Pig kidney transplantation in baboons treated intravenously with a bovine serum albumin-Galalpha1-3Gal conjugate

The maintenance of depletion of antibody (Ab) reactive with Galalpha1-3Gal (Gal) on pig vascular endothelial cells by the intravenous (i.v.) infusion of a synthetic Gal conjugate has been proposed as a means of delaying Ab-mediated rejection of transplanted pig organs in primates. We have therefore studied the effect of the continuous i.v. infusion of bovine serum albumin conjugated to multiple synthetic Gal type 6 oligosaccharides (BSA-Gal) on anti-Gal Ab levels and on graft survival in baboons undergoing pig kidney transplantation. Group 1 baboons (n=3) underwent extracorporeal immunoadsorption of anti-Gal Ab, a cyclophosphamide (CPP)-based immunosuppressive regimen, and a non-transgenic pig kidney transplant. Group 2 (n=2) were treated identically to Group 1 but, in addition, received a continuous i.v. infusion of BSA-Gal. Group 3 (n=2) were treated identically to Group 2, but without CPP. A single baboon (Group 4) underwent extracorporeal immunoadsorption, a CPP-based regimen, and continuous i.v. BSA-Gal therapy for 28 days, but did not receive a pig kidney transplant. Two of the transplanted pig kidneys in Group 1 were excised on post transplant days 7 and 13 for a rejected ureter, and disseminated intravascular coagulation (DIC), respectively. The third baboon died of sepsis on day 6. All transplanted ureters and kidneys showed some histopathologic features of acute humoral xenograft rejection. Group 2 baboons were euthanized on days 8 and 11, respectively, for liver failure. At autopsy, there were histopathological features of widespread liver necrosis, but the pig kidneys and ureters showed no features of rejection. The pig kidneys in Group 3 baboons were excised for renal vein thrombosis (day 9) and DIC (day 12); there was no histological signs of rejection in the pig kidneys or ureter, although there were focal areas of modest liver injury in one baboon on biopsy. The single Group 4 baboon showed no biochemical or histological features of liver injury. Anti-Gal Ab levels returned in Group 1, but were maintained at negligible levels in the baboons in Groups 2 to 4 that received BSA-Gal therapy. Continuous i.v. therapy with BSA-Gal is largely successful in maintaining depletion of circulating anti-Gal antibodies and in preventing or delaying Ab deposition and acute humoral xenograft rejection in porcine grafts, but may be associated with liver injury when administered in the presence of a pig kidney transplant and CPP therapy. The mechanism of the hepatic injury remains uncertain

Correlation of biochemical and hematological changes with graft failure following pig heart and kidney transplantation in baboons

We have explored biochemical and hematologic parameters that might indicate acute humoral xenograft rejection (AHXR) following pig organ transplantation in baboons. Baboons (n = 15) received an immunosuppressive regimen, and underwent a miniature swine or hDAF kidney (Group 1, n = 6) or heart (Group 2, n = 7) transplantation. Control baboons (Group 3, n = 2) received the immunosuppressive regimen without organ transplantation. Blood chemistry and hematologic parameters were measured daily. Baboon and porcine cytomegalovirus were monitored. In Groups 1 and 2, organ grafts survived for up to 29 days. A plasma fibrinogen of 600 U/L and aspartate transaminase of >300 U/L, were associated with the development of AHXR in both heart and kidney grafts. In Group 1, a decrease in platelet count of >150,000/microL within 3 days, or a count of 500 U/L was associated with graft failure. In Group 3, no abnormalities were observed. The possibility that porcine CMV may play a role in graft injury could not be excluded. Noninvasive parameters were identified that have predictive potential for AHXR. Monitoring of these might enable therapeutic intervention to reverse rejection