A novel approach for prevention of lethal GVHD by selective elimination of alloreactive donor lymphocytes prior to stem cell transplantation

Abstract

Objective Experiments were designed to investigate a new concept aiming for induction of graft-vs-malignancy (GVM) effect prior to stem cell transplantation (SCT). Mismatched lymphocytes given pre-SCT will be followed by a selective elimination of alloreactive donor lymphocytes, thus avoiding lethal graft-vs-host disease (GVHD). Methods Recipient mice treated with sublethal total-body irradiation (TBI) received a single injection of allogeneic splenocytes, either naïve or rIL-2 activated (ADL), for induction of GVHD. To prevent lethal GVHD, cyclophosphamide (Cy) (200 mg/kg) or TBI (9 Gy) were given 4 days after cell inoculation. One day later, treated mice were rescued with syngeneic bone marrow cells. Results Both Cy and TBI significantly ( p < 0.001) prevented GVHD in all recipients inoculated with either naïve cells or ADL and all recipients survived more than 250 days. Control mice not rescued with CY or TBI died of GVHD within 20 to 25 days. A significant proportion of recipients inoculated with 4T1 tumor cells, treated with ADL followed by TBI 9 Gy, survived more than 250 days disease-free in comparison with 22 days in untreated control mice ( p <0.001). Conclusions Attempting to induce short, yet effective, GVM effects before rather than after SCT, thus avoiding lethal GVHD, may represent an innovative approach for more effective yet safer use of SCT for tumor immunotherapy.