Delayed graft function (DGF) is a form of acute kidney injury (AKI) resulting in post- transplantation oliguria, increased allograft immunogenicity and risk of acute rejection episodes resulting in decreased long-term survival. DGF necessitates dialysis in the first week after surgery and occurs in 20% to 50% of patients receiving a cadaver graft. DGF is usually the result of ischemic damage to the graft before or during harvesting and is further aggravated by the reperfusion syndrome, a multifactorial event in which polymorphonuclear cells play a major role. The pathogenesis of ischemic reperfusion injury (IRI) during transplantation involves a complex interaction between altered microcirculatory hemodynamics, endothelial and epithelial cells, and infiltration of immune cells. Dendritic cells (DCs) play a central role in activating or inhibiting innate and adaptive effectors involved in AKI. In kidney IRI model, transfer of S1pr3-/- bone marrow derived DCs (BMDCs) prior to ischemia protects mice kidneys from injury. The majority of transferred S1pr3-/- BMDCs are found in the spleen as early as 30 minutes after injection and prior splenectomy abrogates the S1pr3-/- BMDC dependent protection. In the spleen, S1pr3-/- BMDCs induce an increase in Tregs to inhibit innate immune response associated with IRI. Therefore, in transplantation, donor kidney DCs from S1pr3-/- mice will migrate out of the transplanted kidney into the receipt spleen. In the spleen, donor derived S1pr3-/- DCs will induce an increase in recipient Tregs to suppress the innate immune response to attenuate IRI associated with transplantation. Accordingly, we hypothesize that: 1) donor DC activation controls severity of AKI in kidney transplantation and 2) pharmacological modulation of donor S1P1 can protect kidneys from IRI.
In Specific aim 1 we will test the hypothesis that S1P1 receptor activation of donor DCs regulates IRI in syngeneic mouse kidney transplant.
Specific Aim 2 will test the hypothesis that treatment of the donor with FTY720 reduces IRI in syngeneic kidney transplant. This will be examined using a rodent kidney transplant model. The results of these specific aims will yield important information about the role of S1P1 on donor DCs to attenuate or prevent transplant associated DGF. These are previously unexplored questions that may reveal novel targets to prevent DGF and possibly promote recovery due to the DCs S1P1 dependent increase in recipient Tregs. The knowledge gained through this project will form the basis of independent publications and an individual R01 application by the PI.
In the immediate postoperative period in renal transplantation, delayed graft function (DGF) is the most common complication. It can affect up to 50% of the cadaveric kidney transplants and leads to prolonged hospital stays with additional invasive procedures. Complications associated with DGF lead to additional cost to the patient and further financial burden on the health-care system. Treatment strategies are limited to supportive care and new therapeutic interventions are urgently needed. Exploring therapeutic therapies to prevent or reduce ischemic injury and speed recovery from complications will allow better graft function by reducing DGF associated with transplantation.
