Perfusion-based renal allograft modification to attenuate ischemia/reperfusion injury

Baylor University, Waco TX

Investigators

Abstract

Project Summary/Abstract Perfusion-based renal allograft modification to attenuate ischemia/reperfusion injury Reducing the timing and dose of systemic immunosuppression in transplant patients is an important clinical need. Pre-transplant ex vivo organ perfusion provides a unique opportunity for the chemical modification of allograft surfaces to facilitate engraftment and reduce inflammation and immunogenicity following transplantation. In our published and preliminary studies, we have used covalent modifications to deliver potent therapeutics to donor graft in murine islet and renal transplant models. Additionally, recent preliminary data supports that the covalent modification of renal tissue by ex vivo perfusion is well-tolerated (with no adverse impact on renal function observed) and durable (with intact modifications observed at 35 days post-transplant). The long-term objective of this research is to test the potency and safety of this novel strategy for localized drug delivery in transplantation. The proposed studies will explore the preparation and targeted and sustained delivery of an integrin inhibitor, immobilized via pre-transplant ex vivo perfusion, in a well-characterized murine model of kidney transplantation. We hypothesize that covalent kidney graft modification with a releasable small molecule integrin inhibitor prior to transplantation will decrease immune cell recruitment to the graft after reperfusion. The ameliorated tissue damage and donor antigen release will translate into reduced anti-donor adaptive immune responses and improved transplant outcome without impairing systemic protective immunity. Specific Aim 1. To test the efficacy and safety of renal graft modification with small molecule integrin inhibitor for the modulation of ischemia reperfusion injury and the improvement of transplant survival and function. This will be achieved in following steps: 1.a. To evaluate drug delivery by, and in vivo effects of, the ex vivo covalent modification of renal tissue. 1.b. To determine the effects of renal graft chemical modification with small molecule LFA-1 inhibitors on the extent of ischemia/reperfusion injury (IRI) and subsequent local and systemic alloimmune responses. 1.c. To test the effects of local vs systemic LFA-1 inhibition on protective immune responses. 1.d. To test the efficacy of donor graft chemical modification with LFA-1 inhibitor in prolonging renal allograft survival in sensitized recipients. 1.e. To use the results from experiments in 1.a-d to further optimize the strategy for renal graft modification with small molecule integrin inhibitors. This high-risk, high-reward application will establish the proof of principle for pretransplant donor graft chemical modification and localized integrin inhibition and will provide a foundation for future mechanistic experiments and translational studies using large animal and human organs.