Immunity and tolerance are related, and governed by antigen migration and localization.

T HE PURPOSE of this communication is to describe a recently delineated principle of immunology1 that can be summarized in one line: immunity, or alternatively tolerance, to any antigen is governed by the migration and localization of that antigen. This concept, which has been developed with transplantation models 2-4 and from observations after clinical and experimental infe£tions 5-7 has been described elsewhere in more detai1. 1 Here, we will be concerned mainly with the relation between donor leuko-cyte chimerism and transplantation tolerance, focusing at first on clinicopathologic observations in transplant recipients made in 1991-1992 that prompted reconsideration of a number of long held convictions. The most important new finding reported in 1992 was the presence of multiline age donor leukocyte microchimerism in the blood, skin, lymph nodes, and other tissues of organ allograft recipients up to 30 years after successful transplan-tation. 2-4 The persistence of the disseminated donor leu-kocytes for this long implied (as was subsequently proved 8 • 9) that precursor or stem cells are included in the burst of donor leukocytes that briefly constitute 1 % to 20% of the recipient circulating mononuclear cells after organ transplantation (Fig 1, upper panel). Although the number of these donor cells is greatest with transplantation of the intestine or liver,10,11 the same events on a smaller scale occur after transplantation of organs like the kidney and heart. 12 Another change during the early postoperative period is disappearance of the resident donor mononuclear leuko-cytes from the graft and their replacement by recipient cells of the same lineages (Fig 1, lower). Although this was observed in hepatic allografts nearly 30 years ago,13 it was assumed at first to be a unique feature of liver transplants. After the same changes were found in intestinal allo-grafts,11,14 evidence quickly accrued that this was a generic phenomenon; ie, it occurred in all successfully transplanted organs. 3 ,15 These discoveries, showing that both the "accepted" allograft and recipient became genetic composites, suggested an explanation for two enigmatic observations reported for the first time in 1963 16 that had allowed the development of organ transplantation as a practical and 0041-1345/99/$-see front matter PII S0041-1345(98)00004-4 1406 reproducible clinical service. First, kidney rejection developing in patients immunosuppressed with azathioprine could be consistently reversed with large doses of pred-nisone. The second, and more important, observation was that renal allografts self-induced variable degrees of donor-specific tolerance, manifested by the subsequent ability to reduce …