A cellular viewpoint of anti-FVIII immune response in hemophilia A.

A large proportion of hemophilia A patients who receive replacement therapy, develop an immune response toward the infused factor VIII (FVIII). In this review, we discuss recent progress in several aspects of the anti-FVIII immune response, focusing on the sites of FVIII endocytosis (marginal zone of the spleen and bleeding site), the type of antigen-presenting cells (dendritic cells, macrophages and B cells) and endocytic receptors, implicated in FVIII presentation to T cells during primary and secondary immune response. Although it is becoming increasingly clear that regulatory T cells are involved in FVIII tolerance in healthy subjects and potentially in patients without inhibitors, we would like to demonstrate that little is known about the different T cells subsets and the cytokines network, which are also crucial for the development of allo- and autoimmune diseases.

Varied immune response to FVIII: presence of proteolytic antibodies directed to factor VIII in different human pathologies.

The versatility of antibodies is demonstrated by the various functions that they mediate such as neutralization, agglutination, fixation of the complement and its activation, and activation of effector cells. In addition to this plethora of functions, antibodies are capable of expressing enzymatic activity. Antibodies with catalytic function are a result of the productive interplay between the highly evolved machinery of the immune system and the chemical framework used to induce them (antigens).

Naturally occurring auto-antibodies in homeostasis and disease.

Antibodies with germline or close to germline configuration exist in vertebrates, and these so-called 'naturally occurring auto-antibodies' (NAb) are directed to self and altered self components. Such NAbs have been attracting increasing interest because several of them, including some in their recombinant forms, have therapeutic potential. Whereas a large number of IgM and IgG NAbs have tissue homeostatic roles, others modulate and regulate cellular and enzyme properties.

Modulation of the cellular immune system by intravenous immunoglobulin.

Intravenous immunoglobulin (IVIg) is therapeutically used in a variety of immune-mediated diseases. The beneficial effects of IVIg in auto-antibody-mediated diseases can be explained by neutralization, accelerated clearance and prevention of Fcgamma-receptor binding of auto-antibodies. However, the means by which IVIg exerts therapeutic effects in disorders mediated by cellular immunity have remained enigmatic.

Role of vitronectin-like protein in Agrobacterium attachment and transformation of Arabidopsis cells.

The role of plant vitronectin-like protein (Vn) in Agrobacterium-host plant interactions and receptor-specific bacterial attachment is unclear and still open to debate. Using a well-established Agrobacterium-mediated Arabidopsis transformation system, the marker gene beta-glucuronidase (GUS) of Escherichia coli, and biochemical and cytological methods, such as ELISA tests, immunoblots, immunolocalization, and functional in vitro binding assays, we have reassessed the role of Vn in receptor-specific bacterial attachment and transformation. We provide evidence that Vn is present in the host plant cells and anti-human vitronectin antibody cross-reacts with a 65-kDa protein from Arabidopsis cells.

The role of VWF in the immunogenicity of FVIII.

Up to 33% of patients with severe haemophilia A develop inhibitory antibodies to factor VIM (FVIII) that can significantly impair treatment with FVIII. The plasma protein von Willebrand factor (VWF) binds to FVIII and is known to be important for the functioning of FVIII. Accumulating data suggest that VWF may also be important for reducing the immunogenicity of therapeutically administered FVIII in patients with haemophilia A.

Auditing protein therapeutics management by professional APCs: toward prevention of immune responses against therapeutic proteins.

Alloimmunization is a crippling concern in the management of patients undergoing administration of protein therapeutics as evidenced in replacement therapy and other treatment procedures. Several issues in the genesis and modulation of such deleterious immune responses have been studied. While authors have focused on the downstream events of the specific immune response and suggested modification of protein therapeutics to eliminate epitopes that interact with B cell receptors, T cell receptors, or MHCII molecules, the mechanisms underlying Ag interaction with APCs, a step upstream of immune effectors, have been grossly neglected.

Functional variability of antibodies upon oxidative processes.

Reactive oxygen species (ROS) released from activated phagocytes are involved in the innate immune defense against pathogens. However, when released in excess and when the antioxidant systems are impaired, ROS may induce cellular and tissue damage and dissociation of iron ions or iron containing compounds (heme) from protein-bound state. Free iron ions and free heme are prooxidative.

In silico identified CCR4 antagonists target regulatory T cells and exert adjuvant activity in vaccination.

Adjuvants are substances that enhance immune responses and thus improve the efficacy of vaccination. Few adjuvants are available for use in humans, and the one that is most commonly used (alum) often induces suboptimal immunity for protection against many pathogens. There is thus an obvious need to develop new and improved adjuvants.

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.

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.

Natural anti-endothelial cell antibodies.

Anti-endothelial cell antibodies (AECA) are detectable in a heterogenous group of autoimmune and inflammatory conditions. These antibodies have also been detected in healthy individuals. Nevertheless, most of the literature focuses on AECA in pathological conditions and their targets and functions in healthy individuals remain to be clarified.

Insight into the mechanism of the acquired antibody auto-reactivity.

A fraction of antibodies present in all healthy individuals begins to recognize large number of self-antigens only after a transient exposure to certain protein-destabilizing conditions, including low or high pH, high salt concentration, chaotropic factors and redox-active agents. Recent findings on the molecular mechanisms of the inducible antibody auto-reactivity, obtained by using kinetic and thermodynamic analysis on the interactions of single monoclonal antibody with its cognate antigen are discussed in the review.

Induction of maturation and activation of human dendritic cells: a mechanism underlying the beneficial effect of Viscum album as complimentary therapy in cancer.

Background: Viscum album (VA) preparations have been used as a complimentary therapy in cancer. In addition to their cytotoxic properties, they have also been shown to have immunostimulatory properties. In the present study, we examine the hypothesis that the VA preparations induce activation of human DC that facilitates effective tumor regression.

Hydrolysis of coagulation factors by circulating IgG is associated with a reduced risk for chronic allograft nephropathy in renal transplanted patients.

Chronic allograft nephropathy (CAN), a major cause of late allograft failure, is characterized by a progressive decline in graft function correlated with tissue destruction. Uncontrolled activation of the coagulation cascade by the stressed endothelium of the graft is thought to play an important role in the pathophysiology of CAN. In this study, we demonstrate that circulating IgG from renal-transplanted patients are endowed with hydrolytic properties toward coagulation factors VIII and IX, but fail to hydrolyze factor VII and prothrombin.

Factor VIII hydrolysis mediated by anti-factor VIII autoantibodies in acquired hemophilia.

Acquired hemophilia is a rare hemorrhagic disorder caused by the spontaneous appearance of inhibitory autoantibodies directed against endogenous coagulation factor VIII (FVIII). Inhibitory Abs also arise in patients with congenital hemophilia A as alloantibodies directed to therapeutic FVIII. Both autoimmune and alloimmune inhibitors neutralize FVIII by steric hindrance.

Dynamics of factor VIII interactions determine its immunologic fate in hemophilia A.

Procoagulant factor VIII (FVIII) is either produced endogenously under physiologic conditions, or administered exogenously as a therapeutic hemostatic drug in patients with hemophilia A. In the circulation, FVIII interacts with a multitude of glycoproteins, and may be used for coagulation at the sites of bleeding, eliminated by scavenger cells, or processed by the immune system, either as a self-constituent or as a foreign antigen. The fate of FVIII is dictated by the immune status of the individual, the location of FVIII in the body at a given time point, and the inflammatory microenvironment.

Infection of macrophages and dendritic cells with primary R5-tropic human immunodeficiency virus type 1 inhibited by natural polyreactive anti-CCR5 antibodies purified from cervicovaginal secretions.

Heterosexual contact is the primary mode of human immunodeficiency virus (HIV) type 1 (HIV-1) transmission worldwide. The chemokine receptor CCR5 is the major coreceptor that is associated with the mucosal transmission of R5-tropic HIV-1 during sexual intercourse. The CCR5 molecule is thus a target for antibody-based therapeutic strategies aimed at blocking HIV-1 entry into cells.

Identification of target antigens of antiendothelial cell antibodies in healthy individuals: A proteomic approach.

In order to identify target antigens of anti-endothelial cell (anti-EC) antibodies (AECA) in healthy individuals, we have used a proteomic approach combining 2-DE and immunoblotting. Whole cell protein extracts obtained from human umbilical vein EC (HUVEC) cultures were used as a source of antigens. Serum IgG from 12 healthy blood donors were tested at a concentration of 200 microg/mL.

Factor VIII inhibitors: role of von Willebrand factor on the uptake of factor VIII by dendritic cells.

In patients with haemophilia A, factor VIII (FVIII) therapy leads to the development of anti-FVIII alloantibodies that inhibit FVIII pro-coagulant activity, in up to 25% of the cases. At a time when efficient viral screening procedures are at place, development of inhibitors poses the greatest threat to haemophilia A patients. Various risk factors, both patient and product-related, are responsible for the development of inhibitory antibodies.

Antiangiogenic treatment prevents adventitial constrictive remodeling in graft arteriosclerosis.

Background: Lumen loss in graft arteriosclerosis is the consequence of the development of a thick neointima and constrictive arterial remodeling. The latter is due to adventitial chronic inflammation and excessive perivascular collagen deposition. We reasoned that blockade of the portal of entry of inflammatory effectors may constitute a strategy to prevent constrictive arterial remodeling.