Transplantation tolerance from a historical perspective

Abstract

Although transplantation immunology as a distinctive field began with the development of experimental models that showed the feasibility of bone marrow transplantation, organ engraftment was accomplished first in humans, and was thought for many years to occur by drastically different mechanisms. Here, we present our view of the concepts of allograft acceptance and acquired tolerance from a historical perspective, and attempt to amalgamate them into simple and unifying rules that might guide improvements in clinical therapy.

Figure 1. Old and new views of transplantation immunology

a | Illustrates 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 | A mirror image of (a) and depicts the early understanding of successful bone marrow (BM) transplantation as a complete replacement of the recipient immune system by that of the donor, with the potential complication of an unopposed lethal unidirectional graft-versus-host (GVH) response: that is, rejection of the recipient by the graft. c | Shows the current view of bidirectional and reciprocally modulating immune responses of coexisting immune-competent cell populations that lead to organ engraftment, despite a usually dominant HVG reaction. The transplanted organ, which initially loses most of its passenger leukocytes, apparently remains an important site for donor precursor and stem cells (bone silhouette). d | Represents the current conceived mirror image of (c) and shows the reversal of the size proportions of the reciprocally modulating donor and recipient populations of immune cells after successful BM transplantation.

Figure 2. Contemporaneous HVG (upright curves) and GVH (inverted curves) responses following 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 host-versus-graft (HVG) reaction of organ transplantation (shown here), the graft-versus-host (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.