Reversing Graft Rejection by Targeting Innate Immune Memory with Novel Nanobiologics

About This Grant

PROJECT SUMMARY A key risk factor to long-term outcomes is persistent and reoccurring early acute T cell mediated rejection (TCMR) episodes, which occur in a significant fraction of patients despite rejection treatment. Thus, a key deficit in the field is a lack of available immunomodulating therapeutics that both effectively control acute TCMR and improve long-term outcomes. Recent evidence demonstrate that at the core of acute and chronic TCMR lies innate immune memory (IMem). Our supporting data now demonstrate that monocytic allogeneic IMem (Allo-IMem) responses activates two independent pathways: mTORi and the inducible form of Heat Shock protein 70 (Hsp70i). Consequently, we hypothesize that targeting both mTOR and Hsp70i in innate immune cells will profoundly inhibit Allo-IMem responses and effectively reverse ongoing acute TCMR, significantly improving long-term allograft outcomes. Our efforts will aim at : 1) Investigating the role of Hsp70i in Allo-IMem responses and TCMR in transplantation. 2) Investigating the therapeutic efficacy of inhibiting Allo-IMem and reversing TCMR through nanobiologic targeting of both mTOR and Hsp70i pathways in innate immune cells. Overall, our project promises to identify a novel molecular target and improve therapeutic approaches to effectively control Allo-IMem and TCMR responses, thus improving clinical outcomes in transplanted patients.