Suppression of tumor necrosis factor alpha production by a human immunoglobulin preparation for intravenous use

133

Immune globulin for intravenous use (IVIG) has been used in many inflammatory conditions due to its immunomodulatory potential. The effector mechanisms are incompletely understood. This study dealt with the effects of IVIG on cytokine production in vitro. Cytokine synthesis was identified at the single‐cell level using cytokine‐specific MAb and indirect immunocytochemical techniques. Peripheral blood mononuclear cells (PBMC) were stimulated for 96 h by immobilized anti‐CD3 MAb or by a combination of a protein kinase C activator (PMA) and a calcium ionophore (ionomycin). The addition of IVIG (6 mg/ml) caused a marked inhibition of proliferation and blast transformation despite unaffected cell survival. Anti‐CD3‐stimulatcd cultures containing IVIG exhibited a significant inhibition of production of T‐cell derived lymphokines IL‐2, IL‐10, TNF‐β, IFN‐1 and TNF‐α (made by both monocytes and T cells), while synthesis of the monokinc IL‐8 was significantly increased. The expression of IL‐2 receptors was significantly suppressed. Similar but transient inhibition of most T‐cell products (IL‐2, IL‐3, IL‐4, IL‐5, IL‐10, TNF‐β and GM‐CSF) was noted in the PMA/ionomycin‐containing cultures. In contrast, no effects were found on IFN‐γ or TNF‐α production. The supcrantigen streptococcal pyrogenic exotoxin‐A (SPE‐A) induced vigorous cell activation and extensive cytokine synthesis. IVIG was added either at the beginning or 24 h after the initiation of cultures in order to elucidate the importance of direct toxinneutralization. Addition of IVIG from the beginning of cultures induced a strong reduction of blast transformation and an almost complete inhibition of lymphokinc production, in particular of IFN‐γ and TNF‐β. Supplementation with IVIG 24 h after initiation of cultures also led to a significant decrease in lymphokine synthesis. Monokine production (IL‐1α, IL‐1β, IL‐lra, IL‐6 and IL‐8) was either unaffected or even increased. These two facts argue against direct antigen‐neutralization as being the only mechanism at work. However, in IVIG‐exposed PBMC stimulated with LPS, IL‐6 production was significantly r,educed. A significant upregulation of IL‐lra was noticed in unstimulated PBMC cultured with IVIG. The results in all the experiments did not indicate a cytotoxic effect by IVIG on cell survival and the production of certain cytokines were unaffected. Instead, the authors believe that the results suggest a previously little examined functional link where the humoral immune response may have direct immunoregulatory effects on the cellular immune system.

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Intravenous immune globulin affects cytokine production in T lymphocytes and monocytesjmacrophages

Andersson

Skansén-Saphir²,

Sparrelid³

et al. 1996

133

“…It has been reported previously that homologous IgG suppresses the production of cytokines in vitro from human monocytes and mononuclear cells [24][25][26], but the mechanism of this action has remained unclear. It has further been reported that the production of IL-1a and TNF-a from macrophages (rabbit) stimulated by LPS is also suppressed by addition of heterologous (human) IgG [27,28]. This action is thought to be associated with the Fc region.…”

Section: Groups Activated T Cells Macrophages Activated T Cells Macromentioning

confidence: 95%

Intravenous immunoglobulin (IVIG) treatment of experimental colitis induced by dextran sulfate sodium in rats

Shintani

Nakajima

Nakakubo

et al. 1997

SUMMARYWe investigated the therapeutic effect and immunological action mechanism of IgG in experimental colitis induced by 3% dextran sulfate sodium in rats. Intravenous injection of homologous (rat) IgG (400 mg/kg per day) caused a significant suppression of occult blood discharge and ulcerative lesions in the colon, while no suppressive effect was observed in the case of heterologous (human) IgG. The positive effect of rat IgG on the lesions was also clearly shown by the histological examinations. Generation of proinflammatory cytokines, i.e. tumour necrosis factor-alpha (TNF-a) and IL-1a, in the lesions was found to be inhibited by administration of rat IgG. Little or no suppressive action was exerted by human IgG. Careful examination of recruited T cells and macrophages, both of which are thought to play important roles in the development of ulcerative colitis, indicated that rat IgG, but not its human counterpart, decreased the number of immunocompetent cells in colonic mucosa. Meanwhile, in an in vitro study, both forms of IgG were shown to suppress production of TNF-a and IL-1a from lamina propria mononuclear cells isolated from rat colon. These findings suggest that, mainly by suppressing recruitment of immunocompetent cells into the lesions, homologous IgG may reduce the occurrence of colitis.

“…A decreased production of IL-l has been observed after infusion of IVIG in patients suffering with Kawasaki disease [25] and in rabbits injected with lipopolysaccharide (LPS) that had been pretreated with IVIG (23]. It has been suggested that IVIG suppresses LPS-induccd production of TNF-a and IL-l through an increase in I intracellular levels of cAMP following the interaction of IVIG with Fer receptors on monocytes [26,27]. A marked increase in plasma levels of IL-lra with !000-fold molar excess of IL-lra to IL-l(:J in some patients has been reported in a recent study [28].…”

Section: Modulation Of Synthesis and Release Of Cytokines And Cytokinmentioning

confidence: 99%

Mechanisms of action of intravenous immune globulin in immune-mediated diseases

Mouthon

Kaveri

Spalter

et al. 1996

184

Intravenous immune globulin (IVIG) exhibits a number of immunomodulatory properties that are mediated by the Fe portion of IgG and by the spectrum of variable (V) regions contained in the immune globulin preparations. Five predominant and non‐exclusive mechanisms of action have been proposed to account for the immunomodulatory effects of IVIG in immune‐mediated diseases: (i) functional blockade of Fe receptors on splenic macrophages: (ii) inhibition of complement‐mediated damage, an effect that is dependent on the ability of IgG to bind C3b and C4b and thus reduce the number of activated complement fragments that may deposit on target surfaces of complement activation: (iii) modulation of the production of cytokines and cytokine antagonists: (iv) neutralization of circulating autoantibodies by complementary (e.g. anti‐idiotypic) antibodies in IVIG, a mechanism that accounts for the rapid decrease in titre of circulating autoantibodies that is often observed within hours following the infusion of IVIG: (v) selection of immune repertoires, a complex set of effects that may be observed in individuals receiving IVIG far beyond the half‐life of the infused immunoglobulin and that is directly relevant to the ability of IVIG to, for example, suppress autoantibody‐producing clones in patients with antibody‐mediated autoimmune disease and modulate graft versus host disease (GVHD). IVIG has been shown to downrcgulate or activate B‐cell clones expressing surface IgG that is complementary (anti‐idiotypic) to V regions of antibodies present in IVIG. IVIG has been shown also to interact with surface molecules of T cells that are essential to immune regulation, such as the αβ TCR, CD5, CD4, non‐polymorphic determinants of MHC class I molecules and adhesion molecules of T and B cells. The complex interactions of IVIG with functional molecules of cells of the immune system are relevant to its therapeutic effects in T cell‐ as well as B cell‐ mediated diseases and indeed, to our understanding of the physiological role of normal IgG and antibody networks in controlling autoreactivity in healthy individuals.