Nontransgenic hyperexpression of a complement regulator in donor kidney modulates transplant ischemia/reperfusion damage, acute rejection, and chronic nephropathy.
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.
D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D004727:Endothelium / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000378:metabolism; D006084:Graft Rejection / Q000503:physiopathology / Q000517:prevention & control; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D007674:Kidney Diseases / Q000517:prevention & control; D016030:Kidney Transplantation; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D011956:Receptors, Cell Surface / Q000378:metabolism; D017463:Receptors, Complement 3b / Q000737:chemistry*; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000517:prevention & control*; D014019:Tissue Donors
D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D017463:Receptors, Complement 3b; C478157:m-pSCR1-3 protein, human