IL-2- and IL-15-Activated Donor NK Cells Infusion Reduces GVHD and Prolongs Survival in Melanoma-Bearing Mice after MHC-Mismatched Hematopoietic Cell Transplantation.

The function of NK cells is regulated by a balance between signals transmitted via actvating and inhibitory receptors, including killer-immunoglobulin-like receptors (KIRs). Murine NK cells express subgroups of H-2-specific receptors of the C-type lectin superfamily, termed Ly49, that regulate their function. We investigated if alloreactive NK cells would reduce GVHD and mediate graft-versus-tumor effects in mice undergoing MHC-mismatched allogeneic HCT. Six-week-old female C57BL/6 mice were injected intravenously with 2×105 B16 melanoma cells via lateral tail vein. seven days following melanoma inoculation, melanoma-bearing mice were irradiated (1000cGy) with 6MV X—ray and transplanted with 5x106 bone-marrow cells and 10x106 splenocytes from MHC-mismatched BALB/c mice. One day following transplantation, recipient mice were given a single infusion of donor IL-2 and IL-15-activated NK cells. Recipients of alloreactive NK cells had a significant reduced clinical GVHD scores(p<0.01), less melanoma lung metastasis, 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 melanoma-bearing mice survival via graft-versus-tumor effects following MHC-mismatched allogeneic HCT.