Organ transplantation is one of the great success stories of modern medicine. However, the supply of suitable organs lags far behind the need and many patients die while waitlisted for organs. While there have been many recent strides in organ procurement, preservation and follow-up immune suppression, prevention of ischemia-reperfusion injury (IRI) remains problematic. IRI occurs when the ischemic/hypoxic organ is connected to the recipient's circulation. This storm of reactive oxygen species, inflammatory mediators and prothombotic factors damages the new organ and wreaks havoc upon the recipient as well. Current work indicates that enhancing the beneficial, low levels of nitric oxide (NO) produced by eNOS and nNOS can dramatically improve IRI and transplant outcomes. The founders of Vasculox have discovered a ligand-receptor system, thrombospondin-1 (TSP1) and CD47, that continually opposes the action of beneficial NO in all vascular cells. Knocking out CD47 in mice or blocking CD47 with a monoclonal antibody (mAb) results in enhanced tissue perfusion in a number of surgical ischemia models and substantial protection in models of liver and hindlimb IRI. Further, our initial studies in an ex vivo rat liver machine perfusion system support the efficacy of anti- CD47 therapy for IRI. In this phase one proposal, we seek to perform proof of concept studies in a well-characterized in vivo model of rat kidney transplantation.
In Aim 1, we will test the efficacy of anti-CD47 mAb treatment of the donor kidney during cold ischemia to protect it from IRI. Preliminary studies indicate that the anti-CD47 mAb can be administered in the cold preservation medium flush at organ harvest.
Aim 2 will determine if parenteral anti-CD47 mAb treatment of the recipient (in addition to pretreatment of the donor kidney) will further improve transplant outcomes. In both aims, readouts of kidney function (urine production, creatinine, BUN and soluble enzyme release) and cytokine levels will be monitored. Cyclic GMP levels in kidneys and plasma nitrite levels will be determined to confirm the mechanism of anti-CD47 mAb action in this model. The data obtained in this phase I project will establish proof of concept for anti-CD47 mAb therapy in kidney transplantation.
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. 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 is developing a monoclonal antibody that targets CD47 and in this project aims to test the efficacy of such an antibody in an animal model of kidney transplantation. This will provide critical proof of concept for development of a humanized anti-CD47 antibody for use in organ transplantation thereby improving the outcome for all transplant recipients and expanding the number of organs available for transplantation.
| Lin, Yiing; Manning, Pamela T; Jia, Jianluo et al. (2014) CD47 blockade reduces ischemia-reperfusion injury and improves outcomes in a rat kidney transplant model. Transplantation 98:394-401 |
