Solid organ and vascularized composite allotransplantation have distinct requirements for localized delivery of <i>enhanced costimulation blockade</i>to control rejection

Abstract We recently demonstrated, in a mouse heart transplant model, the therapeutic effect of Enhanced Costimulation Blockade: transient combination CTLA4-Ig with JAK inhibitor Tofacitinib (Tofa). In same we also proved efficacy graft-localized delivery by means Tofa releasing hydrogel (Tofa-Hydro). this study, implemented orthotopic hind-limb VCA model to delineate any differential drug requirement. Moreover, explored potential Tofa-containing lipid nanoparticles (LNp) achieving selective targeting immune cells and its effect. Local injections Tofa-Hydro combined promoted survival, although smaller benefit (MST=23 days vs CTLA4-Ig-only MST=14 days). identified LNp formulation negligible toxicity favorable encapsulation efficiency. Live animal imaging flow analysis indicated these particles have unique property accumulating draining lymphoid tissues, minimal distribution other deliver their cargo multiple cells. Four post-transplant SQ Tofa-LNp (with CTLA4-Ig) graft survival longer than (MST&amp;gt;60 Our results reveal that SOT differ topography inflammatory events contribute rejection. This novel observation suggests different activatory mechanisms allopriming two systems, they share utilization signaling pathways. Nevertheless, our study demonstrates localized actuation enhanced costimulation blockade safer regulation DOD Award # W81XWH-18-1-0789