Prevention of lethal acute GVHD with an agonistic CD28 antibody and rapamycin.

Successful hematopoietic cell transplantation (HCT) from an allogeneic donor ideally should produce tolerance to recipient alloantigens while preserving anti-infectious and antitumor immunity. Rapamycin together with costimulation blockade can induce tolerance in organ allograft models by inhibiting G(1) --> S-phase progression and promoting T-cell apoptosis. In contrast to blocking costimulation through CD28, administration of agonistic CD28-specific antibody 37.51 partially prevents lethal graft-versus-host disease (GVHD) by selective depletion of alloreactive T cells in mice. We hypothesized that combining rapamycin with agonistic CD28 treatment would improve GVHD control by tolerizing a small subset of alloreactive T cells that might escape effects of the CD28-specific antibody. A short course of rapamycin plus agonistic CD28 treatment showed synergism at suboptimal doses, was highly effective in preventing lethal GVHD, and was superior to rapamycin plus CD28 blockade in a major histocompatibility complex class I- and II-mismatched HCT model. The combination treatment reduced the number of proliferating, alloreactive cells in the recipient, promoted donor B- and T-cell reconstitution, and reduced inflammatory cytokine levels. Administration of rapamycin plus agonistic CD28 antibodies offers a promising new therapeutic approach to facilitate tolerance after HCT.