Targeted Nanotherapy to Donor Organ Endothelia Modulates Early Immune Responses and Protects Against Late Graft Failure

ABSTRACT Transplantation is an accepted and highly successful therapy for end stage organ diseaseWhile success rates and survival have risen steadilydue largely to improved immunosuppression regimesthere is a growing appreciation that damage and inflammation that occur early in the life of the graftsignificantly impact chronic rejection and thus long term survivalCentral to these early event injuries is the activation of donor endothelial cellsECsthatupon reperfusionpromote inflammationcytokine releaseand priming and proliferation of graft infiltrating memory T cellsModulation of the endothelium prior to transplantation may reduce early graft injury and chronic rejectionIn an EC T cell co culture systemEC pre treatment with the immunosuppressive drugrapamycinresults in reduced EC activationreduced alloreactive memory T cell activationand further skews the T cell response to a graft protective regulatory T cell phenotypeall factors that would protect the organ from chronic rejectionIn this proposalwe optimize a means to effectively deliver rapamycin to the donor organ endothelium prior to transplantation in a clinically relevant paradigmWeToleRaM NanotechLLCwww toleramnano comhave designeddevelopedand characterized a novel EC targeted drug delivery vehiclereferred to as Targeted Rapamycin MicelleTRaMthat we have shown improves cellular and graft penetrationWe hypothesize that organ pre treatment with Targeted Rapamycin Micelle will improve rapamycin uptakehalf lifeand significantly impair EC activationcytokine releaseand T cell co stimulationthereby reducing early graft injury to protect against the development of chronic rejection Project Narrative While organ transplantation is effectivethe overall success of the transplantation is adversely affected by the quality of the donor organ and the prevalence and proliferation of memory T cells which are unresponsive to conventional immunosuppressive regimesHerewe propose to utilize a novel bioengineered therapeutic delivery system to pretreat donor organsspecifically the donor endotheliumwith rapamycin to reduce endothelial activation and endothelial T cell co stimulatory activity to optimize transplantation outcome