Combined vitamin D, ibuprofen and glutamic acid decarboxylase-alum treatment in recent onset Type I diabetes: lessons from the DIABGAD randomized pilot trial.

AIM: Double-blind placebo-controlled intervention using glutamic acid decarboxylase (GAD)-alum, vitamin D and Ibuprofen in recent onset Type I diabetes (T1D). METHODS: 64 patients (T1D since <4 months, age 10-17.99, fasting sC-peptide ≥0.12 nmol/l, GADA-positive) were randomized into Day(D) 1-90 400 mg/day Ibuprofen, D1-450 vitamin D 2000 IU/day, D15, 45 sc. 20 µg GAD-alum; as A but placebo instead of Ibuprofen; as B but 40 µg GAD-alum D15, 45; placebo. RESULTS: Treatment was safe and tolerable. No C-peptide preservation was observed. We observed a linear correlation of baseline C-peptide, HbA1c and insulin/per kilogram/24 h with change in C-peptide AUC at 15 months (r = -0.776, p < 0.0001). CONCLUSION: Ibuprofen, vitamin D + GAD-alum did not preserve C-peptide. Treatment efficacy was influenced by baseline clinical and immunological factors and vitamin D concentration. Clinical Trial Registration: NCT01785108 (ClinicalTrials.gov).

Role of natural antibodies in immune homeostasis: IVIg perspective.

Intravenous immunoglobulin (IVIg) has increasingly been used for the treatment of autoimmune and systemic inflammatory diseases in addition to supportive therapy of immunodeficient patients. Although a considerable progress has been made in understanding the mechanisms by which IVIg exerts immunomodulatory functions in these diseases, they remain not fully elucidated. The mode of action of IVIg is complex, involving interference with activation of complement and the cytokine network, modulation of: idiotype network, expression of Fc receptors, and activation, differentiation and effector functions of T and B cells and of antigen-presenting cells such as dendritic cells. The therapeutic effects of IVIg most likely reflect the functions of natural antibodies in maintaining immune homeostasis in healthy individuals.

Modulation of human dendritic cell maturation and function by natural IgG antibodies.

Dendritic cells (DCs) are professional antigen-presenting cells, which have a central role in the initiation of primary immune responses and in maintaining immune tolerance. The functions of DCs can be regulated both by environmental signals as well as signals delivered by endogenous molecules. Recently we have examined regulation of human DCs by B cells via natural IgG antibodies. Natural antibodies (NAbs) are defined as antibodies that circulate in normal individuals in the absence of deliberate immunization or microbial aggression. We demonstrate that the differentiation of DCs is severely impaired in primary immunodeficient patients such as X-linked agammaglobulinemia (XLA) and common variable immunodeficiency (CVID) at least in part due to the deficiency of circulating NAbs. Further, we show that NAbs are able to restore normal phenotypes of DCs from patients with XLA and CVID. Our results suggest that B cells promote bystander DC development through NAbs and the interaction between NAbs and DCs may play a role in steady-state migration of DCs.

Intravenous immunoglobulins in autoimmune and inflammatory diseases: a mechanistic perspective.

Initially used for the treatment of immunodeficiencies, intravenous immunoglobulins (IVIg) have increasingly been used as immunomodulatory agents in autoimmune and inflammatory disorders. The mode of action of IVIg is enigmatic, probably involving Fc-dependent and/or F(ab')2-dependent nonexclusive mechanisms of action. IVIg broadly interacts with the different components of the immune system: cytokines, complement, Fc receptors, and several cell surface immunocompetent molecules. IVIg has also an impact on effector functions of immune cells. These mechanisms of action of IVIg reflect the importance of natural antibodies in the maintenance of immune homeostasis. We discuss here the recent advances in the understanding of immunoregulatory effects of IVIg, and we pointed out the need for new strategies to overcome the predicted increasing worldwide shortage of IVIg.

Intravenous immunoglobulin in autoimmune and inflammatory diseases: more than mere transfer of antibodies.

Initially used for the treatment of immunodeficiencies, intravenous immunoglobulin (IVIg) has increasingly been used as an immunomodulatory agent in immune thrombocytopenic purpura, autoimmune neuropathies, systemic lupus erythematosus, myasthenia gravis, Guillain-Barré syndrome, and Kawasaki disease. Although IVIg benefits have been reported in many autoimmune and systemic inflammatory diseases, its mechanisms of immunomodulation are not fully understood and probably involve Fc-dependent and/or F(ab')(2)-dependent mutually non-exclusive effects. These mechanisms of action of IVIg reflect the importance of natural antibodies in the maintenance of immune homeostasis. We discuss here the recent advances in the understanding of immunoregulatory effects of IVIg.

[Use of intravenous polyclonal immunoglobulins in autoimmune and inflammatory disorders]. / Utilisation des immunoglobulines polyclonales intraveineuses dans les pathologies auto-immunes et inflammatoires.

Initially used for the treatment of immunodeficiencies, intravenous immunoglobulins (IVIg) have increasingly been used as immunomodulatory agent in autoimmune and inflammatory disorders. The mode of action of IVIg is enigmatic, probably involving Fc-dependent and/or F(ab')2-dependent non-exclusive mechanisms of action. IVIg broadly interacts with the different components of the immune system: cytokines, complement, Fc receptors and several cell surface immunocompetent molecules. IVIg also has an impact on effector functions of immune cells. These mechanisms of action of IVIg reflect the importance of natural antibodies in the maintenance of immune homeostasis. We discuss here the recent advances in the understanding of immunoregulatory effects of IVIg, and we pointed out the need of new strategies to overcome the predicted increasing worldwide shortage of IVIg.

Comparative study of the anti-inflammatory effect of two intravenous immunoglobulin preparations manufactured by different processes.

Intravenous immunoglobulin (IVIG) is increasingly used in the treatment of diverse immune-mediated disorders. Since several preparations of IVIG are available for therapy, it is possible that different manufacturing processes might influence clinical efficacy of IVIG. An insight into the mechanisms of action of such different IVIG preparations is therefore necessary that will provide further guidelines for the utility of IVIG preparations in autoimmune and inflammatory diseases. Since endothelial cells (EC) influence the inflammatory process via production of cytokines, chemokines and expression of adhesive molecules, we analyzed the anti-inflammatory effect on EC of two IVIG preparations: caprylated IVIG (IVIG-C) versus solvent/detergent-treated IVIG (IVIG-SD) preparation. We found that both IVIG preparations inhibit in an equivalent manner, the expression of different pro-inflammatory factors such as IL-6, IL-8, GM-CSF, IL-1beta and TNF-alpha and the adhesion molecules ICAM-1 and VCAM-1. Our results thus suggest that the caprylate while inactivating the virus and enhancing the yield of IgG during IVIG formulation, does not modulate the immunomodulatory properties of IVIG at EC level and that the two preparations show similar anti-inflammatory effects.

Immunoglobulin G-reactive antibodies from sera of healthy individuals enriched in IgG2--therapeutic potential in HIV-1 infection.

OBJECTIVE: To characterize the functional properties of natural autoantibodies capable of preventing in vitro infection by HIV-1, present in normal human serum (NHS), and denoted as IgG-reactive antibodies. METHODS: IgG-reactive antibodies were affinity purified both from normal human serum (NHS) and from a GammaBind G Sepharose Flowthrough (GBF) fraction of NHS by affinity chromatography on IgG coupled to CNBr-activated Sepharose (IgG-Sepharose). RESULTS: The GBF fraction was shown, by Capture ELISA relative to isotype-matched standards, to contain in addition to IgM and IgA isotypes, a low but constant level of IgG isotype. About 15% of the GBF fraction's IgG, compared to only about 0.3% of the NHS IgG, was affinity purified on IgG-Sepharose. On IgG subclass analysis, in contrast to the characteristic dominance of IgG1 in pooled NHS, the IgG-reactive antibodies obtained from NHS and from the GBF fraction each showed a dominance of IgG2. Western blot analysis confirmed the abundance of IgG2, a major IgG subclass reactive against carbohydrate antigens, and showed the presence of IgG2 dimers. The IgG-reactive antibodies separated from the GBF fraction were able to neutralize HIV-1(BaL) strain with approaching 100% and 80% effectiveness at 2 microg/ml and 0.6 microg/ml, respectively, as well as the primary isolates HIV-1(NDK) (X4-tropic isolate) and HIV-1(JR-CSF) (R5-tropic isolate) with an IC50 between 0.4 microg/ml and 1.8 microg/ml for two different preparations. CONCLUSION: These findings further support our previous proposal for IgG-reactive antibody preparations to be used in the treatment of HIV-1 infected individuals.

Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis.

The clinical use of intravenous immunoglobulin (IVIg) based on its immunomodulatory and anti-inflammatory potential remains an ongoing challenge. Fcgamma receptor-mediated effects of IVIg, although well elucidated in certain pathologies, cannot entirely account for its proven benefit in several autoimmune disorders mediated by autoreactive T cells. In this study, we show that prophylactic infusion of IVIg prevents the development of experimental autoimmune encephalomyelitis (EAE), an accepted animal model for multiple sclerosis (MS). The protection was associated with peripheral increase in CD4+CD25+Foxp3+ regulatory T cell (Treg) numbers and function. The protection was Treg-mediated because IVIg failed to protect against EAE in mice that were depleted of the Treg population. Rather than inducing de novo generation from conventional T cells, IVIg had a direct effect on proliferation of natural Treg. In conclusion, our results highlight a novel mechanism of action of IVIg and provide a rationale to test the use of IVIg as an immunomodulatory tool to enhance Treg in early onset MS and other autoimmune and inflammatory conditions.

Intravenous immunoglobulin: an update on the clinical use and mechanisms of action.

Initially used as a replacement therapy for immunodeficiency diseases, intravenous immunoglobulin (IVIg) is now widely used for a number of autoimmune and inflammatory diseases. Considerable progress has been made in understanding the mechanisms by which IVIg exerts immunomodulatory effects in autoimmune and inflammatory disorders. The mechanisms of action of IVIg are complex, involving modulation of expression and function of Fc receptors, interference with activation of complement and the cytokine network and of idiotype network, regulation of cell growth, and effects on the activation, differentiation, and effector functions of dendritic cells, and T and B cells.

Molecular mechanisms underlying the immunomodulatory effects of mistletoe (Viscum album L.) extracts Iscador.

Viscum album (VA) preparations (Iscador) consist of aqueous extracts from different types of European mistletoe. Biologically active components of VA extracts include mistletoe lectins (ML) and viscotoxins. The treatment with VA extracts or with purified ML has been shown to be associated with tumor regression in several in vivo experimental models of tumoral implantation. The mechanisms underlying the anti-tumoral activity of VA or ML are complex and involve apoptosis, angiogenesis and immunomodulation. This review provides an account of the current status of the understanding of the VA-associated immunomodulation in various cell types including lymphoblastoid, monocytic or endothelial cell lines.