Foreignness is threatening. The immune system, the primary arbiter of self and nonself, will reject an organ transplant unless constrained by life-long administration of multiple immune suppressive drugs. Immunosuppressive therapy, while facilitating graft success, heightens susceptibility to infection and the development of malignancy. The challenge then is to educate the immune system to tolerate the allograft in the absence of exogenous immunosuppressants. Deletion of autoreactive T cells and B cells, and immune mechanisms including suppressor and anergy, have all been advanced as the basis for tolerance to self-antigens, and the avoidance of autoimmunity (1-3). The central question is whether the principles of self-tolerance can be exploited to achieve allograft permissive tolerance, the Holy Grail of the transplantation biologist. In this issue of Proceedings, Azuma et al.(4) inform us of a potential clinically applicable strategy for the creation of transplantation tolerance and preservation of long-term allo-graft function. They demonstrate that blockade of the CD28/B-7 costimulation pathway (5-8), in a rat renal allograft model, prevents the development of chronic rejection. It is shown that a single application of CTLA4 Ig, a recombinant fusion protein of the T-cell surface molecule CTLA4 and IgGl heavy chain, reduces cellular traffic into the allografts, constrains intrarenal display of mRNA encoding T-cell and macrophage proteins and prevents histological and functional deterioration of the allograft.

The very first successful renal transplantation was performed in 1954 at the then Peter Bent Brigham Hospital (Boston) by a multidisciplinary team led by Dr. Joseph Murray. The current report, communicated by Dr. Murray and coming from the same pioneering institution, invites consideration of new knowledge of T-cell immunobiology and mechanisms of rejection thatcan contribute to the developmentof tolerogenic regimens in the clinic. Accordingly, I shall comment on the signaling features ofT lymphocytes-the primary cells responsible for allograft rejection-and the mechanisms of rejection from the perspective of finer regulation of the antiallograft repertory.