title: Role of Natural Killer Cells in Intravenous Immunoglobulin-Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg(-/-) (NSG) Mice.
abstract: Although clinical studies have yet to demonstrate clearly the use of intravenous immunoglobulin (IVIG) for prevention of graft-versus-host disease (GVHD), their effective use in a xenogeneic mouse model has been demonstrated. We aimed to determine the mechanism of action by which IVIG contributes to GVHD prevention in a xenogeneic mouse model. NOD/LtSz-scidIL2rg(-/-) (NSG) mice were used for our xenogeneic mouse model of GVHD. Sublethally irradiated NSG mice were injected with human peripheral blood mononuclear cells (huPBMCs) and treated weekly with PBS or 50 mg IVIG. Incidence of GVHD and survival were noted, along with analysis of cell subsets proliferation in the peripheral blood. Weekly IVIG treatment resulted in a robust and consistent proliferation of human natural killer cells that were activated, as demonstrated by their cytotoxicity against K562 target cells. IVIG treatment did not inhibit GVHD when huPBMCs were depleted in natural killer (NK) cells, strongly suggesting that this NK cell expansion was required for the IVIG-mediated prevention of GVHD in our mouse model. Moreover, inhibition of T cell activation by either cyclosporine A (CsA) or monoclonal antihuman CD3 antibodies abolished the IVIG-induced NK cell expansion. In conclusion, IVIG treatment induces NK cell proliferation, which is essential for IVIG-mediated protection of GVHD in our mouse model. Furthermore, activated T cells are mandatory for effective IVIG-induced NK cell proliferation. These results shed light on a new mechanism of action of IVIG and could explain why the efficacy of IVIG in preventing GVHD in a clinical setting, where patients receive CsA, has never been undoubtedly demonstrated.
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Gregoire-Gauthier
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Fontaine
authors.affiliation: Department of Health Biochemistry, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
authors.forename: Lionel
authors.initials: L
authors.lastname: Benchimol
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Université Paris Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Nicoletti
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.
authors.forename: Silvia
authors.initials: S
authors.lastname: Selleri
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.
authors.forename: Mame Massar
authors.initials: MM
authors.lastname: Dieng
authors.affiliation: CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Department of Pediatrics, Université de Montréal, Montreal, Quebec, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada. Electronic address: elie.haddad@umontreal.ca.
authors.forename: Elie
authors.initials: E
authors.lastname: Haddad
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000473:pathology / Q000637:transplantation*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID
keywords: Graft-versus-host disease; Intravenous immunoglobulin; NSG mice; Natural killer cells; Xenogeneic mouse model