History of clinical transplantation

How transplantation came to be a clinical discipline can be pieced together by perusing two volumes of reminiscences collected by Paul I. Terasaki in 1991-1992 from many of the persons who were directly involved. One volume was devoted to the discovery of the major histocompatibility complex (MHC), with particular reference to the human leukocyte antigens (HLAs) that are widely used today for tissue matching.1 The other focused on milestones in the development of clinical transplantation.2 All the contributions described in both volumes can be traced back in one way or other to the demonstration in the mid-1940s by Peter Brian Medawar that the rejection of allografts is an immunological phenomenon.3,4 © 2008 Springer New York

Importance of intrathymic mixed chimerism for the maintenance of skin allograft tolerance across fully allogeneic antigens in mice

In B6 (H-2b) mice that had been given, neonatally, 1×108 B6AKF1 spleen cells intraperitoneally (i.p.), only a moderate prolongation of donor (AKR:H-2k) skin graft survival was observed. In such B6 mice, no mixed lymphocyte reaction (MLR) to AKR could be detected on day 35 (35 days after birth), but it was clearly evident on day 84. Similarly, neither Vβ6+ (reactive to MTV-7-encoded antigens) nor Vβ11+ (reactive to I-E+MTV-derived superantigens) T cells were detected on day 35, but both were clearly evident on day 84 in both the thymus and the lymph nodes, thus indicating the breakdown of intrathymic mixed chimerism at the antigen-presenting cell level. Furthermore, by day 84, all skin grafts from AKR had already been rejected in such B6 mice. In the periphery, however, Vβ6+, but not Vβ11+, T cells were clonally anergic on day 84, based on a stimulation assay with anti-T-cell receptor (TCR) monoclonal antibody (mAb), thus suggesting that tolerance to some antigens, but not to others, may be induced by the clonal anergy in fully allogeneic combinations, and that the clonal anergic state may be masked by other proliferative responses. These results therefore indicate the importance of intrathymic mixed chimerism (central tolerance) and the limitations of clonal anergy (peripheral tolerance) in maintaining tolerance across fully allogeneic antigen barriers