Tchavdar Vassilev

Tchavdar Vassilev
Bulgarian Academy of Sciences | BAS · Stefan Angelov Institute of Microbiology

Ph.D., D.Sci.

About

86
Publications
7,031
Reads
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2,060
Citations
Citations since 2017
8 Research Items
554 Citations
2017201820192020202120222023020406080100120
2017201820192020202120222023020406080100120
2017201820192020202120222023020406080100120
2017201820192020202120222023020406080100120
Additional affiliations
July 2011 - February 2012
Universitätsklinikum Jena
Position
  • Guest Professor
July 1998 - September 1999
Princeton University
Position
  • Visiting scientist
October 1995 - April 1997
French Institute of Health and Medical Research
Position
  • Visiting scientist

Publications

Publications (86)
Article
Full-text available
Mild modification of intravenous immunoglobulin (IVIG) has been reported to result in enhanced polyspecificity and leveraged therapeutic effects in animal models of inflammation. Here, we observed that IVIG modification by ferrous ions, heme or low pH exposure, shifted the repertoires of specificities in different directions. Ferrous ions exposed F...
Article
Full-text available
Specific antibody reactivities are routinely used as biomarkers, but the antibody repertoire reactivity (igome) profiles are still neglected. Here, we propose rationally designed peptide arrays as efficient probes for these system level biomarkers. Most IgM antibodies are characterized by few somatic mutations, polyspecificity, and physiological au...
Article
Full-text available
Background A proportion of the human IgM repertoire (IgM igome) antibodies is partially autoreactive and by interacting with intrinsic structures, this part can reflect changes in the internal environment. Thus, it can be a potential source of biomarkers for various pathological processes. The aim of the current study is to create an optimal librar...
Article
Specific antibody reactivities are routinely used as biomarkers but the use of antibody repertoire profiles is still awaiting recognition. Here we suggest to expedite the adoption of this class of system level biomarkers by rationally designing a peptide array as an efficient probe for an appropriately chosen repertoire compartment. Most IgM antibo...
Preprint
Full-text available
Specific antibody reactivities are routinely used as biomarkers but the use of antibody repertoire profiles is still awaiting recognition. Here we suggest to expedite the adoption of this class of system level biomarkers by rationally designing a peptide array as an efficient probe for an appropriately chosen repertoire compartment. Most IgM antibo...
Chapter
Immunoglobulins (antibodies) are glycoprotein molecules that play a key role in adaptive immunity. They protect us in the hostile environment of bacteria, viruses, and parasites. There are five classes of human immunoglobulins—IgM, IgG, IgA, IgE, and IgD. Most IgM antibodies (1.5 mg/mL plasma) are “natural”—i.e., they are produced even without an a...
Article
Full-text available
Antibody repertoires of healthy humans and animals contain a fraction of antibodies able to acquire additional polyspecificity following exposure to several biologically relevant redox molecules (free heme, reactive oxygen species, ferrous ions, HOCl, etc.). The physiological role of these "hidden" polyspecific antibodies is poorly understood. Simi...
Article
Polyreactive antibodies represent a considerable fraction of the immune repertoires. Some antibodies acquire polyreactivity post-translationally after interaction with various redox-active substances, including heme. Recently we have demonstrated that heme binding to a naturally polyreactive antibody (SPE7) results in a considerable broadening of t...
Article
Full-text available
Sepsis is a major cause for death worldwide. Numerous interventional trials with agents neutralizing single pro-inflammatory mediators have failed to improve survival in sepsis and aseptic systemic inflammatory response syndromes. This failure could well be explained by the widespread gene expression dysregulation known as "genomic storm" in these...
Poster
We present a pilot study based on immunosignatures related to known brain malignancies. Our aim is to find specific patterns of antibody production against tumor epitopes in the diagnostic work-up. Material and methods: Surgically treated patients in the Clinic of Neurosurgery at St. Ivan Rilski University Hospital, Sofia, Bulgaria, were included....
Article
The normal immune repertoire contains natural polyreactive antibodies (Abs) as well as antibodies that could acquire polyreactivity following interac- tion with protein-modifying agents. The list of molecules able to induce polyre- activity of Abs includes reactive oxygen species (ROS), free ferrous ions and heme. The molecular mechanisms of this p...
Article
A fraction of antibodies from healthy immune repertoires binds to heme and acquires ability to recognize multiple antigens. The mechanism and functional consequences of heme-mediated antigen binding promiscuity (polyreactivity) are not understood. Here, we used SPE7, a mouse monoclonal IgE specific for dinitrophenyl that has been thoroughly charact...
Article
Despite the paradigm that carbohydrates are T cell-independent antigens, isotype-switched glycan-specific immunoglobulin G (IgG) antibodies and polysaccharide-specific T cells are found in humans. We used a systems-level approach combined with glycan array technology to decipher the repertoire of carbohydrate-specific IgG antibodies in intravenous...
Article
Full-text available
The aim of this study was to investigate the immunomodulatory capacity of native and Fe(II)-exposed intravenous immune globulin (IVIg) in multiple low dose streptozotocin-induced diabetes and to delineate the mechanisms of their influence on immune cell functions. Optimal doses (200-600mg/kg) of IVIg prevented the development of hyperglycemia, glyc...
Article
Full-text available
The aim of this study was to investigate the immunomodulatory capacity of native and Fe2+ exposed IVIG in multiple low dose streptozotocin induced diabetes and to delineate the mechanisms of their influence on immune cell functions. Optimal doses (200-600mg/kg) of IVIGs prevented the development of hyperglycemia, glycosuria and attenuated mononucle...
Article
Full-text available
We read with great interest the recent paper by Azmi et al. [1][1] who reported the in vitro and in vivo anti-lymphoma activity of novel specific inhibitors of nuclear export (SINE). The authors focused on targeting a main nuclear export protein called chromosome maintenance region 1 (CRM1) or
Article
Full-text available
An Ab molecule or a BCR that is able to bind multiple structurally unrelated Ags is defined as polyreactive. Polyreactive Abs and BCRs constitute an important part of immune repertoires under physiological conditions and may play essential roles in immune defense and in the maintenance of immune homeostasis. In this review, we integrate and discuss...
Article
Targeting autoreactive B lymphocytes at any stage of their differentiation could yield viable therapeutic strategies for treating autoimmunity. All currently used drugs, including the most recently introduced biological agents, lack target specificity. Selective silencing of double stranded DNA-specific B cells in animals with spontaneous lupus has...
Article
Passive immunotherapy with modified intravenous immunoglobulins (IVIg) improves survival in experimental sepsis by attenuating inflammatory and coagulation pathways Tchavdar L. Vassilev 1* • 1 Bulgarian Academy of Sciences, Bulgaria T. Vassilev1, I. Djoumerska-Alexieva1, J. Dimitrov2, L. Roumenina2, E. Voynova1, I. Nina Ivanovska1, K. Srini2; 1St...
Article
Intravenous immunoglobulin preparations (IVIg) that have undergone a mild oxidizing treatment with ferrous ions have an increased polyspecificity, which is not associated with a higher propensity to form aggregates. Among other biological properties of the modified IVIg, a protective effect in LPS sepsis model stands out as the native preparation i...
Article
Full-text available
Polyspecificity (polyreactivity) is currently considered an intrinsic property of a subset of antibodies, primarily of naturally occurring autoantibodies. Polyspecificity is no longer viewed as a biologically irrelevant stickiness. Furthermore, the capacity to bind defined sets of unrelated antigens finds its structural explanation. What is most in...
Article
Full-text available
Normal intravenous immunoglobulin (IVIg) preparations are potentially promising drugs for the adjunctive treatment of sepsis as the pool of IgG antibodies neutralizes a wide array of pathogens plus their virulence factors and in addition possesses broad anti-inflammatory and immunomodulating activities. However, several high quality clinical studie...
Article
Intravenous immunoglobulins (IVIG) are known to have a therapeutic effect in some autoimmune diseases. We examined the effect of IVIG and heme-exposed IVIG on the development of immune mediated diabetes induced in C57BL/6 mice by multiple low doses of streptozotocin. IVIG were used in a dose of 200mg/kg daily for 15 days. Treatment with IVIG result...
Article
All currently used drugs for treatment of autoimmune diseases are unselective and target diseases-associated as well as disease-irrelevant immune cells. This stresses the need for development of agents a ecting pathological auto-reactive lymphocytes only. In addition, drugs targeting the long-lived plasmacytes (that are resistant to all conventiona...
Article
Full-text available
Exposure of polyclonal IgG to some protein-destabilizing agents results in a significant increase of its antigen-binding polyspecificity. This newly acquired enhancement of pre-existing immunoreactivity has been shown to be a result of structural changes in the antigen-binding sites of some immunoglobulin molecules and leads to the recognition of a...
Article
Full-text available
Nucleic acids are known to induce complement activation, which results in the masking and removal of apoptotic cells exposing nuclear components. Dysregulation of these events is characteristic of SLE, a systemic autoimmune disease characterized by the appearance of ANAs. In this study, we aimed to investigate the relationship between development o...
Article
A novel approach for the selective silencing of targeted autoreactive B lymphocytes is reviewed that mimics the physiological mechanisms for suppressing B cell activity. It is based on the use of bi- or tri-specific chimeric antibodies that cross-link BCRs with a pre-selected antigen-binding specificity with one or more inhibitory types of receptor...
Article
Polyspecific antibodies represent a significant fraction of the antibody repertoires in healthy animals and humans. Interestingly, certain antibodies only acquire a polyspecific antigen-binding behavior after exposure to protein-modifying conditions, such as those found at inflammation sites, or used in small- and large-scale immunoglobulin purific...
Article
IgG molecules are exposed on a regular basis to acidic conditions during immunoaffinity purification procedures, as well as during the production of some therapeutic immunoglobulin preparations. This exposure is known to induce in them an antigen-binding polyreactivity. The molecular mechanisms and the possible biological significance of this pheno...
Conference Paper
Full-text available
IvIgs have been proved to be beneficial in the treatment of autoimmune and systemic inflammatory diseases. The immunomodulatory effect of IvIgs has been explained by several mutually nonexclusive mechanisms. However, the therapeutic effect of IvIgs in diabetogenesis has not been studied. Therefore, we analyzed their effects in the multiple low dose...
Article
Full-text available
Type 1 diabetes mellitus is an autoimmune disease in which pathologic autoreactive T cells attack the insulinsecreting pancreatic islets of Langerhans. Intravenous immunoglobulin has been shown to have a therapeutic eff ect in some autoimmune diseases. Th e therapeutic effect of intravenous immunoglobulin has not been tested in type 1 diabetes mell...
Article
Full-text available
Intravenous immunoglobulin (IVIg) preparations are known to modulate autoimmune/inflammatory diseases through several F(ab')(2)- and Fc-dependent mechanisms. In this study, we show that the in vitro and the in vivo exposure of B lymphocytes from lupus-prone and from healthy mice to IVIg results in an increased expression of their surface inhibitory...
Article
Full-text available
Normal pooled human IVIg are produced using various blood protein fractionation technologies and as a result they may well differ in their biological properties. We have demonstrated that exposure of IVIg, for a period as short as 15 min, to protein-destabilizing agents like acidic pH, ROS or pro-oxidative ferrous ions dramatically increases the pa...
Article
All B cell targeting therapeutic approaches used at present are unspecific and there is an urgent need for agents that silence selectively pathological autoreactive B lymphocytes only. We hypothesized that this aim could be achieved by chimeric antibodies that cross-link B cell immunoglobulin receptors with inhibitory receptors on the surface of th...
Article
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...
Article
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 antibod...
Article
Full-text available
There is an urgent and unmet need for therapeutic agents targeting selectively disease-associated B-lymphocytes in autoantibody-mediated diseases. We have constructed a chimeric molecule able to cross-link cell surface immunoglobulin with the inhibitory complement receptor type 1 (CD35) on DNA-specific B cells from SLE (systemic lupus erythematosus...
Article
Full-text available
Natural polyreactive IgG antibodies are found in the sera of all healthy individuals. The in vitro exposure of pooled human IgG to protein-destabilizing chemical or physical factors has been previously shown to result in the exposure of their "hidden" polyspecificity. We hypothesize that such an enhancement of their pre-existing immunoreactivity ma...
Article
The pathological DNA-specific B lymphocytes in lupus are logical targets for a selected therapeutic intervention. We have hypothesized that it should be possible to suppress selectively the activity of these B cells in lupus mice by administering to them an artificial molecule that cross-links their surface immunoglobulins with the inhibitory Fcgam...
Article
Full-text available
Various pathological processes are accompanied by release of high amounts of free heme into the circulation. We demonstrated by kinetic, thermodynamic, and spectroscopic analyses that antibodies have an intrinsic ability to bind heme. This binding resulted in a decrease in the conformational freedom of the antibody paratopes and in a change in the...
Article
The ability of aluminium phosphate and calcium phosphate to stimulate the synthesis of tetanus toxoid-specific anaphilactic and antitoxic antibodies is compared. The observed differences in the kinetics of IgG1a, IgG3b, and antitoxines are quantitative–titres alter application of aluminium phosphate are higher. Booster immunization with aluminium b...
Article
Full-text available
The complement system and circulating antibodies play a major role in the defence against infection. They act at the sites of inflammation, where the harsh microenvironment and the oxidative stress lead to the release of free iron ions and haeme. The aim of this study was to analyse the consequences of the exposure of C1q and immunoglobulins to iro...
Article
Polyspecificity is defined as the ability of a given antibody molecule to bind a large panel of structurally diverse antigens. A fraction of circulating IgG in all healthy individuals acquires promiscuous antigen-binding activity only after a transient exposure to certain protein destabilizing factors. The molecular mechanisms of this phenomenon ar...
Article
Previous studies of an experimental human immunoglobulin preparation for intravenous use, containing normal pooled IgM (IVIgM), have shown its beneficial therapeutic effect in experimental autoimmune diseases. The mechanisms of its immunomodulatory activity remain however, poorly understood. In the experiments reported here, IVIgM inhibited the pro...
Article
Killed viral vaccines are known to induce primarily antibody responses. By contrast DNA vaccination using naked DNA encoding viral antigens induces both humoral and cellular immune responses. Various approaches have been used to construct DNA vaccines with build-in adjuvanticity. We hypothesized that sequences encoding a common epitope of influenza...
Article
Full-text available
Polyspecific antibodies represent a first line of defense against infection and regulate inflammation, properties hypothesized to rely on their ability to interact with multiple antigens. We demonstrated that IgG exposure to pro-oxidative ferrous ions or to reactive oxygen species enhances paratope flexibility and hydrophobicity, leading to expansi...
Article
Natural immunoglobulin G (IgG) autoantibodies are present in the plasma of healthy individuals and, as a result, in pooled therapeutic intravenous immunoglobulin (IVIg) preparations. The production processes of commercial IVIg preparations involve different fractionation and virus-inactivation steps that include in some cases treatments at extreme...
Article
Natural polyreactive IgG autoantibodies are present in the plasma of healthy individuals and as a result in pooled therapeutic intravenous immunoglobulin (i.v.Ig) preparations. The spectrum of self-antigens to which these autoantibodies bind, their fate after intravenous infusion and their biological activity are not well understood. The identity o...
Article
A major event in the pathogenesis of systemic lupus erythematosus (SLE) is the breaking of tolerance to native DNA and the appearance of IgG anti-double-stranded (ds) DNA antibodies. The mechanisms of the losing of tolerance are not well understood. Continuous efforts have been made in the past to induce anti-native DNA IgG autoantibodies in non-au...
Article
Full-text available
Diphtheria toxin is produced by growing Corinebacterium diphtheriae either in a semisynthetic casein-based medium or in the Pope-Lingood meat extract based medium. The World Health Organization advises the use of the semisynthetic one, as it has important advantages. Data on the composition of casein-based media and their ability to support high to...
Article
Full-text available
The use of semi-synthetic broths for cultivation of Corynebacterium diphtheriae instead of a meat extract-based broth avoids the presence of highly undesirable bovine meat antigens in the diphtheria toxoid. As information on the composition of casein digest-based broths used for the production of diphtheria toxoid is scarce, we have now developed o...
Article
Serum IgM has been shown to participate in the control of IgG autoreactivity in healthy subjects. We have recently shown that an immunoglobulin preparation of pooled normal human IgM (IVIgM) contains anti-idiotypic antibodies against disease-associated IgG autoantibodies in autoimmune patients and protects rats from experimental autoimmunity. The a...
Article
Full-text available
Intravenous immunoglobulin (IVIg) therapy is associated with a broad range of immunomodulatory activities. Several of the postulated mechanisms of IVIg action relate to the presence of antibodies to molecules relevant for regulation of the immune response. This article reports that IVIg contains antibodies to the Arg-Gly-Asp (RGD) sequence, and the...
Article
Intravenous immunoglobulin (IVIg) therapy is associated with a broad range of immunomodulatory activities. Several of the postulated mechanisms of IVIg action relate to the presence of antibodies to molecules relevant for regulation of the immune response. This article reports that IVIg contains antibodies to the Arg-Gly-Asp (RGD) sequence, and the...
Article
Normal human serum contains IgM antibodies that regulate the natural autoantibody activity of IgG in autologous serum. In the present study, we show that pooled normal human IgM (IVIgM) purified from plasma of more than 2,500 healthy donors and processed in a similar fashion to that of therapeutic preparations of pooled normal human IgG (IVIg) supp...
Article
Normal human serum contains IgM antibodies that regulate the natural autoantibody activity of IgG in autologous serum. In the present study, we show that pooled normal human IgM (IVIgM) purified from plasma of more than 2,500 healthy donors and processed in a similar fashion to that of therapeutic preparations of pooled normal human IgG (IVIg) supp...
Article
Significant progress has been made in understanding the mechanisms by which intravenous immunoglobulins (IVIg) exert immunomodulatory effects in the treatment of autoimmune diseases. A unique property of immunoglobulins is the diversity of variable (V) regions. The evidence discussed in this communication supports our notion that the diversity of V...
Article
Antibodies to a wide spectrum of infectious agents belonging to the IgA, IgM and IgG isotypes are thought to be one of the protective factors in human milk. Cow milk-fed newborns are at an increased risk of infections as well as of allergic diseases and of necrotising enterocolitis. A reasonable approach would be to add to the milk formula fed to t...
Article
Pooled therapeutic intravenous immunoglobulin (IVIg) is increasingly used for the treatment of autoimmune and systemic inflammatory diseases. The lack of a clear understanding of the mode of action of IVIg has been an obstacle to a more rational use and schedule of administration of IVIg and to the improvement of the existing IVIg preparations. Sev...
Article
Secretory antibodies against bacteria and viruses in human colostrum and milk are known to be important protective factors for the breast-fed infant. The authors have shown by enzyme immunoassay that colostrum contains IgA and IgM antibodies to a number of autoantigens: native DNA, actin, myosin, myoglobin, laminin, transferrin and thyroglobulin. T...
Article
Full-text available
Intravenous immunoglobulin (IVIg) is increasingly used for the treatment of autoimmune diseases and the prevention of infections and of graft versus host reactions in recipients of allogeneic bone marrow transplants. The immunomodulatory effects of IVIg are largely dependent on their ability to interact with membrane molecules of lymphocytes. We re...
Article
Antibodies to a wide spectrum of infectious agents belonging to the IgA, IgM and IgG isotypes are thought to be one of the protective factors in human milk. Cow milk-fed newborns are at an increased risk of infectious and allergic diseases as well as of necrotizing enterocolitis. We developed a pasteurized immunoglobutin preparation from pooled don...
Article
The beneficial effect of intravenous immunoglobulin (IVIg) therapy in patients with autoimmune diseases is at least partially dependent on the content in IVIg of antibodies capable of interacting with variable regions (idiotypes) of autoantibodies. In the present study, we have evaluated the antibody activity to a panel of self and environmental an...
Article
IVIg are increasingly used for the treatment of autoimmune diseases. In the present study, we show that IVIg contain antibodies directed against CD5, a cell surface molecule of T cells which is also a marker of the autoantibody-producing CD20+ ('B-1') subset of B lymphocytes. Antibodies to the CD5 molecule were demonstrated in IVIg by the ability o...
Chapter
Expression of autoreactivity is efficiently regulated under physiological conditions to maintain the homeostasis of the immune system, thus preventing the emergence of autoaggressive T and B cell clones. Selection of preimmune repertoires and control of autoreactivity in healthy individuals involve variable (V) region interactions between antibodie...
Article
The levels of IgG subclasses were determined, by radial immunodiffusion using monoclonal antibodies, in 16 production batches of two human immunoglobulin preparations for intravenous use--Immunovenin and Immunovenin-intact. While the partially degraded preparation--Immunovenin contained exclusively IgG1, the subclass distribution in Immunovenin-int...
Article
A critical overview of present-day ideas on the mode of action of immune response adjuvants is presented. Data supporting the hypothesis that the suppression of the non-immune elimination of antigen or/and of the secretion of inhibitory factors by macrophages could be an important mechanism by which many adjuvants potentiate the immune response are...
Article
The protective effect of two different human immunoglobulin preparations for intravenous use and one specific staphylococcal immunoglobulin for intramuscular application were compared in mice infected with the capsular Staphylococcus aureus Smith stra