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Spring 1994Volume 1, Number 1 |
An intriguing hypothesis suggests that a bidirectional cell migration in transplant recipients is the first step in the acquisition of donor- specific immunologic tolerance (Transplantation 1993;55:1272). The hypothesis was suggested by the recent observation that successful whole organ allografts mirror a state of allogeneic chimerism that results from the migration of bone marrow-derived cells present within the transplanted organs into the recipient. This ubiquitous seeding of donor dendritic and other immune cells in the recipient of any successful allograft parallels the reverse traffic of recipient cells into donor organs (Lancet 1992;339:1579) [see figure 1]. For decades it has been known that recipient cells migrate into transplanted organs and that some donor cells can leave transplanted organs and tissues. However, donor cell migration within the recipient was previously thought to induce an immune response to allogeneic or xenogeneic tissues, and therefore to relate more to rejection than graft acceptance. Chimerism was considered a transitory phenomenon in which donor cells persisted in the recipient organs (eg, spleen) for only a few months following transplantation.
Figure 1. Following organ transplantation, it was first discovered (1969) that recipient cells migrate into donor organs (the liver graft becomes a chimera), and it was later (1992) proved that systemic chimerism occurs as a result of a two-way traffic. Modified from Starzl et al. Hepatology 1993;17:1127-1152.
Recent findings by Starzl and colleagues clearly demonstrate that donor cells in the recipients of successful kidney and liver allografts can persist for decades. The high content of bone marrow-derived cells in the liver might explain "hepatic tolerogenicity," — why a liver transplant is more readily accepted than other organs, and why donor livers enhance the survival of other organs and tissues transplanted from the same donor. If the presence of significant numbers of donor bone marrow-derived cells in the liver accounts for the immunological advantage of this organ, other organs containing fewer bone marrow-derived cells may have a similar tolerogenic potential, although at a lower level (Immunology Today 1993; 14:326) [see figure 2].
Figure 2. The presence of significant numbers of donor bone marrow-derived cells in the liver may account for the immunological advantage of the liver. Other organs that contain fewer bone marrow-derived cells may still retain a tolerogenic potential, but at a lower level. Modified from Starzl et al. Hepatology 1993;17:1127-1152.
The two-way traffic following successful organ allografts and xenografts justifies the strategy of infusion of donor-specific bone marrow-derived cells to enhance allograft and xenograft survival. In fact, since the pioneering experiments of Billingham, Brent, and Medawar demonstrating donor-specific tolerance following infusion of donor lymphoid cells, several attempts have been made to achieve a similar effect in immunocompetent adult recipients. Dr. Anthony Monaco first performed a combined bone marrow/kidney allograft two decades ago, and the results were presented at the first meeting of the American Society of Transplant Surgeons in 1975. Several attempts to enhance graft acceptance by donor-specific transfusion have followed, including, most recently, extensive clinical trials of bone marrow/kidney transplantation by Dr. Henry Barber at the University of Alabama. Clinical trials are in progress to determine the role of cell migration in graft acceptance and to define the critical factors for tolerance induction. If graft acceptance can be induced by donor bone marrow cell infusion, a significant new application for bone marrow transplantation will evolve.
Several issues require further elaboration, including the best way to induce the chimeric state, whether a certain threshold or degree of chimerism is necessary for tolerance, and what qualitative and quantitative characteristics of infused bone marrow are required to obtain tolerance. In fact, not all cell types may be necessary to induce graft acceptance, and a bone marrow component approach may ultimately become the ideal tolerogenic treatment. Other variables to be defined include the ideal induction treatment and the most appropriate tests to determine when graft acceptance and tolerance are achieved, allowing discontinuation of immunosuppressive treatment. In addition to organ transplantation, application of the cell migration concept may increase the indications for tissue and cell transplant procedures (ie, islet cell transplantation in diabetes) that are currently limited by the risks associated with immunosuppressive therapy.
Camillo Ricordi, MD
University of Miami School of Medicine
Miami, Florida
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