Lessons of organ-induced tolerance learned from historical clinical experience

Abstract

Although the reductionist approach has served science well for 400 years, the accumulation of details can obscure the truth if the original premise is incorrect. One such premise has been that successful organ transplantation and bone marrow engraftment are fundamentally different outcomes involving separate and distinct mechanisms. Some historical clinical observations pointed to a different conclusion almost from the beginning and included clues about how to induce tolerance with the aid of immunosuppression.

Figure 1

Long-term survival and drug-free tolerance in kidney allograft recipients treated in 1962 to 1963. Follow-up is to May 2003. Cr, serum creatinine. Black boxes, off immunosuppression.

Figure 2

Rather than producing rejection (thick dashed arrows), the donor-specific immune response to allografts may be exhausted and deleted as depicted by the fall of the initially ascending continuous thin lines, (1) if the unmodified recipient response is too weak to eliminate the migratory donor cells (spontaneous tolerance models), (2) when recipient immune responsiveness is weakened in advance of transplantation (the pretreatment principle), or (3) when the recipient response is reduced into the deletable range after transplantation with just the right amount of immunosuppression. However, over treatment after transplantation (shown in D with multilayered bars), reduces the efficiency and extent of clonal exhaustion-deletion and is therefore antitolerogenic (see text for details). Tx, transplantation.

Figure 3

Current protocol of immunosuppression in which pre-treatment is given with a large dose of a potent ALG (thymoglobulin) followed by tacrolimus monotherapy to which other agents are added only for rejection. The inverted curve at the bottom shows the usually silent graft-versus-host (GVH) reaction. HVG, host-versus-graft.