Anthony J. Demetris

A panel of recognized experts in liver transplantation pathology, hepatology, and surgery was convened for the purpose of developing a consensus document for the grading of acute liver allograft rejection that is scientifically correct, simple, and reproducible and clinically useful. Over a period of 6 months pertinent issues were discussed via electronic communication media and a consensus conference was held in Banff, Canada in the summer of 1995. Based on previously published data and the combined experience of the group, the panel agreed on a common nomenclature and a set of histopathological criteria for the grading of acute liver allograft rejection, and a preferred method of reporting. Adoption of this internationally accepted, common grading system by scientific journals will minimize the problems associated with the use of multiple different local systems. Modifications of this working document to incorporate chronic rejection are expected in the future.

The enzyme alpha1,3-galactosyltransferase (alpha1,3GT or GGTA1) synthesizes alpha1,3-galactose (alpha1,3Gal) epitopes (Galalpha1,3Galbeta1,4GlcNAc-R), which are the major xenoantigens causing hyperacute rejection in pig-to-human xenotransplantation. Complete removal of alpha1,3Gal from pig organs is the critical step toward the success of xenotransplantation. We reported earlier the targeted disruption of one allele of the alpha1,3GT gene in cloned pigs. A selection procedure based on a bacterial toxin was used to select for cells in which the second allele of the gene was knocked out. Sequencing analysis demonstrated that knockout of the second allele of the alpha1,3GT gene was caused by a T-to-G single point mutation at the second base of exon 9, which resulted in inactivation of the alpha1,3GT protein. Four healthy alpha1,3GT double-knockout female piglets were produced by three consecutive rounds of cloning. The piglets carrying a point mutation in the alpha1,3GT gene hold significant value, as they would allow production of alpha1,3Gal-deficient pigs free of antibiotic-resistance genes and thus have the potential to make a safer product for human use.

Improvements in the prevention or control of rejection of the kidney and liver have been largely interchangeable (1, 2) and then applicable, with very little modification, to thoracic and other organs. However, the mechanism by which anti rejection treatment permits any of these grafts to be "accepted" has been an immunological enigma (3, 4). We have proposed recently that the exchange of migratory leukocytes between the transplant and the recipient with consequent long-term cellular chimerism in both is the basis for acceptance of all whole-organ allografts and xenografts (5). Although such chimerism was demonstrated only a few months ago, the observations have increased our insight into transplantation immunology and have encouraged the development of alternative therapeutic strategies (6).

Polyomavirus type BK (BK virus) is a nonenveloped virus with circular, double-stranded DNA that has 70 percent homology with simian virus 40. It was first recognized as a member of the polyomavirus family in 1971, after isolation from the urine of a renal-transplant recipient with ureteral stenosis.1,2 Subsequent studies documented a worldwide rate of seroprevalence in adults of 60 to 80 percent, with first infections usually occurring in childhood by the respiratory route, followed by latency of the virus in the urogenital tract. Among renal-transplant recipients who are receiving immunosuppressive therapy, 10 to 60 percent have reactivation of polyomavirus . . .