Organ transplantation is a lifesaving option for those with end stage renal disease. In spite of many improvements in organ procurement, transplant procedures and immune suppression, the damage done by ischemia-reperfusion injury (IRI) remains problematic, leading to primary graft nonfunctional, delayed graft function and graft failure. The critical shortage of donor kidneys has increased the use of expanded criteria organs (ECD) and donation after cardiac death (DCD) organs that are even more susceptible to IRI damage. Thus reducing IRI will not only improve the success rate of standard criteria (SCD) organs, but may also allow greater use of ECD and DCD organs, thus increasing the number of transplants that can be performed and lives that can be saved. Enhanced nitric oxide (NO) signaling can benefit preservation of kidneys during transport and alleviate IRI upon transplantation. However, the founders of Vasculox discovered that thrombospondin-1 (TSP1) binding to its receptor, CD47, limits NO signaling throughout the vascular system thereby worsening IRI. Blocking the TSP1-CD47 system with anti-CD47 monoclonal antibodies (CD47mAbs) dramatically improves outcomes in models of kidney, liver, brain, hindlimb and soft tissue IRI. In our Phase I grant period, we have shown that treatment of harvested rat kidneys with CD47mAbs prior to 6 hr. of cold ischemia provides substantial protection against histological damage and improves markers of both kidney damage and function. Most significantly, treatment of donor kidneys with a CD47mAb also enhances survival of the recipient. Vasculox has successfully humanized a CD47mAb (CD47humAb) for use in transplantation that has the unique property of binding to many species including rodent, pig and human. Here we will to test the CD47humAb in both small (rat) and large (pig) animal models of kidney transplantation.
Our specific aims are:
Aim 1. Rat kidney SCD and DCD transplants. 1A. Determine in a syngeneic transplant model if kidneys subjected to warm ischemic times to mimic DCD kidneys can be rescued by treating the donor kidney and/or recipient with CD47humAb. 1B. Test the efficacy of the CD47humAb in an allogeneic (Brown Norway to Lewis) rat kidney transplant model with the use of an immunosuppressive drug (tacrolimus) under SCD and DCD conditions to mimic the mismatch that occurs with human donors/recipients.
Aim 2. Porcine kidney DCD transplants. Determine if CD47humAb therapy can improve the performance of kidneys subjected to a period of warm ischemia to mimic the transplantation of marginal DCD kidneys. Dr. Douglass Hanto, who developed this model in pigs, is our consultant for this study. Following his protocol, we will introduce a 60 minute warm ischemic time prior to harvest and cold storage to mimic human DCD kidney transplantation. This will establish proof of concept for CD47humAb treatment in a large animal model for the use of marginal organs that are more susceptible to IRI and therefore worse transplant outcomes.
The founders of Vasculox, Inc. have discovered a regulatory receptor, CD47 that inhibits nitric oxide signaling in all vascular tissues. Nitric oxide provides many beneficial effects in the vascular system, including limiting ischemia-reperfusion injury that occurs during organ transplantation. Therefore, blocking CD47 and preventing nitric oxide inhibition improves ischemia-reperfusion injury and holds promise as a means to improve the condition of organs destined for transplant and to control the damage to the recipient caused by ischemia-reperfusion injury. Vasculox has developed a humanized monoclonal antibody that targets CD47 and in this project aims to test the efficacy of such an antibody in animal models of kidney transplantation that reflect the situation of the human transplant patient. This will advance our humanized CD47mAb toward our goal of FDA approval for kidney transplantation thereby improving outcomes for all transplant recipients and allowing the use of marginal kidneys thereby expanding the number of organs available for transplantation and the number of lives that can be saved.