Neutrophils induced licensing of natural killer cells.

Natural killer (NK) cells acquire effector function through a licensing process and exert anti-leukemia/tumor effect. However, there is no means to promote a licensing effect of allogeneic NK cells other than cytomegalovirus reactivation-induced licensing in allogeneic hematopoietic stem cell transplantation in human. In mice, a licensing process is mediated by Ly49 receptors which recognize self-major histocompatibility complex class I. The distribution of four Ly49 receptors showed similar pattern in congenic mice, B10, B10.BR, and B10.D2, which have B10 background. Forty Gy-irradiated 2 × 10(6) B10.D2 cells including splenocytes, peripheral blood mononuclear cells in untreated mice, or granulocyte colony-stimulating factor treated mice were injected intraperitoneally into B10 mice. We found that murine NK cells were effectively licensed by intraperitoneal injection of donor neutrophils with its corresponding NK receptor ligand in B10 mice as a recipient and B10.D2 as a donor. Mechanistic studies revealed that NK cells showed the upregulation of intracellular interferon-γ and CD107a expression as markers of NK cell activation. Moreover, enriched neutrophils enhanced licensing effect of NK cells; meanwhile, licensing effect was diminished by depletion of neutrophils. Collectively, injection of neutrophils induced NK cell licensing (activation) via NK receptor ligand interaction.

A feasibility study on the prediction of acute graft-vs.-host disease before hematopoietic stem cell transplantation based on fetomaternal tolerance.

The contact between the immune systems of mother and child during pregnancy affects an immune response of the child against noninherited maternal antigens (NIMA) and the mother against inherited paternal antigens (IPA). However, the immunologic effects of developmental exposure to NIMA or IPA are heterogeneous, and can be either tolerogenic or immunogenic. Although we have reported that prediction of acute graft-vs.-host disease (GVHD) is feasible in a murine model, there has been no literature in human. We devised a novel method for predicting a tolerogenic effect by using mixed lymphocyte reaction combined with enzyme-linked immunospot (MLR-ELISPOT) assay. The assay can evaluate reactivity of interferon-γ spot-forming cells of donor against the recipient. Although we have shown only two examples of mother to child reactivity so far, our preliminary results suggest that this pre-screened assay may be used to predict acute GVHD. The clinical trial is in progress to evaluate MLR-ELISPOT assay as a predicting measure of acute GVHD in haploidentical transplantation from NIMA or IPA-mismatched family donor.