title: IL-12/15/18-preactivated NK cells suppress GvHD in a mouse model of mismatched hematopoietic cell transplantation.
abstract: Mismatched hematopoietic cell transplants for treating leukemia are complicated by graft versus host disease (GvHD). Here, we show that adoptively transferred IL-12/15/18-preactivated NK cells suppress GvHD in a mouse model of fully mismatched hematopoietic cell transplantation. These IL-12/15/18-preactivated NK cells maintained Eomesodermin (Eomes) and T-bet expression upon transfer and, while there was no evidence of direct killing of donor T cells or host DCs by the IL-12/15/18-preactivated NK cells, proliferation of donor T cells was inhibited. Strikingly, the graft versus leukemia effect mediated by donor T cells was retained, resulting in improved overall survival of mice that received lymphoma cells, donor allogeneic T cells, and IL-12/15/18-preactivated NK cells. These results suggest that IL-12/15/18-preactivated NK cells may be useful in improving immunotherapy of mismatched hematopoietic cell transplantation. Compared with previously proposed protocols, our findings suggest that in vitro NK-cell preactivation with this cytokine cocktail offers the significant advantage that cytokines do not need to be administered systemically to sustain NK-cell activity, thus avoiding toxicity.
authors.affiliation: Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Hüber
authors.affiliation: Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Doisne
authors.affiliation: Department of Obstetrics and Gynaecology, University of Cambridge School of Clinical Medicine, National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, Cambridge, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Colucci
mesh_terms: D000818:Animals; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000209:etiology* / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology; D020382:Interleukin-18 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D010641:Phenotype; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D000098815:T-bet Transcription Factor
chemical_list: D016207:Cytokines; C491198:Eomes protein, mouse; D019409:Interleukin-15; D020382:Interleukin-18; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma
keywords: Cytokine-induced NK cells; GvHD; HSCT; Lymphoma