Abstract
Alloreactive natural killer (NK) cells with killer immunoglobulin-like receptor (KIR) ligand incompatibility have been implicated to reduce graft-vs-host disease (GVHD) and leukemia relapse in humans undergoing MHC-mismatched T-cell depleted allogeneic hematopoietic cell transplantation (HCT). Analogous to human NK KIR, murine NK cells express subgroups of MHC-specific receptors of the C-type lectin superfamily, termed Ly49, that regulate their function. In MHC-mismatched HCT, the infusion of alloreactive Ly49-mismatched NK cells decreases the incidence of GVHD. We investigated if an infusion of alloreactive NK cells would reduce GVHD and further mediate anti-tumor effects in mice undergoing MHC-matched allogeneic HCT. Balb/c mice were injected intravenously with 105 RENCA tumor cells. Ten days following tumor injection, mice were irradiated (950cGy) and transplanted with 15×106 and 8×106 splenocytes and bone-marrow cells respectively from MHC-matched B10.d2 donors. Five days following transplantation, recipients were given a single infusion of either 0.5–1×106 Ly49 ligand-matched (Ly49G2; non-alloreactive to Balb/c) or Ly49 ligand-mismatched (Ly49C; alloreactive to Balb/c) donor NK cells. Recipients of Ly49 ligand-mismatched NK cells had a significant reduction in the incidence of GVHD (p<0.01-figure), and prolonged survival (median 84 vs 39 days; p<0.01-figure) compared to HCT recipients not receiving NK cells. Recipients of Ly49 ligand-matched NK cells had the same incidence of GVHD and similar survival compared to controls not receiving NK cells. Pulmonary tumor burden was significantly (p<0.01) lower in recipients of Ly49-mismatched or Ly49-matched NK cells compared to mice not receiving NK cells. These data provide in vivo evidence that a single infusion of alloreactive donor NK cells can prolong survival by both reducing GVHD and mediating anti-tumor effects following MHC-matched allogeneic HCT.
Significant reduction in GVHD and improved survival in RENCA tumor bearing mice undergoing an allogeneic HCT that received an infusion of alloreactive NK cells (Ly49C:thick line) compared to transplant recipients receiving non-alloreactive NK cells (Ly49G2:thin line) or no NK cells (dotted line)
Significant reduction in GVHD and improved survival in RENCA tumor bearing mice undergoing an allogeneic HCT that received an infusion of alloreactive NK cells (Ly49C:thick line) compared to transplant recipients receiving non-alloreactive NK cells (Ly49G2:thin line) or no NK cells (dotted line)
Disclosure: No relevant conflicts of interest to declare.
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