Targeted delivery of immunosuppressive agents to the graft endothelium for the prevention of rejection in lung transplantation

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Project Abstract Lung transplantation (LTx) remains the only available treatment for patients with end-stage pulmonary disease. Yet, outcomes after LTx are worse compared to the transplant of other solid organs (SOT). Immunosuppressive regimes used in LTx have been derived from experiences with other SOTs. Yet, such a strategy may be flawed, as recent data has demonstrated clear differences in the immune responses in the lung. Unlike other SOTs where initiation of rejection depends on cell trafficking to graft-draining lymphoid organs, in the lung lymphocyte priming occurs in the lung graft itself. There is thus an urgent need to develop novel approaches to improve LTx survival. As most lungs transplanted into recipients are harvested from brain dead (BD) donors, there are important biological consequences that must be considered, particularly the massive inflammatory activity and cytokine release, which results in the activation of a panoply of cell types. This includes the upregulation of cellular adhesion molecules (CAM), in particular VCAM-1 and ICAM-1, priming the graft for rejection. Ischemia- reperfusion injury caused by the transplant procedure has the potential to drive this CAM activation higher. We thus propose to investigate a novel bi-functional approach to the prevention of LTX rejection, focused on the development of nanoagents with the potential to block CAM-based priming of the graft concomitant with the delivery of immunosuppressives. Specifically, we will: 1) Identify peptides capable of binding ICAM-1 or VCAM- 1 with the ability to suppress immune cell trafficking and T cell priming; and 2) Investigate advanced bi-functional nanoagents designed to localize to the lung and inhibit rejection. The overall goal is the validation of a novel targeted therapeutic regime with the potential to obviate the need for systemic immunosuppression.