MHC discrepancies between host tissues and allogeneic NK cells expanded by IL-15 and 4-1BBL ex vivo contribute to GVHD but not GVT (P2150)

Abstract

Abstract NK cell biology after allogeneic bone marrow transplant (alloBMT) is mainly drawn from studies infusing unmanipulated NK cells. We studied the impact of activating murine NK cells with the co-stimulatory molecule 4-1BBL during expansion with IL-15 ex vivo, and then infused these cells to determine safety and efficacy after alloBMT. NK cells were harvested from Balb/c (H-2d), DBA/2 (H-2d), or CB6F1 (H-2d x H-2b) spleens and cultured with IL-15 in the presence of irradiated artificial APCs transfected with or without 4-1BBL. The addition of 4-1BBL+ cells to IL-15 expanded NK cells decreased yields by up to 50%. The combination of 4-1BBL/IL-15 completely abrogated cytotoxicity against Yac-1 lymphoma, whereas IL-15 alone led to augmented IFNγ production and cytotoxicity. After T cell depleted (TCD) MHC-mismatched alloBMT (CB6F1→Balb/c), recipients of allogeneic NK cell infusions expanded with IL-15/4-1BBL showed weight loss in a dose-dependent fashion and increased lethality from GVHD. Similar results were also seen with CB6F1→C57BL/6. Prior to infusion, IL-15/4-1BBL combination led to less Fas ligand+ NK cells, but after alloBMT, FasL+ NK cells increased. After TCD MHC-matched alloBMT (DBA/2→Balb/c), infusion of NK cells expanded with IL-15 or IL-15/4-1BBL did not cause GVHD, implying MHC discrepancies between donor NK cells and GVHD target tissues contribute to the enhanced alloreactivity induced by 4-1BBL. No differences in graft-versus-tumor effects were observed in vivo.