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Biomedical subjects

Jagadeesh Bayry

Publications and source records attributed to Jagadeesh Bayry.

At least 19 recordsLinked to original sources
PubMed2006

VWF protects FVIII from endocytosis by dendritic cells and subsequent presentation to immune effectors.

Von Willebrand factor (VWF) is a chaperone molecule for procoagulant factor VIII (FVIII). Its role in the reduction of the immunogenicity of therapeutic FVIII in patients with hemophilia A has been evoked but lacks clear cellular and molecular rationale. Here, we demonstrate that VWF protects FVIII from being endocytosed by human dendritic cells (DCs) and subsequently presented to FVIII-specific T cells. The immunoprotective effect of VWF requires a physical interaction with FVIII because the endocytosis of FVIII was significantly restored on hindering the formation of the VWF-FVIII complex. Interestingly, VWF had no direct inhibitory effect either on the ability of DCs to present antigenic peptides or on the activation potency of CD4+ T cells. We thus propose that VWF may reduce the immunogenicity of FVIII by preventing, upstream from the activation of immune effectors, the entry of FVIII in professional antigen-presenting cells.

Antigen Presentation↗
PubMed2006

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.

Caprylates↗
PubMed2006

Catalytic IgG from patients with hemophilia A inactivate therapeutic factor VIII.

Factor VIII (FVIII) inhibitors are anti-FVIII IgG that arise in up to 50% of the patients with hemophilia A, upon therapeutic administration of exogenous FVIII. Factor VIII inhibitors neutralize the activity of the administered FVIII by sterically hindering its interaction with molecules of the coagulation cascade, or by forming immune complexes with FVIII and accelerating its clearance from the circulation. We have shown previously that a subset of anti-factor VIII IgG hydrolyzes FVIII. FVIII-hydrolyzing IgG are detected in over 50% of inhibitor-positive patients with severe hemophilia A, and are not found in inhibitor-negative patients. Although human proficient catalytic Abs have been described in a number of inflammatory and autoimmune disorders, their pathological relevance remains elusive. We demonstrate here that the kinetics of FVIII degradation by FVIII-hydrolyzing IgG are compatible with a pathogenic role for IgG catalysts. We also report that FVIII-hydrolyzing IgG from each patient exhibit multiple cleavage sites on FVIII and that, while the specificity of cleavage varies from one patient to another, catalytic IgG preferentially hydrolyze peptide bonds containing basic amino acids.

Adolescent↗
PubMed2006

Interaction of foot-and-mouth disease virus with dendritic cells.

Despite several decades of investigation, the manner in which foot-and-mouth disease virus (FMDV) interacts with the innate and adaptive immune compartments is not completely understood. The importance of elucidating this relationship is emphasized by the inability of current FMDV vaccines to provide long-term protection and the recent outbreaks of FMDV in formerly disease-free countries. Dendritic cells (DCs) are professional antigen-presenting cells that have evolved to monitor the environment and provide a link between the innate and adaptive immune systems. Comprehending the cross-talk between DC and FMDV will provide valuable information towards understanding the host response to the virus and will aid in the design of effective tools and vaccines to block virus spread.

Animals↗
PubMed2006

Interleukin-12 is associated with the in vivo anti-tumor effect of mistletoe extracts in B16 mouse melanoma.

Viscum album (VA) preparations consist of aqueous extracts of different types of lectins of mistletoe. VA exert cytotoxic and immunomodulatory properties that may be relevant for the inhibition of tumor growth. We addressed the effects of VA preparation VA Qu FrF on growth of B16F1 melanoma implanted in mice and on proliferation and cytokine synthesis of splenocytes. In C57BL6 mice, inhibition of tumor growth by VA was associated with an enhancement of splenocyte proliferation and with an up-regulation of IL-12 secretion. In IL-12-deficient strain of mice the inhibition of melanoma growth by VA and the splenocyte proliferation were abrogated. Results from the present study strongly suggest a crucial role of IL-12 in the anti-tumor properties of VA extracts.

Animals↗
PubMed2006

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.

Angiogenesis Inhibitors↗
PubMed2005

Intravenous immunoglobulin in autoimmune disorders: an insight into the immunoregulatory mechanisms.

Intravenous immunoglobulin (IGIV) has increasingly been used for the treatment of autoimmune and systemic inflammatory diseases in addition to supportive therapy of immunodeficient patients. IGIV is beneficial in several diseases, including acute and chronic/relapsing diseases, autoimmune diseases and inflammatory disorders. Therapeutic efficacy of IGIV has also been established in a number of dermatologic diseases. Although a considerable progress has been made in understanding the mechanisms by which IGIV exerts immunomodulatory functions in autoimmune diseases, they remain not fully elucidated. The mode of action of IGIV is complex, involving modulation of expression and function of Fc receptors, interference with activation of complement and the cytokine network, modulation of idiotype network, regulation of cell growth, alteration of cellular adhesion process, and effects on the activation differentiation and effector functions of T and B cells and of antigen-presenting cells. The therapeutic effects of IGIV most likely reflect the functions of natural antibodies in maintaining immune homeostasis in healthy people. The ability of IGIV to interact through V regions with complementary V regions of antibodies and antigen receptors as well as with relevant soluble and surface molecules provides the basis for inducing the selection of immune repertoires. Since IGIV is frequently used to treat autoimmune and inflammatory diseases for which evidence of its efficacy is insufficiently documented, controlled trials, particularly of some neurologic and dermatologic diseases, are imperative.

Animals↗
PubMed2005

Modulation of dendritic cell maturation and function by B lymphocytes.

Investigating the signals that regulate the function of dendritic cells (DC), the sentinels of the immune system, is critical to understanding the role of DC in the regulation of immune responses. Accumulating lines of evidence indicate that in addition to innate stimuli and T cell-derived signals, B lymphocytes exert a profound regulatory effect in vitro and in vivo on the Ag-presenting function of DC. The identification of B cells as a cellular source of cytokines, chemokines, and autoantibodies that are critically involved in the process of maturation, migration, and function of DC provides a rationale for immunotherapeutic intervention of autoimmune and inflammatory conditions by targeting B cells. Conversely, efficient cross-presentation of Ags by DC pulsed with immune complexes provides an alternative approach in the immunotherapy of cancer and infectious diseases.

Animals↗
PubMed2005

High levels of catalytic antibodies correlate with favorable outcome in sepsis.

Sepsis is the leading cause of death in intensive care units and results from a deleterious systemic host response to infection. Although initially perceived as potentially deleterious, catalytic antibodies have been proposed to participate in removal of metabolic wastes and protection against infection. Here we show that the presence in plasma of IgG endowed with serine protease-like hydrolytic activity strongly correlates with survival from sepsis. Variances of catalytic rates of IgG were greater in the case of patients with severe sepsis than healthy donors (P < 0.001), indicating that sepsis is associated with alterations in plasma levels of hydrolytic IgG. The catalytic rates of IgG from patients who survived were significantly greater than those of IgG from deceased patients (P < 0.05). The cumulative rate of survival was higher among patients exhibiting high rates of IgG-mediated hydrolysis as compared with patients with low hydrolytic rates (P < 0.05). An inverse correlation was also observed between the markers of severity of disseminated intravascular coagulation and rates of hydrolysis of patients' IgG. Furthermore, IgG from three surviving patients hydrolyzed factor VIII, one of which also hydrolyzed factor IX, suggesting that, in some patients, catalytic IgG may participate in the control of disseminated microvascular thrombosis. Our observations provide the first evidence that hydrolytic antibodies might play a role in recovery from a disease.

Antibodies, Catalytic↗
PubMed2005

Intravenous immunoglobulin in neurological disorders: a mechanistic perspective.

Intravenous immunoglobulin (IVIg) has been used in the treatment of primary and secondary antibody deficiencies for over 25 years. It is a safe preparation with no long-term side effects. IVIg was first demonstrated to be effective in autoimmune disorders, two decades ago, in the treatment of acute immune thrombocytopenia. Since then, the therapeutic efficacy of IVIg has been established in Guillain Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis (MG), dermatomyositis (DM), Kawasaki syndrome and the prevention of graft-versus-host disease in recipients of allogeneic bone marrow transplants and reported in a large number of other autoimmune and systemic inflammatory conditions.

Animals↗
PubMed2005

Common variable immunodeficiency: the immune system in chaos.

Common variable immunodeficiency (CVID) is a heterogeneous disorder that is associated with low serum-immunoglobulin concentrations, defective specific-antibody production and an increased susceptibility to bacterial infections of the respiratory and gastrointestinal tracts. In spite of the identification of genes that are associated with several known primary immunodeficiencies, the basic immunologic and molecular defects of the majority of patients with CVID have remained obscure. Most of the studies aimed at understanding the immunopathogenesis of CVID suggest that this condition is primarily a T-cell disorder, although renewed attention on the genetic linkage and haplotype analysis in families of patients with CVID and on the role of dendritic cells and B cells has revealed several interesting features. This new information should assist in understanding the pathogenesis of CVID and improving the therapeutic strategies.

B-Lymphocytes↗
PubMed2005

Intravenous immunoglobulin and dendritic cells.

Intravenous immunoglobulin (IVIg) has increasingly been used for the treatment of autoimmune and systemic inflammatory diseases, and in supportive therapy of immunodeficient patients. Available clinical and experimental evidence suggests, however, that a wide spectrum of immune-mediated conditions could benefit from IVIg, including acute and chronic/relapsing diseases and autoimmune diseases mediated by pathogenic autoantibodies or by autoaggressive T-cells. Dendritic cells (DCs) are professional antigen-presenting cells and because of their capacity to stimulate naïve T-cells, they play a central role in the initiation of primary immune responses. Several immunomodulatory agents have been shown to inhibit DC activation. Recently, we examined the effects of IVIg on differentiation, maturation, and functions of DCs. We demonstrate that DCs are one of the targets for the immunomodulatory effects of IVIg.

Animals↗
PubMed2004

Natural antibodies sustain differentiation and maturation of human dendritic cells.

The differentiation and maturation of dendritic cells (DCs) is governed by various signals in the microenvironment. Monocytes and DCs circulate in peripheral blood, which contains high levels of natural antibodies (NAbs). NAbs are germ-line-encoded and occur in the absence of deliberate immunization or microbial aggression. To assess the importance of NAbs in the milieu on DC development, we examined the status of DCs in patients with X-linked agammaglobulinemia, a disease characterized by paucity of B cells and circulating antibodies. We demonstrate that the in vitro differentiation of DCs is severely impaired in these patients, at least in part because of low levels of circulating NAbs. We identified NAbs reactive with the CD40 molecule as an important component that participates in the development of DCs. CD40-reactive NAbs restored normal phenotypes of DCs in patients. The maturation process induced by CD40-reactive NAbs was accompanied by an increased IL-10 and decreased IL-12 production. The transcription factor analysis revealed distinct signaling pathways operated by CD40-reactive NAbs compared to those by CD40 ligand. These 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.

Adolescent↗
PubMed2004

Common variable immunodeficiency is associated with defective functions of dendritic cells.

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and defects in T-cell functions that could be primary or secondary. We addressed whether CVID is associated with impairment in the dendritic cell (DC) compartment, as DCs play a central role in the development of adaptive immunity. We demonstrate that DCs from CVID patients display severely perturbed differentiation, maturation, and function, and express markedly reduced levels of the costimulatory molecules that are critical for T-cell stimulation. Patients' DCs induced weak proliferation of allogeneic T cells and produced significantly low amounts of interleukin-12 (IL-12) upon CD40 signaling. Multiple defects in the immune system, including malfunctioning of DCs, appear to be prominent features of CVID patients. Impairment in both the innate and adaptive compartments of the immune system may thus cumulatively account for the inability of CVID patients to eradicate pathogens through conventional immune pathways, thus resulting in an increased risk for recurrent bacterial infections.

Cell Differentiation↗