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Role of Natural Killer Cells in Intravenous Immunoglobulin-Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg(-/-) (NSG) Mice.
Biol Blood Marrow Transplant. 2015 May; 21(5):821-8.BB

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+Show Affiliations

CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.Department of Health Biochemistry, Université de Sherbrooke, Sherbrooke, Quebec, Canada.CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Université Paris Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France.CHU Sainte-Justine Research Center, Montreal, Quebec, Canada; Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.CHU Sainte-Justine Research Center, Montreal, Quebec, Canada.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25596424

Citation

Gregoire-Gauthier, Joëlle, et al. "Role of Natural Killer Cells in Intravenous Immunoglobulin-Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg(-/-) (NSG) Mice." Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, vol. 21, no. 5, 2015, pp. 821-8.
Gregoire-Gauthier J, Fontaine F, Benchimol L, et al. Role of Natural Killer Cells in Intravenous Immunoglobulin-Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg(-/-) (NSG) Mice. Biol Blood Marrow Transplant. 2015;21(5):821-8.
Gregoire-Gauthier, J., Fontaine, F., Benchimol, L., Nicoletti, S., Selleri, S., Dieng, M. M., & Haddad, E. (2015). Role of Natural Killer Cells in Intravenous Immunoglobulin-Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg(-/-) (NSG) Mice. Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation, 21(5), 821-8. https://doi.org/10.1016/j.bbmt.2015.01.006
Gregoire-Gauthier J, et al. Role of Natural Killer Cells in Intravenous Immunoglobulin-Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg(-/-) (NSG) Mice. Biol Blood Marrow Transplant. 2015;21(5):821-8. PubMed PMID: 25596424.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Role of Natural Killer Cells in Intravenous Immunoglobulin-Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg(-/-) (NSG) Mice. AU - Gregoire-Gauthier,Joëlle, AU - Fontaine,François, AU - Benchimol,Lionel, AU - Nicoletti,Simon, AU - Selleri,Silvia, AU - Dieng,Mame Massar, AU - Haddad,Elie, Y1 - 2015/01/14/ PY - 2014/07/27/received PY - 2015/01/08/accepted PY - 2015/1/18/entrez PY - 2015/1/18/pubmed PY - 2016/1/26/medline KW - Graft-versus-host disease KW - Intravenous immunoglobulin KW - NSG mice KW - Natural killer cells KW - Xenogeneic mouse model SP - 821 EP - 8 JF - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation JO - Biol. Blood Marrow Transplant. VL - 21 IS - 5 N2 - 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. SN - 1523-6536 UR - https://www.unboundmedicine.com/medline/citation/25596424/Role_of_Natural_Killer_Cells_in_Intravenous_Immunoglobulin_Induced_Graft_versus_Host_Disease_Inhibition_in_NOD/LtSz_scidIL2rg__/____NSG__Mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1083-8791(15)00024-5 DB - PRIME DP - Unbound Medicine ER -