REPLY TO "CHIMERISM AND CLONAL EXHAUSTION"

Abstract

We agree with Dr. Starzl that there is some concordance between our two models of transplant tolerance, although we maintain that there is a difference in the immune mechanism. In both models, donor leukocyte migration to recipient tissues is central to the process, although in our model it is not necessary for this to result in persistent microchimerism. Both models also predict that the outcome of the tolerance process will be deletion or inactivation of alloreactive clones of T cells. The major difference between the two models is in the immune events which link donor cell migration with recipient T-cell deletion or inactivation. The Pittsburgh group uses their observation of persistent donor-derived microchimerism in tolerant recipients to infer a limited graft-versus-host reaction mediated by "donor veto/suppressor cells, cytokine profile changes or enhancing antibodies" as the tolerance mechanism (1). Consequently, they have attempted to promote transplant acceptance by infusing donor bone marrow to increase the graft-versus-host reaction and subsequent microchimerism (2). Our model is based on the paradoxical observation of massive upregulation of interleukin-2 and interferon-γ mRNA in the recipient lymphoid tissues of tolerant animals (3,4). Parallel observations in immunological models of high-dose or activation-associated tolerance have led us to propose these as mechanisms of transplant tolerance. This leads to predictions different from those of the Pittsburgh model. For instance, we predict that increasing the amount of transplanted tissue and donor leukocytes promotes tolerance rather than rejection and that interfering with early immune activation by treating transplant recipients with some kinds of immunosuppressive drugs reduces tolerance. We have tested both these predictions and found that they are supported by experimental evidence (3,5,6). We believe that definition of the immune mechanism of this powerful model of transplant tolerance will come from examination of the early immune changes in recipient lymphoid tissues rather than from determining the nature of persistent microchimerism. G.A. Bishop J. Sun A.G.R. Sheil G.W. McCaughan A.W. Morrow Gastroenterology and Liver Centre; Centenary Institute for Cancer Medicine and Cell Biology and University of Sydney; Sydney, Australia