IL-2- and IL-15-Activated Alloreactive NK Cells Infusion Reduces GVHD, Mediates Graft-Versus-Leukemia Effects and Prolongs Survival in Recipients of MHC-Mismatched Hematopoietic Cell Transplantation.

Alloreactive NK cells with killer immunoglobulin-like receptor (KIR) ligand incompatibility have been implicated to reduce graft-vs-host disease (GVHD) and myeloid leukemia relapse in clinical hematopoietic cell transplantation (HCT). Murine NK cells express subgroups of H-2-specific receptors of the C-type lectin superfamily, termed Ly49, that regulate their function. IL-2 and IL-15 are two important NK cell growth cytokines. We investigated if IL-2- and IL-15-activated alloreactive NK cells would reduce GVHD and mediate graf-versus-leukemia effects in mice undergoing MHC-mismatched allogeneic HCT. 6–8-week-old female specific pathogen-free BALB/c mice were injected intravenously with 1×10⁶ EL9611 erythroblastic leukemia via lateral tail vein. Eight days following leukemia inoculation, leumemia-bearing mice were irradiated (800cGy) with 6MV X—ray and transplanted with 5x10⁶ bone-marrow cells and 10x10⁶ splenocytes from MHC-mismatched C57BL/6 mice. One day following transplantation, recipient mice were given a single infusion of 1×10⁷ IL-2- and IL-15-activated donor NK cells. Recipients of alloreactive NK cells had a significant reduced clinical GVHD scores(p<0.01), and prolonged survival (p<0.01) compared to HCT recipients not receiving alloreactive NK cells. These data provide an in vivo evidence that a single infusion of alloreactive NK cells can reduce GVHD and prolong leukemia-bearing mice survival via graft-versus-leukemia effects following MHC-mismatched allogeneic HCT.