Porcine Cytomegalovirus Infection Is Associated With Early Rejection of Kidney Grafts in a Pig to Baboon Xenotransplantation Model

Abstract

Background Recent survivals of our pig-to-baboon kidney xenotransplants have been markedly shorter than the graft survivals we previously reported. The discovery of high levels of porcine CMV (pCMV) in one of the rejected xenografts led us to evaluate whether this reduction in graft survival might be due to the inadvertent introduction of pCMV into our GalT-KO swine herd. Methods Archived frozen sections of xeno-kidney grafts over the past 10 years were analyzed for the presence of pCMV, using real-time PCR. Three prospective pig-to-baboon renal transplants using kidneys from swine delivered by caesarian section (C-section) and raised in isolation were likewise analyzed. Results Kidney grafts from which 8 of the 18 archived samples were derived were found to be pCMV-negative, had a mean graft survival of 48.3 days and were from transplants performed before 2008. None had shown signs of DIC and were lost due to either proteinuria or infectious complications. In contrast, 10 of the archived samples were pCMV positive, were from kidney transplants with a mean graft survival of 14.1 days, had been performed after 2008 and had demonstrated early vascular changes and decreased platelet counts. Three prospective xenografts from swine delivered by C-section were pCMV negative and survived an average of 53.0 days. Conclusions Decreased survivals of GalT-KO renal xenografts in this laboratory correlate temporally with latent pCMV in the donor animals and pCMV in the rejected xeno-kidneys. Transmission of pCMV to swine offspring may be avoided by C-section delivery and scrupulous isolation of donor animals.

A Bridge to Somewhere

“…Latent transmission of pCMV has been associated with both decreased survival (average 13.7 days versus 53.2 days) and upregulation in endothelial cell activation after pig-to-baboon kidney xenotransplantation. 4 Modifications to avoid pCMV transmission, including sterile cesarean derivation and high-efficiency particulate absorption cage housing allowed for our miniature swine donor to remain pCMV-negative on the day of transplant. (3) The addition of belatacept costimulation blockade: In a pig-to-primate kidney xenotransplantation model, low anti-pig antibody titer recipients receiving belatacept demonstrated increased survival (21 days versus 6 days) when compared with primate recipients of a similar regimen without the use of belatacept.…”

Recent Progress in Xenotransplantation, with Emphasis on Virological Safety

“…Second, microbiological characterization of the donor pigs has, in the past, not been sufficiently thorough, and as a result, pig to non-human primate transplantations have been performed that resulted in the transmission of pathogenic microorganisms and the premature death of the recipients. For example, the transmission of PCMV to cynomolgus monkeys and baboons, significantly reducing survival time, has been reported [62,63]. Additional financial support and scientific investigations have to be devoted to studies of viral safety, the results of which should automatically contribute to increasing the survival times of xenotransplants and their recipients.…”

“…HCMV infections are in many cases fatal for immunosuppressed allotransplant recipients [71]. Although PCMV is more closely related to HHV-6 and HHV-7 than to HCMV, designated now as HHV-5 [72], it has been shown that transmission of PCMV in pig to non-human primate kidney transplantation drastically reduced the survival time of the recipients [62,63], suggesting that PCMV may have a similar effect in humans. PLHV-1, -2, and -3 were found in large numbers on farm pigs (in 78%, 41%, and 59% of the lung tissue samples, and in 59%, 26% and 62% of the spleen samples, respectively [73]).…”

“…In contrast to PERVs, transmission of herpesviruses has been observed in experimental xenotransplantations, e.g., porcine cytomegalovirus (PCMV) from pig to cynomolgus monkeys [62] and baboons [63]. Transmission of a baboon cytomegalovirus (BCMV) after transplantation of baboon tissues to human recipients was also described [64].…”

Virus safety of islet cell transplantation from transgenic pigs to marmosets

“…Presently, there is no experience with the elimination of these viruses from infected herds. Importantly and in addition to safety issues, transmission of PCMV together with the transplant from pigs to non-human primates significantly reduced the survival time of a pig xenotransplant in the recipients Yamada et al, 2014).…”