PubMed Health⌕ Search

Biomedical subjects

S V Kaveri

Publications and source records attributed to S V Kaveri.

At least 55 records · Page 3Linked to original sources
PubMed1999

[Immunomodulatory effects of intravenous immunoglobulins in autoimmune diseases].

PURPOSE: Intravenous immunoglobulins (IVIg) therapy has been reported to be beneficial in a large number of autoantibody-mediated or self-reactive T cells-associated autoimmune diseases. Thus, the beneficial effect of IVIg is probably due to multiple distinct mechanisms. MAIN POINTS: The immunoregulatory effect of IVIg in autoimmune diseases is dependent on: interaction of the Fc portion of IVIg with Fc receptors on leucocyte surfaces; interaction of infused IgG with complement components; modulation of synthesis and release of cytokines produced by lymphocytes and monocytes: V region-dependent neutralization of circulating autoantibodies by infused IgG; selection of immune repertoires; modulation of cell proliferation, particularly through modulation of Fas-induced apoptosis; interaction of IVIg with numerous other molecules onto the surface of T and B cells. PERSPECTIVES: Better understanding of these mechanisms should allow a better definition of the spectrum of diseases likely to benefit from IVIg treatment.

Apoptosis↗
PubMed1999

Stability of natural self-reactive antibody repertoires during aging.

We have used a quantitative immunoblotting technique to analyze the repertoires of self-reactive antibodies in serum samples obtained from the same five healthy adults over a 25-year interval. The average age of the donors was 43 years at the time of the first serum sample and 69 years at the time of the second serum sample. The antibody repertoires of IgM and IgG were found to be strikingly similar among individuals in both early and late samples. Densitometric profiles of self-reactivity of serum IgM and of purified serum IgG remained unchanged over the 25-year interval. The total reactivity of serum IgG decreased significantly over the 25-year period. The observed stability of the natural self-reactive IgM and IgG antibody repertoires with aging supports the view that autoreactive B cells in the normal immune system are positively selected for reactivity with a limited set of immunodominant self-antigens throughout life.

Adult↗
PubMed1999

Catalytic activity of antibodies against factor VIII in patients with hemophilia A.

Hemophilia A is an X chromosome-linked recessive disorder resulting in defective or deficient factor VIII (FVIII) molecules, which, in its severe form, is a life-threatening and crippling hemorrhagic disease. Infusion of homologous FVIII to patients with severe hemophilia A results, in 25% of patients, in the emergence of alloantibodies against FVIII (inhibitors)( ref. 1) that inhibit FVIII procoagulant activity by steric hindrance of the interaction of FVIII either with stabilizing molecules, with molecules essential for its activity or with activating molecules. Here, we report on the proteolysis of FVIII by alloantibodies of two patients with severe hemophilia A, demonstrating a previously unknown mechanism by which FVIII inhibitors may prevent the pro-coagulant function of FVIII. The kinetic parameters of FVIII hydrolysis indicate a functional role for the catalytic immune response in the inactivation of FVIII in vivo. The characterization of alloantibodies against FVIII as site-specific proteases may provide new approaches to the treatment of FVIII inhibitors.

Antibodies, Catalytic↗
PubMed1998

Therapeutic preparations of normal polyspecific IgG (IVIg) induce apoptosis in human lymphocytes and monocytes: a novel mechanism of action of IVIg involving the Fas apoptotic pathway.

Therapeutic preparations of normal human IgG for i.v. use (i.v.Ig) exhibit a broad spectrum of immunoregulatory activities in vitro and in vivo. I.v.Ig has been shown to inhibit the proliferation of activated B and T lymphocytes and of several autonomously growing cell lines. In this study, we demonstrate that i.v.Ig induces apoptosis in leukemic cells of lymphocyte and monocyte lineage and in CD40-activated normal tonsillar B cells, involving, at least in part, Fas (CD95/APO-1) and activation of caspases. I.v.Ig-induced apoptosis was higher in Fas-sensitive HuT78 cells than in Fas-resistant HuT78.B1 mutant cells, and soluble Fas inhibited IVIg-induced apoptosis. I.v.Ig immunoprecipitated Fas from Fas-expressing transfectants and recognized purified Fas/glutathione-S-transferase fusion proteins upon immunoblotting. Affinity-purified anti-Fas Abs from i.v.Ig induced apoptosis of CEM T cells at a 120-fold lower concentration than unfractionated i.v.Ig. Inhibitors of cysteine proteases of the caspase family, caspase 1 (IL-1beta-converting enzyme) and caspase 3 (Yama/CPP32b), partially inhibited i.v.Ig-induced apoptosis of CEM cells. Furthermore, cleavage of poly(A)DP-ribose polymerase into an 85-kDa signature death fragment was observed in CEM cells following i.v.Ig treatment. Thus, normal IgG induces apoptosis in lymphocytes and monocytes. Our results provide evidence for a role of Fas, bring new insights into the mechanisms of action of i.v.Ig in autoimmune diseases, and suggest a role of normal Ig in controlling cell death and proliferation.

Animals↗
PubMed1998

Self-reactive antibodies (natural autoantibodies) in healthy individuals.

Antibodies that are present in the serum of healthy individuals in the absence of deliberate immunization with any antigen, are refered to as natural antibodies. A vast majority of natural antibodies react with one or more self antigens and are termed as natural autoantibodies. The importance of natural autoantibodies in immune regulation has long been neglected, since tolerance to self was thought to be primarily dependent on the deletion of autoreactive clones, rather than on peripheral suppressive mechanisms. Clonal deletion and energy cannot account, however, for the prevalence of natural autoreactivity among healthy individuals. It is now well established that autoreactive antibodies and B cells, and autoreactive T cells, are present in healthy individuals, and in virtually all vertebrate species. Autoreactive repertoires are predominantly selected early in ontogeny. Questions pertaining to the role of natural antibodies in the regulation of the immune response and maintenance of immune homeostasis and to the distinction between natural autoreactivity and pathological autoimmunity have not been adequately addressed. Here, we focus on the current knowledge on the physicochemical and functional properties of NAA in man, and the use of NAA for therapeutic intervention. reserved.

Autoantibodies↗
PubMed1998

Normal immunoglobulin G protects against experimental allergic encephalomyelitis by inducing transferable T cell unresponsiveness to myelin basic protein.

Normal human IgG for intravenous use (IVIg), administered intraperitoneally, protected Lewis rats against experimental allergic encephalomyelitis (EAE) induced by immunization with myelin basic protein (MBP). We demonstrate that protection was associated with an acquired unresponsiveness of lymphocytes to MBP and a decreased ability of the cells to produce IL-2, IFN-gamma and TNF-alpha and, to a lesser degree, IL-4 and IL-10, in the presence of the antigen. Lymph node (LN) cells of protected rats failed to passively transfer EAE to naive syngeneic animals. Our observations indicate that, rather than inducing selective immune deviation, IVIg induces preferential MBP unresponsiveness of Th1 cells. Whereas LN and splenic cells of IVIg-treated rats did not proliferate nor secrete IL-2 in the presence of the antigen, proliferation was restored by adding exogeneous recombinant IL-2. In contrast, LN cells of IVIg-treated rats proliferated normally and produced IL-2 in the presence of concanavalin A, indicating the selectivity for MBP of the anergy induced by IVIg when given at the time of immunization with the antigen. Treatment with IVIg also allowed a resistance to the secondary induction of EAE, indicating that IVIg protects from EAE but does not interfere with the processes that eventually lead to resistance to re-challenge. These data document the immunomodulatory effects of IVIg in T cell-dependent experimental autoimmune disease and further suggest a role for normal Ig in the selection of functional T cell repertoires.

Animals↗
PubMed1997

Pooled normal human polyspecific IgM contains neutralizing anti-idiotypes to IgG autoantibodies of autoimmune patients and protects from experimental autoimmune disease.

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) suppresses activity of IgG autoantibodies purified from the serum of patients with autoimmune diseases in vitro. The inhibitory effect of IVIgM was greater or equivalent to that of IVIg on a molar basis. We show that IVIgM contains anti-idiotypic antibodies directed against idiotypic determinants of autoantibodies, in particular by showing that Sepharose-bound IVIgM selectively retained F(ab')2 fragments of IgG autoantibodies. The infusion of (Lewis x Brown-Norway) F1 rats with IVIgM protected the animals against experimental autoimmune uveitis induced by immunization with the soluble retinal S antigen, as evidenced by clinical scoring and histopathological analysis. The present findings provide a rationale for considering pooled IgM for immunomodulation of autoimmune disease.

Animals↗
PubMed1997

Analysis of antibody reactivities toward self antigens of IgM of patients with Waldenström's macroglobulinemia.

By using a quantitative immunoblotting technique, we have analyzed the repertoires of antibody reactivities of IgM directed toward self antigens in the serum of patients with Waldenström's macroglobulinemia (WM) and in the serum of healthy adults. Monoclonal IgM of patients with WM expressed various degrees of polyreactivity and a high degree of heterogeneity with regard to the number and the nature of the protein bands that were recognized in homologous tissue extracts. Heterogeneous patterns of reactivity of WM IgM contrasted with the conserved profiles of reactivity of IgM in the serum of healthy blood donors. Protein bands that were recognized by WM IgM belonged to the restricted set of self antigens recognized in homologous tissues by normal polyclonal IgM, indicating the absence of a disease-specific reactivity profile of monoclonal WM IgM. Thus, monoclonal IgM that is present in large amounts in WM distorts the homogeneous pattern of reactivity of natural antibodies with self antigens which characterizes the natural antibody repertoire of healthy individuals.

Adult↗
PubMed1997

A shift in encephalitogenic T cell cytokine pattern is associated with suppression of EAE by intravenous immunoglobulins (IVIg).

Pooled human polyspecific IgG preparations for intravenous use (IVIg) have been used in a number of antibody mediated autoimmune diseases and recently in some T cell mediated disorders including multiple sclerosis, birdshot retinopathy and rheumatoid arthritis. Furthermore, IVIg has been proven beneficial in the corresponding animal models, i.e. experimental autoimmune encephalomyelitis (EAE), experimental autoimmune uveoretinitis and adjuvant arthritis respectively. The exact mechanisms for IVIg action in T cell mediated disorders are still poorly understood. There is evidence that IVIg treatment in vitro and in vivo decreases or changes the kinetics of the secretion by normal PBMC of a number of cytokines and anti-proliferative effect of IVIg on T cells in vitro and in vivo has also been reported. It remains unclear though to what extent the IVIg effects in T cell mediated autoimmunity are related only to non-specific T cell suppression and whether it also reshapes the autoimmune T cell cytokine profile. In this study we demonstrate that IVIg protects against EAE and that this beneficial effect is associated with a decreased proliferation of T cells specific for the immunizing antigen. Moreover, we show that these antigen-specific cells produce low amount of Th1-type cytokines and transfer an attenuated EAE.

Animals↗
PubMed1996

Intravenous immunoglobulin (IVIg) modulates the expansion of V beta 3+ and V beta 17+ T cells induced by staphylococcal enterotoxin B superantigen in vitro.

The authors investigated the effect of IVIg on T-cell proliferation induced by the superantigen, staphylococcal enterotoxin B (SEB). The addition of IVIg to normal PBMC stimulated with SEB resulted in a threefold increase in the proportion of CD3+ blast cells expressing V beta 3 and V beta 17, two subsets of T cells that selectively expand in the presence of SEB. There was no increase in the proportion of T-cell blasts expressing V beta 2, V beta 8 and V beta 13.6 antigens that do not respond to SEB in the absence of IVIg. As described previously, IVIg inhibited T-cell proliferation independently of V beta specificity. The effects of IVIg were mediated by variable regions of immunoglobulins since they were reproduced with F(ab')2 fragments of IVIg but not with purified Fc fragments of IgG. The observation that SEB-activated T cells are rescued from inhibition of proliferation by IVIg indicates that Mg modulates the effects of superantigen on T cells. These results may be of relevance for understanding the mechanisms underlying the effects of IVIg in patients with diseases in which T-cell superantigens are of pathophysiological significance.

Adjuvants, Immunologic↗
PubMed1996

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

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 Fc 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 downregulate 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 alpha beta 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.

Adjuvants, Immunologic↗
PubMed1995

Invariance and restriction toward a limited set of self-antigens characterize neonatal IgM antibody repertoires and prevail in autoreactive repertoires of healthy adults.

Analysis of the reactivity of IgM with self-antigens in tissues by a quantitative immunoblotting technique showed striking invariance among newborns in the human and in the mouse. The self-reactive repertoire of IgM of adults was also markedly conserved; it comprised most anti-self reactivities that prevailed among neonates. Multivariate analysis confirmed the homogeneity of IgM repertoires of neonates toward self- and non-self-antigens. Multivariate analysis discriminated between newborn and adult repertoires for reactivity with two of five sources of self-proteins and with non-self-antigens. Our observations support the concept that naturally activated B lymphocytes are selected early in development and throughout life for reactivity with a restricted set of self-antigens.

Adult↗
PubMed1995

Selective induction of interleukin-1 receptor antagonist and interleukin-8 in human monocytes by normal polyspecific IgG (intravenous immunoglobulin).

We have investigated the effects of intravenous immunoglobulin (IVIg), a therapeutic preparation of normal human polyspecific IgG, on the synthesis and release of cytokines by peripheral blood monocytes. IVIg was found to selectively induce gene transcription and secretion of interleukin-1 receptor antagonist (IL-1ra) and IL-8 in cultures of normal human monocytes. The addition of IVIg to cultures of purified monocytes induced a dose-dependent secretion of IL-1ra and IL-8 without stimulating the production of IL-1 alpha, IL-1 beta, tumor necrosis factor-alpha or IL-6. The effects of IVIg required both the Fc and F(ab')2 portions of IgG. IVIg-induced production of IL-8 by monocytes was enhanced by lipopolysaccharide (LPS), although LPS inhibited the secretion of IL-1ra, suggesting that IVIg and LPS stimulate distinct intracellular pathways in monocytes. Induction of IL-1ra and IL-8 by IVIg was enhanced in the presence of autologous T lymphocytes. Our observations document the selectivity of the effects of IVIg on the synthesis of cytokines and cytokine antagonists by human monocytes. Induction of IL-1ra and IL-8 by IVIg may contribute to the anti-inflammatory effects of immunoglobulin therapy in patients with autoimmune and systemic inflammatory disorders.

Cell Communication↗
PubMed1995

Variable region-connected, dimeric fraction of intravenous immunoglobulin enriched in natural autoantibodies.

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 antigens of IVIg preparations and their dimer-enriched fractions. Dimers were either obtained by affinity chromatography of IVIg on Sepharose-bound F(ab')2 fragments of IVIg or by size exclusion gel filtration chromatography of IVIg. Enrichment of IVIg in dimers was found to be associated with an increase in the antibody activity against self-antigens as compared with unchromatographed IVIg. Our findings extend previous observations on enhanced autoantibody content of the affinity chromatography-separated 'connected' fraction of IVIg and suggest that therapeutic preparations of IVIg enriched in dimers may be obtained by size exclusion chromatography. Separation by size increases the feasibility of industrial-scale preparation of IVIg with high dimer content that are endowed with high potential immunomodulatory activity in vivo.

Autoantibodies↗
PubMed1994

Analysis of natural and disease-associated autoantibody repertoires: anti-endothelial cell IgG autoantibody activity in the serum of healthy individuals and patients with systemic lupus erythematosus.

The present study demonstrates that natural IgG with anti-endothelial cell activity is present in the serum of healthy individuals and in pooled normal human Ig. By using a novel method that allows for the simultaneous and quantitative assessment of reactivities of antibodies with a large number of antigens in tissues, we observed that natural anti-endothelial cell antibody (AECA) recognizes a restricted set of self antigens in endothelial cells that is conserved among healthy individuals. The extent to which natural AECA activity is expressed in serum and the pattern of reactivity of AECA with endothelial cell antigens showed little variability between individuals. Analysis of AECA in the serum of patients with systemic lupus erythematosus (SLE) revealed a higher amount of activity and a wider spectrum of antigenic specificities than that recognized by natural antibodies in endothelial cell extracts. AECA activity of IgG in whole serum was lower than that of purified IgG in the case of healthy individuals and showed little variation among individuals. In contrast, no difference was found between AECA activity of purified IgG and that of IgG in patients' serum suggesting that SLE sera lack the factors that control expression of AECA activity in the serum of healthy individuals. Our results indicate that natural autoantibodies recognize a restricted and conserved set of self antigens. Our observations further suggest that defective regulation of the expressed autoreactive B cell repertoire is the basis for expansion of novel clonal specificities and enhanced autoantibody activity in serum of patients with autoimmune disease.

Autoantibodies↗