Acute vascular rejection is associated with systemic complement activation ina pig‐to‐primate kidney xenograft model

Abstract

The introduction of h-DAF transgenic porcine organs into pre-clinical pig-to-primate discordant xenotransplantation has led to complete and reliable abrogation of hyperacute xenograft rejection (HAR). Despite additional heavy immunosuppression however, most xenografts are still lost due to acute vascular rejection (AVR), with current treatment protocols being of only limited value. In a life-supporting model of pig-to-primate kidney transplantation, unmodified (n=8) or h-DAF-transgenic (n=9) porcine kidneys were transplanted into cynomolgus monkeys under cyclophosphamide (CyP), cyclosporine and low-dose steroid immunosuppression. Longest recipient survival was 11 days in the control group and 68 days in the h-DAF transgenic group. Stable initial graft function with recipient survival >4 days was generated in eight animals (two controls and six transgenics). In these animals, plasma complement levels were analyzed during ongoing AVR. Compared with baseline levels, a two-fold increase in C3a levels and a four-fold increase in sC5b-9 levels were measured. In parallel to systemic complement activation, increased deposition of C3 and C5b-9 along with massive staining for recipient IgM immunoglobulins was detected in the xenografts on immunohistochemistry. We conclude that acute vascular xenograft rejection of porcine kidneys in cynomolgus monkeys is associated with classical pathway complement activation following binding of induced recipient anti-porcine antibodies. This complement activation can be observed despite membrane bound expression of human complement regulators in the porcine xenografts. Therefore, additional short-term fluid phase complement inhibition seems necessary for the future development of protocols designed for treatment of AVR in the pig-to-primate combination.

Analysis of pig-to-human porcine endogenous retrovirus transmission in a triple-species kidney xenotransplantation model

“…A ''life supporting'' situation was created by ligating the recipient native ureters [25]. We replaced the porcine vena renalis by an interposition graft constructed from human vena saphena (Fig.…”

Monocyte Adhesion to Xenogeneic Endothelium during Laminar Flow Is Dependent on α-Gal-Mediated Monocyte Activation

“…Delayed xenograft rejection (DXR) 3 is an intermediate form of graft rejection characterized by overwhelming monocyte and NK cell infiltration, Ab deposition along the endothelium, endothelial cell activation, thrombosis, and eventually graft loss (1,2). Many components of the innate and acquired immune systems, including xenoreactive Abs, complement, coagulation factors, monocytes, and NK cells, can act independently or in concert to effect xenograft damage, but the mechanisms that initiate DXR are poorly understood (3)(4)(5)(6)(7)(8). Since DXR represents the most important immunological hurdle preventing routine use of xenografts for the treatment of end-organ failure, additional studies are necessary to elucidate the mechanisms underlying DXR.…”

Application of cyclophosphamide-induced tolerance in α1,3-galactosyltransferase knockout mice presensitized with Galα1-3Galβ-4-GlcNAc antigens

“…Donor organs from the pig transgenic for human CRPs, [26][27][28][29] or from the GalT KO pig, 30 have proven effective in preventing HAR. Acute vascular rejection/ delayed xenograft rejection (AVR/DXR) is another potent mechanism in xenogeneic organ transplantation.…”