Adoptive Infusion of Alloreactive Donor NK Cells Reduces GVHD, Mediates Anti-Tumor Effects and Prolongs Survival in Recipients of MHC-Matched Hematopoietic Cell Transplantation.

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. [Display omitted]