Baboon-to-human liver transplantation

Abstract

Our ability to control both the cellular and humoral components of xenograft rejection in laboratory experiments, together with an organ shortage that has placed limits on clinical transplantation services, prompted us to undertake a liver transplantation from a baboon to a 35-year-old man with B virus-associated chronic active hepatitis and human immunodeficiency virus infection. Liver replacement was performed according to conventional surgical techniques. Immunosuppression was with the FK 506-prednisone-prostaglandin regimen used routinely for hepatic allotransplantation, to which a daily non-myelotoxic dose of cyclophosphamide was added. During 70 days of survival, there was little evidence of hepatic rejection by biochemical monitoring or histopathological examination. Products of hepatic synthesis, including clotting factors, became those of the baboon liver with no obvious adverse effects. Death followed a cerebral and subarachnoid haemorrhage that was caused by an angioinvasive aspergillus infection. However, the underlying cause of death was widespread biliary sludge that formed in the biliary tree despite a seemingly satisfactory choledochojejunostomy. During life and in necropsy samples, there was evidence of the chimerism that we believe is integral to the acceptance of both xenografts and allografts. Our experience has shown the feasibility of controlling the rejection of the baboon liver xenograft in a human recipient. The biliary stasis that was the beginning of lethal infectious complications may be correctable by modifications of surgical technique. In further trials, the error of over-immunosuppression should be avoidable.

Fig 1. Clinical course after baboon liver transplant

SM, Solumedrol (methylprednisolone); PGE, prostaglandin E; Bx, biopsy; AST, aspartate aminotransferase; ALT, alanine aminotransferase; Alk Ph, alkaline phosphatase.

Fig 2. Cholangiogram on day 61

The ducts are much larger than at the time of transplantation and the sharp cut off of a major duct (arrow) was probably because of sludge found at necropsy.

Fig 3. Protein electrophoresis of normal human, baboon donor, and patient serum

C3, complement; Tf, transferrin.

Fig 4. PCR amplification of baboon-specific DNA from recipient tissues

Lane LI is the PCR product from baboon liver and contains only 1 % of PCR reaction to avoid overwhelming the other lanes. HE, heart; LU, lung; KI, kidney. LN1 and LN2, lymph nodes 1 and 2. For semiquantitation, either human (HU) or baboon DNA was serially diluted into human DNA at the indicated ratios and tested, showing a baboon DNA concentration of approximately 0·1% in most specimens. Blood (BL) was obtained 35 days post-transplantation and all other samples were taken at necropsy (day 70).

Fig 5. Histopathological studies

Upper figure: 12 days—portal tract with most severe rejection (× 100). Lower figure: 65 days—disruption of epithelium of septal bile duct with no evidence of rejection (× 400).