Separation of antileukemic effects from graft-versus-host disease in MHC-haploidentical murine bone marrow transplantation: participation of host immune cells

Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. In clinical studies of HLA-mismatched HSCT, strong GVL effects have been reported. In the present study, we addressed the mechanism of the GVL and GVH response using MHC-haploidentical murine bone marrow transplantation (BMT) models. Recipient BDF1 (H-2^b/d) mice received T cell-depleted bone marrow and spleen cells from B6C3F1 (H-2^b/k) or C57BL/6 (H-2^b) mice with or without P815 mastocytoma cells (H-2^d) after receiving lethal total body irradiation. B6C3F1 → BDF1 (hetero-to-hetero type) recipients showed more powerful antileukemic effects with less severe GVHD than C57BL/6 → BDF1 (parent-to-F1 type) recipients. Compared with C57BL/6 → BDF1 recipients, significantly higher in vitro cytotoxic activity against P815 cells was observed in B6C3F1 → BDF1 recipients. Significantly lower CXCR3 expression on donor T cells and higher interferon (IFN)-γ expression were considered to be associated with strong antileukemic effects with less severe GVHD in B6C3F1 → BDF1 recipients. Furthermore, host immune cells, especially natural killer cells and CD8⁺ T cells, were found to contribute remarkably to high IFN-γ production in B6C3F1 → BDF1 recipients. Thus, in MHC-haploidentical HSCT, host immune cells may change the balance between GVH and GVL response through IFN-γ production.