From Murine Model to Clinical Trial of Graft-Versus-Gvhd, a Second Transplantation From Another Donor for the Rescue From Refractory Acute Gvhd

[Background] GVHD is still a major obstacle in allogeneic transplantation despite the progress of immunosuppressive drugs and cell therapy such as mesenchymal stem cells. GVHD is caused by donor lymphocytes, mainly T cells, attacking various host tissues. A concept of Graft-versus-autoimmunity (GVA), on the other hand, is suggested from the fact that autoimmune diseases are ameliorated by allogeneic transplantation for accompanying hematologic disorder. GVHD can be thought as a typical autoimmune disease caused by donor T cells. From an experience of the autologous (recipient cells) transplantation for severe GVHD, which resulted in successful control of GVHD, but disease relapse probably due to cancelling the GVL effect, we have pursued the possibility of rescue transplantation from another donor for refractory acute GVHD in a murine model and in a clinical trial. [Methods] In a murine GVHD model of BDF1 (H-2^b/d) to B6C3F1 (H-2^b/k), GVHD mice underwent a second BMT from B6B10F1 (H-2^b/s) following low-dose TBI 2-3 weeks after first BMT. In a clinical trial, 16 patients who developed severe acute GVHD, refractory to three to five lines of GVHD-specific treatments, underwent allogeneic stem cell transplantation using reduced-intensity conditioning regimens with grafts from a second donor. [Results] In the murine model, GVHD could be successfully treated by a second BMT. For successful treatment of GVHD, rapid achievement of full second-donor chimerism was required. The mice were relatively resistant to new development of GVHD by second-donor grafts. The timing of the second BMT, the intensity of conditioning, and donor selection could be important. In the clinical trial, among 15 transplantations that could be evaluated, rescue donor grafts were engrafted in 11 cases and rejected in 4 cases. For patients who achieved rescue donor engraftment, the response rate was 90% (CR 8, PR 2, stable 1). 6 of 8 patients with CR survived without GVHD symptoms, with a median follow-up of 5.8 years. No new development of GVHD by the second graft was observed. In contrast, no long-term survivors were observed in patients who rejected rescue donor grafts. [Conclusions] GVHD could be treated by transplantation using second donor graft, which eliminates first donor lymphocytes in the murine model and the clinical trial. We would like to propose the concept of Graft-versus-GVHD, on the analogy of GVA.