MANIPULATION OF REGULATORY MYELOID CELL DIFFERENTIATION AND FUNCTION AND ITS THERAPEUTIC IMPLICATIONS

Organ transplantation is the definitive treatment for end-stage organ diseases that are otherwise untreatable. Modern immunosuppressants have largely subverted acute allograft rejection through non-specific inhibition of T cell activation and proliferation; however, chronic immunosuppression with current therapies carries increased risks of malignancy, infection and drug-associated toxicities. Furthermore, rates of long-term graft failure, mediated at least in part by chronic alloimmune responses, have not improved significantly. New therapies to modify the immune system and promote long-term graft survival are urgently needed. Myeloid lineage antigen-presenting cells, including dendritic cells (DC) and myeloid-derived suppressor cells (MDSC), are innate immune cells that regulate antigen-specific immunity and are valuable targets to promote immune modulation. In this dissertation, I present data on three pathways that can be modulated to promote expansion and immunosuppressive function of MDSC or downregulate DC immunostimulatory function. Histone deacetylase inhibitors (HDACi) are anti-neoplastic agents that promote tumor cell growth arrest and apoptosis. Recent findings describe novel anti-inflammatory properties. The data presented demonstrate that HDACi promote GM-CSF-mediated MDSC expansion, while impeding DC differentiation and co-stimulatory molecule expression. In addition to modulation of the GM-CSF pathway, new data presented in this thesis demonstrate that the DC-poietin Flt3 ligand (Flt3L) also promotes expansion and activation of MDSC capable of delaying allograft rejection when transferred to heart transplant recipients. STAT3 is a pivotal regulator of Flt3L-driven myeloid cell expansion as STAT3 inhibition blocks expansion of immunostimulatory DC but further promotes MDSC expansion, without altering their suppressive capacity. Lastly, the immunoregulatory role of newly-described rapamycin-resistant outputs of the mammalian/mechanistic Target of Rapamycin (mTOR) in DC was examined. A novel mTOR signaling pathway that negatively regulates DC expression of anti-inflammatory IL-10 and B7-H1 is described. In summary, these data describe growth factor and signaling pathways that can be manipulated for the promotion of MDSC expansion and inhibition of DC stimulatory function. Future studies will be required to translate these findings into relevant organ transplantation models and develop their therapeutic potential. Manipulation of myeloid cell development and function is an innovative approach to immune modulation that may lead to new immunosuppressive strategies