Grant: Project Grant

Blood cancers account for 10% of total cancer death in Canada. Although hematopoietic stem cell (HSC) transplantation (HSCT) is the only cure available so far, its remains ineffective at reconstituting T lymphocytes; a subset of white blood cells critical for providing protection against cancer and pathogens. The importance of T cells combined to their slow/absent recovery post-HSCT position them as a clinical priority for the development of strategies targeting immune reconstitution. With the recent establishment of a new function for interleukin (IL)-21 in stimulating thymic function, we intend to further extend our understanding on the biology of IL-21 in the context of HSCT. More specifically, our team has previously demonstrated that IL-21 stimulates thymic progenitors resulting in immune rejuvenation of aged animals. Furthermore, IL-21 was shown to: i) accelerate T-cell development post-HSCT, ii) lead to the acquisition of anti-tumoral effects without the development of HSCT-related complications, and iii) increase the number of bone marrow (BM) progenitors. The latter observation is particularly interesting as BM progenitors represent the sole building blocks required for thymic seeding and T-cell development. This raises the question as to whether IL-21 could display superior and safer outcomes if targeted to the BM compartment. Therefore, our aims are to: i) test whether an engineered IL-21 variant targeting the BM can further improve T-cell development, ii) understand how targeting IL-21 to the BM affects the nature and migration of progenitor cells to thymic tissues, and iii) explore whether mice treated with BM-targeted IL-21 differ in their susceptibility to develop autoimmune diseases. At the end, our study will pave the path for a new line of investigation aimed at targeting molecules known for stimulating T-cell development and/or HSC proliferation to the BM in order to optimize their immune regeneration potential in subjects undergoing HSCT.