Transplantation of anergic histoincompatible bone marrow allografts

Background Successful allogeneic bone marrow transplantation relies on glob al immunosuppression or elimination of T cells. In contrast, the induction of anergy can inactivate specific sets of alloreactive T cells in the donor marrow. Previous work has shown that anergy can be induced by blocking the interaction of the B7 molecule on the surface of antigen-presenting cells with the CD28 molecule on the surface of T cells, thus preventing key signa ling events essential for the activation of T cells. To investigate the fea sibility of this approach with respect to transplantation of histoincompati ble bone marrow, we undertook a clinical trial of ex vivo induction of aner gy in T cells present in donor marrow to recipient alloantigens. Methods Outcomes in 12 transplant recipients were evaluated. The recipients ' peripheral-blood lymphocytes were collected before myeloablation and serv ed as alloantigen-presenting cells. To induce alloantigen-specific anergy, bone marrow from a donor mismatched with the recipient for one HLA haplotyp e was cocultured with irradiated cells from the recipient for 36 hours in t he presence of CTLA-4-Ig, an agent that inhibits B7:CD28-mediated costimula tion. After conventional myeloablation and immunoprophylaxis, the treated d onor cells were transfused into the recipient. Results After the induction of anergy, the frequency of T cells capable of recognizing alloantigens of the recipient in donor marrow was sharply reduc ed (P<0.001), whereas the responsiveness to alloantigens from persons unrel ated to the recipient or the donor was unaffected (P=0.51). In the 11 patie nts who could be evaluated, the haploidentical bone marrow cells engrafted. Of these 11 patients, 3 had acute graft-versus-host disease (GVHD) confine d to the gastrointestinal tract. No deaths were attributable to GVHD. Five of the 12 patients were alive and in remission 4.5 to 29 months after trans plantation. Conclusions Donor bone marrow treated ex vivo to induce anergy to alloantig ens from the recipient can reconstitute hematopoiesis in vivo with a relati vely low risk of GVHD. (N Engl J Med 1999;340: 1704-14.) (C) 1999, Massachu setts Medical Society.