Intravenous immunoglobulins suppress T-cell priming by modulating the bidirectional interaction between dendritic cells and natural killer cells

Abstract

IntroductionIntravenous immunoglobulins (IVIgs) are pharmaceutical preparations of human IgG purified from pools of plasma of thousands of donors. For decades IVIgs have been established as treatment of autoantibody-mediated 1 and T-cell-mediated inflammatory disorders. 2 The distribution of IgG subclasses in IVIgs is comparable with that of IgG in normal human serum, however, unlike IgG purified from a single individual, therapeutic IVIg preparations contain substantial amounts of IgG dimers and traces of multimers, due to the idiotype-anti-idiotype complex formation between IgG molecules from different individuals. 3,4 In general, IVIgs were shown to be effective in conditions in which the immune system is hyperactive, but still the mechanisms of action by which IVIgs correct immune dysregulation are not fully understood. Various reports showed that the mode of actions of IVIgs is multifaceted and complex, involving interference with different components of the immune system. Clinical and immunologic improvements induced by IVIg treatment are reported to be profound and to extend the half-life of infused IgG, suggesting that IVIgs can modify cellular immune reactivity for prolonged periods. 1,5 Recently, we observed that hyperimmune IVIgs against hepatitis B surface antigen (HBs) protect against acute rejection after liver transplantation, indicating that IVIg treatment can modulate the T-cell-mediated immune response against alloantigens. 6 We and others found that in vitro both anti-HBs IVIgs and nonspecific IVIgs are able to suppress T-cell proliferation and cytokine production, and to impair the allogeneic T-cell stimulatory capacity of monocyte-derived and blood-derived dendritic cells (DCs), [6][7][8][9] demonstrating that IVIgs can suppress T-cell responses both during the priming phase as well as in the effector phase. The importance of DCs as a cellular target of IVIgs in vivo was recently shown in a murine model of immune thrombocytopenic purpura (ITP), in which treatment with IVIgs could be replaced by adoptive transfer of IVIg-treated DCs. 10 With regard to the mechanism by which IVIgs affect DC function, we found that the decreased T-cell stimulatory capacity of IVIg-treated DCs (IVIg-DCs) was associated with induction of cell death in mature DCs. Interestingly, IVIg treatment itself did not induce DC death directly, as the increased death of IVIg-DCs occurred only when cultured with other immune cells (ie, T cells and natural killer [NK] cells). 9 As activated NK cells are capable of killing DCs in a number of circumstances, 11,12 we hypothesized that NK cells may induce apoptosis of IVIg-DCs during the initial phase of DC-NK-cell encounter (ie, before the T-cell activation).Interactions between DCs and NK cells have been documented in a variety of settings, shedding light on the complexity of the bidirectional interaction between these 2 cell types. Bajenoff et al showed that NK cells are present in the medulla and the paracortex of lymph nodes, where they closely interact with DCs. Upon receivi...

Intravenous immunoglobulin and salicylate differentially modulate pathogenic processes leading to vascular damage in a model of Kawasaki disease

“…IVIG reduces cell surface expression of class II MHC on APCs (30,31). IVIG has also been shown to directly inhibit the ability of dendritic cells to prime naive T cells; this occurs through natural killer cell-mediated induction of antibody-dependent cellular cytotoxicity (32).…”

Use of immunoglobulins in the prevention of GvHD in a xenogeneic NOD/SCID/γc− mouse model

“…These results suggest that IVIG do not inhibit the proliferation of human T-cells in mice and support the hypothesis that IVIG reduce GvHD via immunomodulatory actions, as suggested by other authors. [38][39][40][41][42][43] Determination of human plasma cytokine concentration We found a strong increase of IFN-g, IL-17 and IL-2, and a moderate increase of IL-6, IL-8, IL-10 and IL-15 in PBStreated mice when compared with baseline levels (set as levels before huPBMC injection). This confirmed the generation of a human cytokine storm in our xenogeneic GvHD model.…”

“…As inhibition of T-cell proliferation is one of the caveats of immunosuppression because it leads to the inhibition of the graft vs leukemia, this finding could have an impact on clinical practice. Many studies showed that IVIG inhibit T-cell proliferation or induce apoptosis 42,43,[53][54][55][56][57] whereas others failed to demonstrate any direct effect of IVIG on T-cells. 58,59 Interestingly, studies showing an inhibition of T-cell proliferation or an induction of apoptosis were performed in vitro whereas studies that failed to demonstrate any direct effect on T-cell proliferation were performed in vivo.…”

Indirect inhibition of in vivo and in vitro T-cell responses by intravenous immunoglobulins due to impaired antigen presentation

“…These studies showed that IVIg inhibited T-cell proliferation or induced apoptosis. [16][17][18][19][20][21][22] However, other studies reported the absence of effect of IVIg on T cells using alternative experimental conditions, making it difficult to derive strong conclusions on the role of IVIg on T-cell activation, proliferation, and survival. 16,[23][24][25] One possible explanation for the discrepant results could be that ex vivo allogeneic or polyclonal activation of purified cells by lectins, mitogens, or anti-CD3 antibodies is different from the physiologic context, leading to in vivo T-cell activation in response to an (auto)antigen.…”