[en] 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.
Benchimol, Lionel ; Centre Hospitalier Universitaire de Liège - CHU > Autres Services Médicaux > Service d'ORL, d'audiophonologie et de chir. cervico-faciale
Nicoletti, Simon
Selleri, Silvia
Dieng, Mame Massar
Haddad, Elie
Language :
English
Title :
Role of Natural Killer Cells in Intravenous Immunoglobulin-Induced Graft-versus-Host Disease Inhibition in NOD/LtSz-scidIL2rg(-/-) (NSG) Mice.
Publication date :
2015
Journal title :
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
Balduzzi A., Gooley T., Anasetti C., et al. Unrelated donor marrow transplantation in children. Blood 1995, 86:3247-3256.
Ho V.T., Aldridge J., Kim H.T., et al. Comparison of tacrolimus and sirolimus (Tac/Sir) versus tacrolimus, sirolimus, and mini-methotrexate (Tac/Sir/MTX) as acute graft-versus-host disease prophylaxis after reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 2009, 15:844-850.
Anasetti C., Beatty P.G., Storb R., et al. Effect of HLA incompatibility on graft-versus-host disease, relapse, and survival after marrow transplantation for patients with leukemia or lymphoma. Hum Immunol 1990, 29:79-91.
Martin P.J. Increased disparity for minor histocompatibility antigens as a potential cause of increased GVHD risk in marrow transplantation from unrelated donors compared with related donors. Bone Marrow Transplant 1991, 8:217-223.
Sullivan K.M., Kopecky K.J., Jocom J., et al. Immunomodulatory and antimicrobial efficacy of intravenous immunoglobulin in bone marrow transplantation. NEngl J Med 1990, 323:705-712.
Abdel-Mageed A., Graham-Pole J., Del Rosario M.L., et al. Comparison of two doses of intravenous immunoglobulin after allogeneic bone marrow transplants. Bone Marrow Transplant 1999, 23:929-932.
Cottler-Fox M., Spitzer T.R. Immunoglobulin preparations, acute graft-versus-host disease, and infection after marrow transplant. Lancet 1993, 341:1592.
Sullivan K.M., Storek J., Kopecky K.J., et al. Acontrolled trial of long-term administration of intravenous immunoglobulin to prevent late infection and chronic graft-vs.-host disease after marrow transplantation: clinical outcome and effect on subsequent immune recovery. Biol Blood Marrow Transplant 1996, 2:44-53.
Feinstein L.C., Seidel K., Jocum J., et al. Reduced dose intravenous immunoglobulin does not decrease transplant-related complications in adults given related donor marrow allografts. Biol Blood Marrow Transplant 1999, 5:369-378.
Cordonnier C., Chevret S., Legrand M., et al. Should immunoglobulin therapy be used in allogeneic stem-cell transplantation? A randomized, double-blind, dose effect, placebo-controlled, multicenter trial. Ann Intern Med 2003, 139:8-18.
Winston D.J., Antin J.H., Wolff S.N., et al. Amulticenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versus-host disease and infection after allogeneic bone marrow transplantation. Bone Marrow Transplant 2001, 28:187-196.
Cantoni N., Weisser M., Buser A., et al. Infection prevention strategies in a stem cell transplant unit: impact of change of care in isolation practice and routine use of high dose intravenous immunoglobulins on infectious complications and transplant related mortality. Eur J Haematol 2009, 83:130-138.
Gregoire-Gauthier J., Durrieu L., Duval A., et al. Use of immunoglobulins in the prevention of GVHD in a xenogeneic NOD/SCID/gammac- mouse model. Bone Marrow Transplant 2012, 47:439-450.
Ruggeri L., Capanni M., Urbani E., et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002, 295:2097-2100.
Asai O., Longo D.L., Tian Z.G., et al. Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation. JClin Invest 1998, 101:1835-1842.
Aversa F., Terenzi A., Tabilio A., et al. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. JClin Oncol 2005, 23:3447-3454.
Ruggeri L., Mancusi A., Capanni M., et al. Donor natural killer cell allorecognition of missing self in haploidentical hematopoietic transplantation for acute myeloid leukemia: challenging its predictive value. Blood 2007, 110:433-440.
Yamasaki S., Henzan H., Ohno Y., et al. Influence of transplanted dose of CD56+ cells on development of graft-versus-host disease in patients receiving G-CSF-mobilized peripheral blood progenitor cells from HLA-identical sibling donors. Bone Marrow Transplant 2003, 32:505-510.
Cooke K.R., Kobzik L., Martin T.R., et al. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. Blood 1996, 88:3230-3239.
Ito R., Katano I., Kawai K., et al. Highly sensitive model for xenogenic GVHD using severe immunodeficient NOG mice. Transplantation 2009, 87:1654-1658.
Noval Rivas M., Hazzan M., Weatherly K., et al. NK cell regulation of CD4 T cell-mediated graft-versus-host disease. JImmunol 2010, 184:6790-6798.
Rabinovich B.A., Li J., Shannon J., et al. Activated, but not resting, T cells can be recognized and killed by syngeneic NK cells. JImmunol 2003, 170:3572-3576.
Cerboni C., Zingoni A., Cippitelli M., et al. Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK- cell lysis. Blood 2007, 110:606-615.
Olson J.A., Leveson-Gower D.B., Gill S., et al. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood 2010, 115:4293-4301.
Shlomchik W.D., Couzens M.S., Tang C.B., et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999, 285:412-415.
Fujisaki H., Kakuda H., Shimasaki N., et al. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res 2009, 69:4010-4017.
Leveson-Gower D.B., Olson J.A., Sega E.I., et al. Low doses of natural killer T cells provide protection from acute graft-versus-host disease via an IL-4-dependent mechanism. Blood 2011, 117:3220-3229.
Schwab I., Nimmerjahn F. Intravenous immunoglobulin therapy: how does IgG modulate the immune system?. Nat Rev Immunol 2013, 13:176-189.
Anthony R.M., Kobayashi T., Wermeling F., Ravetch J.V. Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway. Nature 2011, 475:110-113.
Gelfand E.W. Intravenous immune globulin in autoimmune and inflammatory diseases. NEngl J Med 2012, 367:2015-2025.
Roussev R.G., Ng S.C., Coulam C.B. Natural killer cell functional activity suppression by intravenous immunoglobulin, intralipid and soluble human leukocyte antigen-G. Am J Reprod Immunol 2007, 57:262-269.
Perricone R., Di Muzio G., Perricone C., et al. High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulins. Am J Reprod Immunol 2006, 55:232-239.
Heilmann L., Schorsch M., Hahn T. CD3-CD56+CD16+ natural killer cells and improvement of pregnancy outcome in IVF/ICSI failure after additional IVIG-treatment. Am J Reprod Immunol 2010, 63:263-265.
Kwak J.Y., Kwak F.M., Ainbinder S.W., et al. Elevated peripheral blood natural killer cells are effectively downregulated by immunoglobulin G infusion in women with recurrent spontaneous abortions. Am J Reprod Immunol 1996, 35:363-369.
Ruiz J.E., Kwak J.Y., Baum L., et al. Effect of intravenous immunoglobulin G on natural killer cell cytotoxicity invitro in women with recurrent spontaneous abortion. JReprod Immunol 1996, 31:125-141.
Ruiz J.E., Kwak J.Y., Baum L., et al. Intravenous immunoglobulin inhibits natural killer cell activity invivo in women with recurrent spontaneous abortion. Am J Reprod Immunol 1996, 35:370-375.
Thum M.Y., Bhaskaran S., Abdalla H.I., et al. Prednisolone suppresses NK cell cytotoxicity invitro in women with a history of infertility and elevated NK cell cytotoxicity. Am J Reprod Immunol 2008, 59:259-265.
van den Heuvel M.J., Peralta C.G., Hatta K., et al. Decline in number of elevated blood CD3(+) CD56(+) NKT cells in response to intravenous immunoglobulin treatment correlates with successful pregnancy. Am J Reprod Immunol 2007, 58:447-459.
Kotlan B., Padanyi A., Batorfi J., et al. Alloimmune and autoimmune background in recurrent pregnancy loss - successful immunotherapy by intravenous immunoglobulin. Am J Reprod Immunol 2006, 55:331-340.
Engelhard D., Waner J.L., Kapoor N., Good R.A. Effect of intravenous immune globulin on natural killer cell activity: possible association with autoimmune neutropenia and idiopathic thrombocytopenia. JPediatr 1986, 108:77-81.
Chong W.P., Ling M.T., Liu Y., et al. Essential role of NK cells in IgG therapy for experimental autoimmune encephalomyelitis. PLoS One 2013, 8:e60862.
Finberg R.W., Newburger J.W., Mikati M.A., et al. Effect of high doses of intravenously administered immune globulin on natural killer cell activity in peripheral blood. JPediatr 1992, 120:376-380.
Bauer S., Groh V., Wu J., et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999, 285:727-729.
Moretta A., Bottino C., Vitale M., et al. Activating receptors and coreceptors involved in human natural killer cell-mediated cytolysis. Ann Rev Immunol 2001, 19:197-223.
Pende D., Parolini S., Pessino A., et al. Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. JExp Med 1999, 190:1505-1516.
Beziat V., Duffy D., Quoc S.N., et al. CD56brightCD16+ NK cells: a functional intermediate stage of NK cell differentiation. JImmunol 2011, 186:6753-6761.
Ravetch J.V., Bolland S. IgG Fc receptors. Ann Rev Immunol 2001, 19:275-290.
Jacobi C., Claus M., Wildemann B., et al. Exposure of NK cells to intravenous immunoglobulin induces IFN gamma release and degranulation but inhibits their cytotoxic activity. Clin Immunol 2009, 133:393-401.
Giordani L., Quaranta M.G., Marchesi A., et al. Increased frequency of immunoglobulin (Ig)A-secreting cells following Toll-like receptor (TLR)-9 engagement in patients with Kawasaki disease. Clin Exp Immunol 2011, 163:346-353.
Vivier E., Tomasello E., Baratin M., et al. Functions of natural killer cells. Nat Immunol 2008, 9:503-510.
Lucas M., Schachterle W., Oberle K., et al. Dendritic cells prime natural killercells by trans-presenting interleukin 15. Immunity 2007, 26:503-517.