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.

Lack of acute xenogeneic graft‐versus‐host disease, but retention of T‐cell function following engraftment of human peripheral blood mononuclear cells in NSG mice deficient in MHC class I and II expression

“…Humanized mice have been widely used to model human immune cell function in vivo (1)(2)(3)(4)(5)(6). In the Hu-PBL-SCID model, a major limitation of studying human T-cell function is the rapid development of fatal xenogeneic GVHD that not only shortens the experimental time window but also confounds the analysis of human T cell function due to the underlying ongoing acute GVHD that eventually kills the mice (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). In the present study, we have overcome this limitation by eliminating expression of murine MHC class I and II in NSG mice.…”

“…The Hu-PBL-SCID model has been used to study human infectious agents, tissue transplantation, and human T-cell immune function (2,(12)(13)(14). One of the primary uses of this model is the study of acute graft-versus-host disease (GVHD) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), a major problem in clinical hematopoietic stem cell transplantation (26). NSG mice engrafted with human PBMCs develop an acute xenogeneic GVHD-like disease upon recognition of the murine cells and tissues by mature human T cells (23).…”

A recombinant human IgG1 Fc multimer designed to mimic the active fraction of IVIG in autoimmunity

“…This limited binding to rat B cells suggests that GL-2045 may not bind to the inhibitory FcγRIIb receptor on the surface of circulating immune cells in the rat. Similarly, based on recent studies demonstrating that NK cells are required for the IVIG-mediated prevention of graft vs. host disease (GVHD) in a mouse model, the inability of GL-2045 to engage rat NK cells may also contribute to the different GL-2045-mediated cytokine changes observed in NHPs vs. rats (48).…”

Potentiation of cytokine-induced proliferation of human Natural Killer cells by intravenous immunoglobulin G

“…Chong et al [60] recently demonstrated that the beneficial effect of IVIG in mice with EAE was absolutely dependent on NK cells and that the upregulation of Treg cells, which is associated with the IVIG-induced EAE disease amelioration, was also dependent on the presence of NK cells in the mice. Furthermore, Gregoire-Gauthier et al [61] reported that in SCID mice during xenogenic graft vs. host disease including with IVIG, resolution of NK cell deficits have been observed [30,[62][63][64][65][66][67][68][69]. Whether this is related to IVIG potentiation of the effects of certain cytokines on NK cells remains to be determined in humans receiving IVIG therapy, and these studies are currently being initiated.…”