Cell migration and chimerism after whole-organ transplantation: The basis of graft acceptance

Abstract

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...

PCR-Based Methodology for Molecular Microchimerism Detection and Quantification

“…Solid organ transplants may also benefit from microchimerism detection, as demonstrated by some authors who have shown that the presence of donor circulating cells after transplantation is directly correlated to a significantly lower incidence of acute rejection (14)(15)(16)(17) or even leads to tolerance (18). Many studies based on microchimerism detection after solid organ transplantation have been published.…”

Microvascular Endothelium of Human Tumor Xenografts Expresses Mouse (= Host) CD31

“…However, it has become clear that caution must be exercised in interpret ing the results of studies based on tumor xenografts in which the vascular supply of a tumor plays a pivotal role [1], Similar to the situation in human allografts [2], xeno transplantation of vascularized tissues is followed by KARGER.…”

Liver Tolerance and the Manipulation of Immune Outcomes

“…Although Starzl and colleagues made this observation 20 years ago, the significance of this "microchimerism" [23] remains enigmatic. Starzl hypothesized that microchimerism is the result of donor T cells depleting graft-specific host T cells and donor cells eliminating graft-specific effector T cells, and that microchimerism is achieved when a balance of graft versus host and host versus graft immune responses is reached [27]. One of the major criticisms of this model is that it is still unclear whether microchimerism is the cause or result of tolerance.…”