T cell death and transplantation tolerance.

In order to achieve central tolerance, long-lasting and massive deletion of donor-specific T cells can be achieved by intense immunosuppression and creation of a mixed donor–recipient chimeric state. To achieve peripheral tolerance, more subtle forms of immunosuppression are required in order to preserve T cell apoptosis. IL-2-dependent AICD is required to deplete alloreactive T cells if nondepletive therapies (e.g., drugs or noncytolytic biologics) are used as the principal treatment modality. In addition, overly intense immunosuppression will block the acquisition of peripheral tolerance because induction of tolerance is an active antigen-driven T cell–dependent process. For example, the combined use of calcineurin inhibitors that block signal 1 plus costimulation blockade that blocks signal 2 causes near total immunosuppression in mice and thereby blocks expression of IL-2, Ag-triggered T cell AICD, and outgrowth of regulatory cells. Following cessation of this intense therapy, acute rejection occurs. In contrast, the use of rapamycin, an agent that blocks the proliferative signals delivered by T cell growth factors but not IL-2-triggered apoptotic signals, in combination with costimulation blockade provides strong synergy as a means to foster peripheral tolerance (Li et al., 1999xBlocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance. Li, Y., Li, X.C., Zheng, X.X., Wells, A.D., Turka, L.A., and Strom, T.B. Nat. Med. 1999; 5: 1298–1302Crossref | PubMed | Scopus (594)See all References(Li et al., 1999).Anti-CD25 mAb treatment is a useful and safe adjunct to conventional immunosuppression. In some experimental allograft models, targeting CD25 or the high-affinity IL-2R complex with IgM antibodies or toxins can produce transplant tolerance (Strom et al., 1992xInterleukin-2 receptor-directed immunosuppressive therapies (antibody- or cytokine-based targeting molecules) . Strom, T.B., Kelley, V.R., Woodworth, T.G., and Murphy, J.R. Immunol. Rev. 1992; 129: 131–163Crossref | PubMedSee all References(Strom et al., 1992). Tolerance occurs because these specific agents kill many IL-2R+-activated T cells, as nonlytic anti-CD25 mAbs fail to produce tolerance. In clinical practice, the anti-CD25 mAbs available are IL-2 receptor antagonists and have, by comparison with agents used in murine systems, a diminished capacity to directly kill CD25+ T cells. Nonlytic anti-CD25 mAbs block IL-2-triggered apoptosis in a murine model (Demirci et al., 2001xIL-15 and IL-2 (a matter of life and death for T cells in vivo) . Demirci, G., Ferrari-Lacraz, S., Groves, C., Coyle, A., Malek, T.R., Strom, T.B., and Li, X.C. Nat. Med. 2001; 7: 114–118Crossref | PubMed | Scopus (245)See all References(Demirci et al., 2001). In short, the ability of anti-CD25 mAbs to aid the induction of peripheral tolerance hangs on the balance of their (untested) ability to directly kill IL-2R+ T cells versus their capacity to block IL-2-mediated apoptosis.The classical separation between deletional central tolerance and peripheral nondepletive tolerant states may be somewhat artificial. It seems likely that central tolerance is rarely created through complete and total clonal deletion alone but that immunoregulatory processes arise to control “escaped” thymic emigrants. Conversely, in peripheral strategies that are not inherently lymphoablative, clonal depletion may be a prerequisite to allow immunoregulation to emerge and be effective. Thus, in the setting of the allograft response, immunoregulation and clonal depletion are inextricably linked. We believe that the classical definitions of central and peripheral transplant tolerance that appear to form extreme and opposing ends of a spectrum actually embody interactive, not alternative, means of creating transplant tolerance.