Chimerism and tolerance in transplantation

Abstract

Studies in experimental models (1953-1956) demonstrated that acquired donor-specific allotolerance in immunologically immature or irradiated animals is strongly associated with donor leukocyte chimerism. Bone marrow transplantation in immune-deficient or cytoablated human recipients was a logical extension (1968). In contrast, clinical (1959) and then experimental organ transplantation was systematically accomplished in the apparent absence of leukocyte chimerism. Consequently, it was assumed for many years that success with organ and bone marrow transplantation involved fundamentally different mechanisms. With the discovery in 1992 of small numbers of donor leukocytes in the tissues or blood of long-surviving organ recipients (microchimerism), we concluded that organ engraftment was a form of leukocyte chimerism-dependent partial tolerance. In this initially controversial paradigm, alloengraftment after both kinds of transplantation is the product of a double immune reaction in which responses, each to the other, of coexisting donor and recipient immune systems results in variable reciprocal clonal exhaustion, followed by peripheral clonal deletion. It was proposed with Rolf Zinkernagel that the individual alloresponses are the equivalent of the MHC-restricted T cell recognition of, and host response to, intracellular parasites and that the mechanisms of immune responsiveness, or nonresponsiveness, are governed by the migration and localization of the respective antigens. Elucidation of the mechanisms of nonresponsiveness (clonal exhaustion-deletion and immune ignorance) and their regulation removed much of the historical mystique of transplantation. The insight was then applied to improve the timing and dosage of immunosuppression of current human transplant recipients.

Fig. 1.

Nine (19%) of the 46 live donor kidney recipients treated at the University of Colorado over an 18-month period beginning in the autumn of 1962. The filled portion of the horizontal bars depicts the time off immunosuppression. Note that the current serum creatinine concentration (CR) is normal in all but one patient. * indicates murdered; kidney allograft was normal at autopsy.

Fig. 2.

Patient survival. The three eras of orthotopic liver transplantation at the universities of Colorado (1963–1980) and Pittsburgh (1981–1993), defined by azathioprine (AZA)-, cyclosporine (CYA)-, and tacrolimus (TAC)-based immune suppression. Stepwise improvements associated with the advent of these drugs also were made with other kinds of organs.

Fig. 3.

Old (A and B) and new (C and D) views of transplantation recipients. (A) The early conceptualization of immune mechanisms in organ transplantation in terms of a unidirectional host versus graft (HVG) response. Although this readily explained organ rejection, it limited possible explanations of organ engraftment. (B) Mirror image of A, depicting the early understanding of successful bone marrow transplantation as a complete replacement of the recipient immune system by that of the donor, with the potential complication of an unopposed lethal unidirectional GVH response, i.e., rejection of the recipient by the graft. (C) Our current view of bidirectional and reciprocally modulating immune responses of coexisting immune competent cell populations. Because of variable reciprocal induction of deletional tolerance, organ engraftment was feasible despite a usually dominant HVG reaction. The bone silhouette in the graft represents passenger leukocytes of bone marrow origin. (D) Our currently conceived mirror image of C after successful bone marrow transplantation. Recipients' cytoablation has caused a reversal of the size proportions of the donor and recipient populations of immune cells.

Fig. 4.

Contemporaneous HVG (upright curves) and GVH (inverted curves) responses after organ transplantation. If some degree of reciprocal clonal exhaustion is not induced and maintained (usually requiring protective immune suppression), one cell population will destroy the other. In contrast to the usually dominant HVG reaction of organ transplantation (shown here), the GVH reaction usually is dominant in the cytoablated bone marrow recipient. Therapeutic failure with either type of transplantation implies the inability to control one, the other, or both of the responses.

Fig. 5.

The reciprocal tolerance induction of the two immune competent cell populations during the first 60 days of passenger leukocyte migration that explains the nonessential role of HLA matching in organ transplantation. Cytoablation of the human bone marrow recipient (e.g., with supralethal irradiation) removes the host arm of the immune interaction, leaving the patient dependent on HLA matching for avoidance of GVHD. The nullification effect of the coexisting donor and recipient cells also explains why lymphoid-rich organs seldom cause GVHD.

Fig. 6.

The routes taken by passenger leukocytes of transplanted organs and infused donor bone marrow cells. The migration is selective at first to host lymphoid organs, but after 15–60 days, surviving leukocytes move secondarily to nonlymphoid sites. With establishment of reverse traffic (nonlymphoid to lymphoid locations), the exhaustion-deletion induced at the outset can be maintained (see text).

Fig. 7.

The role of immunosuppression in deletional tolerance. (A) Spontaneous tolerance (thin line) rather than rejection (thick arrow) may develop in the absence of immunosuppression if the unmodified recipient response is too weak to eliminate the migratory donor cells. (B) The pretreatment principle. Recipient immune responsiveness is reduced into the deletable range by cytoablation or cytoreduction before arrival of the alloantigen. (C) The minimal immunosuppression principle. The recipient response is kept in the deletable range with immunosuppression (black bar) after transplantation. (D) The antitolerogenic effect of overimmunosuppression (multilayered bars) after arrival of the allograft, with variable prevention of clonal exhaustion-deletion (see text). Horizontal axis, time. Tx, transplantation

Fig. 8.

Principles of tolerogenic immunosuppression (Fig. 7 B and C) that can be jointly applied under most circumstances of clinical transplantation to convert rejection (thick dashed arrow) to a response that can be exhausted and deleted.

Fig. 9.

Course of a cadaver kidney recipient in July 2001, after pretreatment with 5 mg/kg ALG. Biopsy-proven rejection in the third week was treated with infusions of 1.0 and 0.5 g of prednisone. Daily tacrolimus (Tac.) (fully shaded area) was begun on the day after operation and spaced to every other day or longer intervals after 6 ½ months. ○ indicates trough levels of tacrolimus. Treatment has been with one dose per week for almost 2 years.