Sirolimus and tacrolimus binding proteins: double-edged swords for GVHD prophylaxis

Postgrafting immunosuppression is the main approach for the prevention of graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation. Controlled trials have found that the combination of cyclosporine, a calcineurin inhibitor that reduces T-cell cytokine gene activation, and methotrexate, a nonselective antimetabolite that facilitates apoptosis of replicating T cells, is more effective than either drug alone. Tacrolimus, a potent inhibitor of calcineurin, was more effective than cyclosporine when each drug was used in combination with methotrexate, but despite the improvement, acute GVHD of grades II to IV (sufficiently serious to require treatment) occurred in 32% of patients after HLA-identical sibling grafts and in 56% of patients after unrelated donor grafts. Antin and colleagues (page 1601) report promising results of a pilot clinical trial combining oral sirolimus (originally named rapamycin) with reduced doses of tacrolimus and methotrexate for GVHD prophylaxis after unrelated or HLA-incompatible related marrow grafts. Among 39 patients, the combination was well tolerated and the incidence of acute GVHD (grades II-IV) was 26%. If confirmed by controlled trials, these results would represent a major improvement in GVHD prevention.

Structurally, sirolimus resembles tacrolimus and binds to the same family of intracellular tacrolimus (FK506)–binding proteins (FKBP12 and others) at a site distinct from tacrolimus. Sirolimus-FKBP complexes inhibit the mammalian target of rapamycin (mTOR), a kinase that regulates cell cycle entry in response to interleukin 2 (IL-2) signaling and other cellular functions. Cell cycle entry in the presence of sirolimus induces T-cell apoptosis, and deprivation of IL-2 signaling renders antigen-activated T cells unresponsive. Both mechanisms are thought to contribute to T-cell immunologic tolerance. Although initial experiments observed antagonism between sirolimus and tacrolimus in vitro, experiments in rats and primates documented bona fide synergy between the 2 drugs in vivo. Free FKBP molecules compete with drug-bound–FKBP complexes for calcineurin and mTOR, thereby limiting the immune suppressive activity of sirolimus and tacrolimus. Combination therapy with sirolimus and tacrolimus decreases the availability of free competing FKBP molecules and therefore produces synergy. The combination of sirolimus and tacrolimus has been effective in pancreatic islets and kidney transplantations and has met with extremely good patient compliance because both drugs are used at low doses. Sirolimus alone is extremely effective in preventing GVHD mortality in mice and rescuing patients with GVHD resistant to cyclosporine and glucocorticoids. The present study by Antin et al has identified both a potential role for sirolimus in GVHD prevention in humans and an effective method for administering it.