyte-derived, cell population (referred to as IFN¿-MdC). The concept involves the elimination and control of IBD-causing auto-reactive lymphocytes. Our early work shows this cell population has unique characteristics, and therapeutic application of the cells reduces IBD in mice. Moreover, we suggest that IFN¿-MdC have a broader therapeutic applicability to other autoimmune diseases where T regulatory cells are thought to be capable of controlling and reversing the disease state. This study will focus on three basic aims. First, experiments will be performed to better characterize the IFN¿-MdC population that we find to be effective both in vitro and in vivo. We will focus on learning which growth factors used for IFN¿-MdC generation are most critical for their immunosuppressive activities. Moreover, we will pinpoint the more exact cell type in the IFN¿-MdC mixed population that mediates their activity and determine what ¿accessory cells¿ may support their development. The goal will be to essentially create a formula for the production of optimally functioning IFN¿-MdC that would involve mixing specific proportions of different purified cell types (e.g. monocytes + CD4 cells). This is a critical step before beginning clinical studies because defining the cells and conditions used to produce IFN¿-MdC will make them therapeutically more reproducibly effective. A second aim of the study will be to determine the mechanism by which IFN¿-MdC function. We expect this is a complex mechanism, likely involving both cell surface (contact) molecules and cytokines. Finally, the third study aim will be to use IFN¿-MdC for the treatment of IBD in humans. Based on the findings in the first two aims, we will develop a clinical protocol for the treatment of Crohn¿s disease in patients. This aspect of the study will likely take place later in the funding period, but nonetheless is a realistic goal of the project. Therefore, we aim with the current proposal to better characterize, mechanistically understand, and refine the optimal clinical use of IFN¿-MdC. Successful accomplishment of the aims could yield a new treatment option for patients with certain types of autoimmune diseases, particularly IBD.
