Nontransgenic Hyperexpression of a Complement Regulator in Donor Kidney Modulates Transplant Ischemia/Reperfusion Damage, Acute Rejection, and Chronic Nephropathy

Abstract

Complement activation during ischemia and reperfusion contributes to the development of tissue injury with severe negative impact on outcomes in transplantation. To counter the effect of complement, we present a strategy to deliver a novel complement regulator stabilized on cell surfaces within donor organs. The membrane-bound complement regulator is able to inhibit complement activation when the donor organ is revascularized and exposed to host-circulating complement. Application of this construct to donor kidneys protected transplanted tissues from ischemia/reperfusion injury and reduced the deposition of activated complement and histological signs of damage under conditions in which a nontargeted control construct was ineffective. Treatment of donor organs in this way improved graft performance in the short and long term. An analysis of the immune response in allograft recipients showed that reducing graft damage at the time of transplantation through complement regulation also modulated the alloresponse. Additionally, the results of perfusion studies with human kidneys demonstrated the feasibility of targeting endothelial and epithelial surfaces with this construct, to allow investigation in clinical transplantation.

Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury

“…These epithelial cells express the central complement component C3 (18,35,36), which, when cleaved, leads to formation of the membrane attack complex C5b-9 and release of C5a (18,20). Both of these complement effectors stimulate proinflammatory responses in epithelial cells and infiltrating leucocytes and can mediate cell death (17,37,38).…”

Altered renal tubular expression of the complement inhibitor Crry permits complement activation after ischemia/reperfusion

“…Studies in complement-deficient mice have shown that these mice are protected from renal failure after ischemia/reperfusion (I/R) (1,2), and that generation of the anaphylatoxin C5a (3) and the membrane attack complex (2) may contribute to the pathogenesis of ischemic ARF. Treatment with agents that inhibit the complement cascade at specific steps during the activation cascade has proven effective at ameliorating ischemic ARF (3,4). Determining the initiating mechanisms of complement activation after renal I/R is essential to the effective use of complement inhibitors for the treatment and prevention of ischemic ARF.…”

Complement—here, there and everywhere, but what about the transplanted organ?

“…This enables the complement regulator to function locally. Previous studies have shown Mirococept to localise to endothelial and epithelial cell surfaces once infused through the renal artery in rat and human donor kidneys [118,119]. This resulted in a decrease in IR injury and less chronic vascular injury in rat donor organs.…”