Transplantation is an accepted and highly successful therapy for end-stage organ disease. While success rates and survival have risen steadily, due largely to improved immunosuppression regimes, there is a growing appreciation that damage and inflammation that occur early in the life of the graft, significantly impact chronic rejection and thus long-term survival. Central to these early event injuries is the activation of donor endothelial cells (ECs) that, upon reperfusion, promote inflammation, cytokine release, and priming and proliferation of graft infiltrating memory T cells. Modulation of the endothelium prior to transplantation may reduce early graft injury and chronic rejection. In an EC/T cell co-culture system, EC pre-treatment with the immunosuppressive drug, rapamycin, results in reduced EC activation, reduced allo- reactive memory T cell activation, and further skews the T cell response to a graft protective regulatory T cell phenotype ? all factors that would protect the organ from chronic rejection. In this proposal, we optimize a means to effectively deliver rapamycin to the donor organ endothelium prior to transplantation in a clinically relevant paradigm. We (ToleRaM Nanotech, LLC, www.toleramnano.com) have designed, developed, and characterized a novel EC-targeted drug delivery vehicle, referred to as Targeted Rapamycin Micelle (TRaM), that we have shown improves cellular and graft penetration. We hypothesize that organ pre-treatment with Targeted Rapamycin Micelle will improve rapamycin uptake, half-life, and significantly impair EC activation, cytokine release, and T cell co-stimulation, thereby reducing early graft injury to protect against the development of chronic rejection.
Project Terms: Affect; Allografting; amphiphilicity; Animals; Biodistribution; Biological Availability; biomaterial compatibility; Biomedical Engineering; Brain Death; Characteristics; Chronic; Clinical; clinically relevant; Coculture Techniques; conditioning; Cryopreservation; CXCL10 gene; CXCL9 gene; cytokine; Data; design; Development; Disease; Drug Delivery Systems; Drug Targeting; Drug usage; Encapsulated; End stage renal failure; Endothelial Cells; Endothelium; Event; Exposure to; Family suidae; Formulation; Future; Goals; graft failure; graft healing; Graft Survival; Grant; Half-Life; Harvest; Homocysteine; Hour; Human; Hydrophobicity; Immune response; Immune system; Immunologics; Immunosuppression; Immunosuppressive Agents; Impairment; improved; In Vitro; in vivo; in vivo Model; Inflammation; Injury; innate immune function; Integrins; Kidney; Kidney Transplantation; Life; Long-Term Effects; Maintenance; Measures; Memory; Metabolic; Methods; Micelles; Modeling; mTOR Inhibitor; Mus; Nanotechnology; nanotherapy; novel; Organ; Organ Donor; Organ Transplantation; Outcome; Penetration; Pharmaceutical Preparations; Phase; phase 2 study; Phenotype; Phospholipids; Polymers; pre-clinical; pre-rapamycin; preservation; Prevalence; Production; Proliferating; Pulsatile Flow; recruit; Regional Perfusion; Regulatory T-Lymphocyte; Reperfusion Injury; Reperfusion Therapy; Resistance; RNA Interference; SCID Beige Mouse; Series; Severities; Sirolimus; Small Business Technology Transfer Research; success; System; T cell response; T memory cell; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Therapeutic; therapy design; Time; transplant model; Transplantation; Treatment Efficacy; treatment strategy; University of Wisconsin-lactobionate solution; uptake; Warm Ischemia;
