Granulocyte colony-stimulating factor-mobilized allogeneic stem cell transplantation maintains graft-versus-leukemia effects through a perforin-dependent pathway while preventing graft-versus-host disease

Minimization of graft-versus-host disease (GVHD) with preservation of the g raft-versus-leukemia (GVL) effect is a crucial step to improve the overall survival of allogeneic bone marrow transplantation (BMT) for patients with hematological malignancies. We and other investigators have shown that gran ulocyte colony-stimulating factor (G-CSF)-mobilized allogeneic peripheral s tem cell transplantation (PBSCT) reduces the severity of acute GVHD in muri ne models. In this study, we investigated whether G-CSF-mobilized PBSC main tain their GVL effect in a murine allogeneic transplant model (B6 --> B6D2F 1). be mice (H-2(b)) were injected subcutaneously with human G-CSF (100 mu g/kg/d) for 6 days and their splenocytes were harvested on day 7 as a sourc e of PBSC. G-CSF mobilization dramatically improved transplant survival com pared with nonmobilized controls (95% v 0%, P < .001). Systemic levels of l ipopolysaccharide and tumor necrosis factor-cu were markedly reduced in rec ipients of allogeneic G-CSF-mobilized donors, but cytolytic T lymphocyte (C TL) activity against host tumor target cells p815 was retained in those rec ipients. When leukemia was induced in recipients by coinjection of p815 tum or cells (H-2(d)) at the time of transplantation, all surviving recipients of G-CSF-mobilized B6 donors were leukemia-free at day 70 after transplant, whereas all mice who received T-cell-depleted (TCD) splenocytes from G-CSF -mobilized B6 donors died of leukemia. When splenocytes from G-CSF-mobilize d perforin-deficient (pfp(-/-)) mice were used for transplantation, 90% of recipients died of leukemia, demonstrating that perforin is a crucial pathw ay mediating GVL effects after G-CSF-mobilized PBSCT. These data illustrate that G-CSF-mobilized allogeneic PBSCT separate GVL from GVHD by preserving perforin-dependent donor CTL activity while reducing systemic inflammation . (C) 1999 by The American Society of Hematology.