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Biomedical subjects

J M Saint-Remy

Publications and source records attributed to J M Saint-Remy.

At least 37 records · Page 2Linked to original sources
PubMed1997

Treatment with dsDNA-anti-dsDNA antibody complexes extends survival, decreases anti-dsDNA antibody production and reduces severity of nephritis in MRLlpr mice.

Lupus nephritis results from the deposition on the glomerular basement membrane of antibodies cross-reacting with dsDNA. In an attempt to suppress the production of such antibodies in the MRLlpr mouse strain, mice were treated by injections of dsDNA-anti-dsDNA antibody complexes formed in an excess of syngeneic polyclonal antibodies to increase the immunogenicity of idiotypes. A first group of mice was treated after the onset of high-affinity anti-dsDNA IgG antibodies (3 months). We show here that fortnightly injections of dsDNA-anti-dsDNA antibody complexes significantly extend mouse survival over that of two control groups treated with either the carrier buffer or with sham complexes. Treated mice produced 5-fold less anti-dsDNA antibodies than control mice and presented a reduced nephritis activity index at the age of 7 months. Specific anti-idiotypic antibody levels were not modified in the treated group, while showing a sharp decrease in the control group between months 6 and 7. Mice of a second group were started on injections of dsDNA-anti-dsDNA complexes at the age of 4 months when nephritis was already ongoing, and were followed until death while receiving fortnightly injections. Forty percent of the treated mice were still alive after one year, while none of the control mice survived. dsDNA-anti-dsDNA complexes have therefore the potential of reducing the production of anti-dsDNA antibody production and the severity of nephritis in MRLlpr mice. These findings could be relevant for the treatment of human lupus.

Animals↗
PubMed1997

Factor VIII inhibitors in previously treated haemophilia A patients with a double virus-inactivated plasma derived factor VIII concentrate.

Antibodies to factor VIII (inhibitors) are usually produced at the beginning of treatment with factor VIII and are rare in multitransfused patients. Such antibodies are deemed to be patient-related, as supported by the description of a number of associated risk factors. However, a second category of inhibitors has recently been identified, namely antibodies occurring in multitransfused patients as a result of exposure to a particular factor VIII concentrate. A first outbreak of product-related inhibitors was recently described. The present paper describes the second well-documented occurrence of such inhibitors. Eight out of 140 multitransfused patients with severe haemophilia A developed an inhibitor to factor VIII shortly after changing treatment to a double-virus inactivated plasma-derived factor VIII concentrate. In addition to solvent-detergent treatment, this concentrate was pasteurised at 63 degrees C for 10 hours. Exposure to the pasteurised product before inhibitor detection ranged from 9 to 45 days. Inhibitor titers varied between 2.2 and 60 Bethesda Units and recovery of transfused factor VIII ranged from 0.21 to 0.68 (expressed as i.u./dl factor VIII rise per i.u./kg administered). In contrast to usual inhibitors in haemophilia A patients, these product-related inhibitors showed complex inhibition kinetics. They were found specific for the factor VIII light chain. The inhibitors gradually declined when exposure to the pasteurised product was stopped, despite further treatment with other factor VIII concentrates. The present data stress the importance of carefully monitored clinical studies, both in previously treated and previously untreated patients, before introduction of a new or modified clotting factor concentrate.

Adolescent↗
PubMed1997

Restricted epitope specificity of anti-FVIII antibodies that appeared during a recent outbreak of inhibitors.

We recently described an outbreak of anti-factor VIII (FVIII) antibodies in a population of haemophilia A patients non-responsive to FVIII (1). To find out what part of the FVIII molecule had been altered, we purified specific anti-FVIII antibodies from the plasma of the five patients showing high titres of inhibitors. An average of 100 micrograms antibodies per ml of initial plasma was recovered by immunoadsorption on insolubilised FVIII. The antibodies followed the normal isotypic distribution, including the presence of specific IgG2 antibodies; the relative increase in IgG4 that is usually observed in patients with long-standing inhibitors, was not present. The regions of FVIII to which human antibodies bound were determined by a competition assay using a panel of murine monoclonal antibodies: two major regions were identified, one located in the A2 heavy chain domain, and the other made of determinants of both the A3 and C2 light chain domains. Affinity-purified antibodies inhibited the function of FVIII as determined in a chromogenic assay. However, variations existed in the affinities with which antibodies bound to soluble FVIII. This study shows that the immunogenicity of two particular regions of FVIII has been altered. A screening for alterations located in these two regions should possibly be included in the preclinical evaluation of FVIII concentrates.

Animals↗
PubMed1996

Neutralizing antiidiotypic antibodies to factor VIII inhibitors after desensitization in patients with hemophilia A.

Hemophilia A patients producing antibodies towards FVIII are usually treated with infusions of high doses of FVIII in an attempt to "desensitize" them. To examine the mechanisms by which such desensitization operates, sequential plasma samples of two unrelated inhibitor patients were analyzed for anti-FVIII and antiidiotypic antibodies before and during infusions of high doses of FVIII. Anti-FVIII antibodies were separated from antiidiotypic antibodies by immunoaffinity chromatography before analysis. We show in the present study that the concentration of anti-FVIII antibodies did not change during a successful desensitization and that antibodies maintained their capacity to inhibit the procoagulant function of FVIII, even though the number of Bethesda units in plasma was reduced to undetectable levels. Using a competition assay with mAbs, we further show that the specificity of human antibodies did not vary significantly during therapy. Finally, we show that the treatment elicited antiidiotypic antibodies, which neutralized the inhibitory capacity of anti-FVIII antibodies. Inhibitor antibodies can therefore not be accurately evaluated in plasma, as their function appears to be neutralized by antiidiotypic antibodies. These findings could have implications for the design of new therapies for hemophilia A patients with inhibitors.

Adolescent↗
PubMed1995

Strategy for pre-clinical evaluation of factor VIII concentrates.

A series of methods and assay systems was designed, using both mouse monoclonal antibodies and purified human polyclonal antibodies, by which alterations in the antigenic properties, and potentially therefore in the immunogenic properties, of FVIII concentrates could be identified. Those methods could be applied to the pre-clinical evaluation of FVIII concentrates. It has become evident that very subtle alterations in FVIII can have dramatic effects on its antigenicity and immunogenicity and it is suggested that an analysis of FVIII preparations, using reagents such as mouse monoclonal antibodies, should be carried out as a pre-clinical evaluation. It is also thought that any haemophiliac patient is at risk of developing anti-FVIII antibodies, even though he had been considered as tolerant to the infusion of FVIII. The diversity of FVIII concentrates now available on the market has multiplied the chances of encountering a product that would give an immune response in some patients and this further stresses the need for a careful check of FVIII concentrates.

Animals↗
PubMed1995

Allergen-sensitive atopic dermatitis is improved by injections of allergen combined with F(ab')2 fragments of specific antibodies.

Symptoms of atopic dermatitis (AD) can be provoked by exposure to airborne allergens. We have previously shown that patients hypersensitive to D. pteronyssinus (Dpt) allergens were improved by administration of complexes composed of specific antibodies and allergen, which reduce the allergen-specific immune response. We now report that similar results can be achieved by using F(ab')2 fragments of specific antibodies instead of whole antibody molecules. Eight adult patients with severe AD were included in a single-blind study. During the first 11 months patients were maintained on injections of carrier buffer alone, in an effort to evaluate the extent of spontaneous improvement. They were then treated with intradermal injections of allergen-F(ab')2 complexes made from autologous specific antibodies and Dpt allergens. The majority of the patients improved spontaneously during the summer months, with an average 30% reduction of symptoms. However, a much more pronounced improvement was observed after 3 months on active therapy, corresponding to a cumulative amount of 60 micrograms F(ab')2 and 15 micrograms allergens. The patients continued to improve over the next 5 months, showing an average 83% reduction of severity scores. The use of F(ab')2 antibody fragments reduces the risk of inducing an anti-allotypic immune response, and raises the possibility of adding adjuvants to allergen-antibody complexes and/or using specific antibodies isolated from pooled gammaglobulins.

Adult↗
PubMed1995

Human auto-anti-idiotypic antibodies to mite-specific IgE can degranulate human basophils in vitro.

BACKGROUND: Anti-idiotypic antibodies (anti-Ids) to specific IgE antibodies are formed spontaneously during an anti-allergen immune response and can be induced by immunotherapy. Although anti-Ids can down-regulate the production of IgE antibodies, at least in experimental models, their possible role in the modulation of target cell reactivity remains ill-defined. OBJECTIVE: The capacity of human anti-Ids to modulate the release of histamine was examined in an in vitro system of human basophil degranulation. Anti-Ids were prepared from the serum of six Dermatophagoides pteronyssinus (Dp)-hypersensitive patients suffering from atopic dermatitis and who had never been desensitized. Basophils were obtained from the blood of atopic donors. The extent of histamine release was determined using a fluorometric assay. RESULTS: We show that: anti-Ids trigger the release of histamine in an allergen-specific, dose- and IgE-dependent manner; the release is not due to the presence of allergen and/or anti-IgE antibodies; and that the degranulating activity can be removed by absorption with affinity-purified anti-Dp antibodies of the corresponding patient. CONCLUSION: These results indicate that spontaneously produced human anti-Ids can modulate the reactivity of human basophils.

Allergens↗
PubMed1995

Specific down-regulation of anti-allergen IgE and IgG antibodies in humans associated with injections of allergen-specific antibody complexes.

Several approaches have recently been put forward describing attempts to suppress the IgE immune response towards allergens, which is thought to be the key event in allergic diseases. In a series of clinical trials we have shown that injections of complexes made up from allergen and specific antibodies are an effective treatment for allergic bronchial asthma and atopic dermatitis. In the work presented here we have examined the humoral immunity changes associated with the use of such complexes in a group of 19 adult patients suffering from atopic dermatitis and hypersensitive to Dermatophagoides pteronyssinus (Dp), and in whom a significant clinical improvement was observed. By comparing serum samples taken prior to and after 4 months of therapy, we show that the administration of immune complexes is associated with: (i) a significant and selective reduction of IgG and IgE antibodies specific for Dp allergens; (ii) a down-regulation that affects only the antibodies present in the complexes; (iii) the induction of corresponding anti-idiotypic antibodies. To our knowledge, this is the first demonstration in humans that an anti-allergen antibody response can be down-regulated in a highly selective manner and that this is accompanied by significant clinical improvement. Moreover, the selective reduction of IgG antibodies could be of value in the treatment of some forms of auto-immune diseases.

Adult↗
PubMed1994

Human interleukin 10 induces naive surface immunoglobulin D+ (sIgD+) B cells to secrete IgG1 and IgG3.

During antigen-induced immune responses, human B cells switch isotype from immunoglobulin M (IgM)-IgD to IgG1-4, IgA1-2, or IgE. In the human, no cytokines have yet been demonstrated to act as switch factors for IgG1, IgG2, and IgG3. In this paper, we report that in response to interleukin 10 (IL-10), anti-CD40 activated tonsillar surface IgD+ (sIgD+) B cells are induced to secrete large amounts of IgM, IgG1, and IgG3 but neither IgG2 nor IgG4. Cord blood purified B cells and lymphocytes from Hyper-IgM patients also produced IgG1 and IgG3 after culture with anti-CD40 and IL-10. In contrast, sIgD- isotype-committed B cells produce IgG1, IgG2, and IgG3 when activated through CD40 in the presence of IL-10. Thus, in addition to its growth-promoting and differentiating activities on human B cells, IL-10 may represent a switch factor for IgG1 and IgG3.

B-Lymphocytes↗
PubMed1994

Identification of a specific epitope on the extracellular domain of the LDL-receptor of Trypanosoma brucei brucei.

We have previously shown that an antiserum raised against the 86-kDa fragment of the low-density lipoprotein-receptor (LDL-receptor) of bloodstream Trypanosoma brucei brucei shows extensive cross-reactivity with the mammalian LDL-receptor. Here we report on the production and characterisation of 30 monoclonal antibodies (mAbs) raised against the same 86-kDa fragment of the T. b. brucei LDL-receptor. Of these, only 8 mAbs recognise in an ELISA test the purified (presumably intact) 145-kDa LDL-receptor. Seven of them also recognise the LDL-receptors isolated from rat and rabbit, whereas one mAb (1A9) is specific for the trypanosome LDL-receptor. A pool of several mAbs inhibits by 90% the specific binding of 125I-LDL to trypanosomes at 4 degrees C, but does not interfere with binding of 125I-LDL to rat fibroblasts. 125I-mAb 1A9 is efficiently taken up by T. b. brucei at 30 degrees C and its uptake is inhibited by an excess of unlabelled LDL particles, indicating that mAb 1A9 follows the LDL-receptor pathway. Uptake of 125I-mAb 1A9 by rat fibroblasts is less efficient and is not significantly reduced by an excess of unlabelled LDL. MAb 1A9 as well as other pooled mAbs activate rabbit complement, leading to lysis of trypanosomes in vitro. We conclude that the T. b. brucei LDL-receptor contains at least one specific epitope that is accessible on live cells to antibodies and which can activate the complement system.

Animals↗
PubMed1994

Healthy subjects produce both anti-factor VIII and specific anti-idiotypic antibodies.

Anti-Factor VIII (FVIII) antibodies were prepared by a combination of salt precipitation, gel filtration chromatography, and specific adsorption over insolubilized FVIII from the serum of 10 healthy subjects with normal levels of FVIII. Antibody specificity was confirmed by the capacity to recognize soluble and insolubilized FVIII and to neutralize FVIII cofactor activity in FX activation. Epitope mapping was carried out using a competition ELISA in which affinity-purified human antibodies inhibited the binding of labeled monoclonal antibodies. In most cases, a single region of the A3 domain of the FVIII light chain was recognized by the antibodies, while the reactivity toward heavy chain epitopes differed from one antibody preparation to the other. Sera or IgG fractions of the serum before immunoadsorption over insolubilized FVIII did not bind to FVIII. The IgG fraction that was not retained on the FVIII immunosorbent contained IgG that bound to the variable part of anti-FVIII mouse monoclonal antibodies and inhibited the binding of labeled FVIII; in addition, the IgG fraction inhibited the binding of affinity-purified human antibodies to FVIII, thereby strongly suggesting the presence of anti-idiotypic antibodies. These findings indicate that the presence of anti-FVIII antibodies is a more universal phenomenon than previously thought and that anti-idiotypic antibodies capable of inhibiting the binding of anti-FVIII antibodies to FVIII are produced spontaneously.

Animals↗
PubMed1994

Injections of complexes made of dsDNA and specific polyclonal antibodies extend MRL lpr mouse survival: a pilot study.

Antibodies towards double-strain (ds) DNA are responsible for the development of lupus nephritis both in human and animal models. A method by which one would suppress the production of pathogenic idiotypes could therefore prevent the development of nephritis. To this end, we prepared polyclonal anti-dsDNA antibodies by immunoaffinity from a serum pool of MRL/MpJ-lpr mice, a strain that develops an early form of nephritis identical to its human counterpart. Antigen-antibody complexes were prepared by addition of dsDNA. Such complexes have the potential of altering the anti-DNA antibody response and boosting the production of specific anti-idiotypic antibodies. Two groups of 14 MRL lpr mice were treated by regular intraperitoneal injections of 10 micrograms dsDNA-anti-dsDNA complexes or carrier buffer, starting at the age of 4 weeks, namely, prior to the appearance of nephritogenic anti-dsDNA IgG antibodies. We show here that such a treatment significantly extended the survival of treated mice compared with the control group. Five treated mice were still alive at month 11 compared with two in the control group. In addition, microscopic kidney examination at the time of death showed less lesions in the treated group compared with controls. This study indicates that complexes made of dsDNA and anti-dsDNA can delay the development of nephritis in the MRL lpr mouse strain.

Animals↗