Bone marrow stem cells develop into hematopoietic and mesenchymal lineages but have not been known to participate in production of hepatocytes, biliary cells, or oval cells during liver regeneration. Cross-sex or cross-strain bone marrow and whole liver transplantation were used to trace the origin of the repopulating liver cells. Transplanted rats were treated with 2-acetylaminofluorene, to block hepatocyte proliferation, and then hepatic injury, to induce oval cell proliferation. Markers for Y chromosome, dipeptidyl peptidase IV enzyme, and L21-6 antigen were used to identify liver cells of bone marrow origin. From these cells, a proportion of the regenerated hepatic cells were shown to be donor-derived. Thus, a stem cell associated with the bone marrow has epithelial cell lineage capability.

The chimeric nature of the transplanted liver was first shown in our long-surviving human recipients of orthotopic hepatic allografts in 1969. 1 When liver grafts were obtained from cadaveric donors of the opposite sex, karyotyping studies showed that hepatocytes and endothelium of major blood vessels retained their donor specificity, whereas the entire macrophage system, including Kuppfer cells, was replaced with recipient cells. 2 Where donor cells that had left the liver had gone was unknown, but their continued presence was confirmed by the acquisition and maintenance in recipient blood of new donor-specific immunoglobulin (Gm) types 1,3 and red-blood-cell alloantibodies, if donors with ABO non-identity were used. 4 Davies et al 5 attributed the secretion of new soluble HLA class I antigens of donor type to transplanted hepatocytes. However, these HLA molecules come from bone-marrow-derived macrophages and/or dendritic cells, 6 and probably have the same origin from migrated donor cells as the additional Gm types and red-cell antibodies.Although this early evidence of systemic mixed allogeneic chimerism was circumstantial, we have recently shown with both anatomical and molecular techniques the presence, in clinically stable patients, of peripherally located donor cells many years after liver replacement. For instance, in patients with type IV glycogen storage disease, a disorder in which an insoluble amylopectin-like polysaccharide accumulates throughout the body because of a deficiency in a branching enzyme, we found resorption of extrahepatic amylopectin after liver replacement. 7 This process could not be explained until the migrated donor cells, which had acted as enzyme couriers, were identified by both HLA monoclonal antibodies (fig 1) and polymerase chain reaction (PCR) studies (fig 2) in the biopsied myocardium and skin of 2 patients, 33 and 91 months after hepatic transplantation.Recent experiments in rats have shown the timing and extent of seeding from the hepatic allograft to both non-lymphoid and lymphoid organs (fig 3). 8 A similar pattern of distribution was found after successful rat-to-mouse bone-marrow transplantation. 9 This similarity between liver transplantation and bone-marrow transplantation has not been reported before. The prompt development, and then the persistence, of this systemic chimerism may help to explain the resistance of the liver to cellular 10 and humoral 11 rejection, as well as its tolerogenicity to other organs from the same donor. 12 The chimeric structure of the transplanted liver was thought to be a unique feature of this organ for many years until we identified lymphoid and dendritic cell replacement under FK 506 immunosuppression in rat 13 and human 14 intestinal allografts; a similar finding has been reported in swine. 15 In our experiments with rats, the two-way traffic was the same, irrespective of whether bowel was transplanted alone or as a part of a multivisceral graft that also contained Correspondence to

Survival has greatly improved over time as management strategies evolved. The current results clearly justify elevating the procedure level to that of other abdominal organs with the privilege to permanently reside in a respected place in the surgical armamentarium. Meanwhile, innovative tactics are still required to conquer long-term hazards of chronic rejection of liver-free allografts and infection of multivisceral recipients.

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). DISCOVERY OF GRAFT CHIMERISM After Liver TransplantationSuccessful transplants were long envisioned as an alien patch in a homogeneous host (Fig. 1, left). The first unequivocal evidence that whole-organ grafts in human beings become genetic composites (chimeras) was obtained in 1969 with karyotyping studies in female recipients of livers obtained from male cadaveric donors. Postoperatively, the hepatocytes and the endothelium of the major blood vessels of the grafts retained their donor sex, whereas the entire macrophage system, including the Kupffer cells, was replaced with recipient female cells (identified by their characteristic Barr bodies) within 100 days (7,8) (Fig. 1, middle). These observations attracted considerable attention at the time, primarily because of their implication that liver-based inborn errors of metabolism could be corrected permanently by liver replacement (9,10). This prediction has been met since then in nearly two dozen such heritable diseases (11). Each report of another liver-based metabolic disorder that was corrected by liver replacement added to the illusion that the composite (chimeric) structure of the hepatic allograft was a special feature of this organ.Address reprint requests to: Thomas E. Starzl, M.D., Ph.D., Department of Surgery, 3601 Fifth Avenue, 5C Falk Clinic, University of Pittsburgh, Pittsburgh, PA, 15213. NIH Public Access Author ManuscriptHepatology. Author manuscript; available in PMC 2010 October 26. Published in final edited form as:Hepatology. 1993 June ; 17(6): 1127-1152. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript After Intestinal TransplantationThe illusion of uniqueness of the hepatic graft was dispelled in 1991 with the demonstration, first in rat models (12) and then in human beings (13), that all successfully transplanted intestines also were chimeric. The epithelium of the bowel remained that of the donor, but lymphoid, dendritic and other leukocytes of recipient phenotype quickly became the dominant cells in the lamina propria, Peyer's patches and mesenteric nodes. The transformation in experimental animals and in human beings (Fig, 2) was the same whether the bowel was transplanted alone or as a part of a multivisceral gra...

SummaryBackground-Insight into the mechanisms of organ engraftment and acquired tolerance has made it possible to facilitate these mechanisms, by tailoring the timing and dosage of immunosuppression in accordance with two therapeutic principles: recipient pretreatment, and minimum use of post-transplant immunosuppression. We aimed to apply these principles in recipients of renal and extrarenal organ transplants.