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Biomedical subjects

Miri Blank

Publications and source records attributed to Miri Blank.

28 records · Page 2Linked to original sources
PubMed2002

Induction of oral tolerance in experimental antiphospholipid syndrome by feeding with polyclonal immunoglobulins.

Intravenous immunoglobulins (IVIG) contain a wide spectrum of anti-idiotypes associated with autoimmune diseases. Since part of these anti-idiotypes may bear an internal image of the eliciting antigen, IVIG might be suitable for induction of oral tolerance. In the current study we attempted to induce tolerance in an experimental model of anti-phospholipid syndrome (APS) by oral administration of IVIG. Naive mice were fed with IVIG, or anti-beta 2GPI-specific anti-idiotypic IVIG(alpha Id). Significantly diminished humoral response was noted in mice IVIG/ IVIG-F(ab')(2)or IVIG(alpha Id)-tolerized mice, accompanied by a significant attenuation of clinical manifestations. The maximal effect was achieved in the mice tolerized before disease induction. Abrogation of T lymphocyte proliferation to beta 2GPI was detected in the mice fed with IVIG prior to beta 2GPI immunization, mediated by TGFbeta and IL-10 secretion. The tolerance induced by IVIG-feeding was nonspecific and could be adoptively transferred to syngeneic mice by CD8alpha (+) cells. These CD8alpha (+) T cells, were found to secrete high levels of TGFbeta and IL-10. In summary, IVIG-induced oral tolerance has a nonspecific immunomodulatory effect in experimental APS, mediated by TGFbeta and IL-10-secreting CD8alpha (+) cells. Our results point to a possible application of IVIG in the induction of oral tolerance against various autoimmune diseases.

Administration, Oral↗
PubMed2002

Induction of biologically active antineutrophil cytoplasmic antibodies by immunization with human apoptotic polymorphonuclear leukocytes.

Translocation of intracellular components to the cell surface during the priming or apoptosis of polymorphonuclear leukocytes (PMN) is an important mechanism for interaction of antineutrophil cytoplasmic antibodies (ANCA) with these antigens. To test the capacity of apoptotic PMN to trigger production of ANCA, six groups of mice were immunized with either live or apoptotic lymphocytes, or with live, apoptotic, formalin-fixed, or lysed PMN. Mice immunized with both live and apoptotic neutrophils developed high titers of antibodies which gave a granular cytoplasmic immunofluorescent pattern. These antibodies were specific for lactoferrin and myeloperoxidase. Following a second intravenous infusion of apoptotic PMNs, mice developed anti-PR3 antibodies. Vasculitis lesions were not found in mice which developed ANCA. The ANCA-containing IgG fraction induced superoxide production by human PMNs. These results support the hypothesis that neutrophil-specific antigens presented on the cell membranes of apoptotic PMN may induce ANCA in the proper conditions.

Animals↗
PubMed2002

Anti-platelet factor 4/heparin antibodies from patients with heparin-induced thrombocytopenia provoke direct activation of microvascular endothelial cells.

Heparin-induced thrombocytopenia (HIT) is a serious complication that occurs in approximately 1-5% of patients treated with heparin and may be associated with severe thrombotic events. HIT is mediated by antibodies directed mostly to epitope(s) formed by complexes between heparin or other anionic mucopolysaccharides and platelet factor 4 (PF4). Anti-PF4/heparin IgG antibodies from six patients with HIT were affinity purified and assessed for interaction with human microvascular and macrovascular endothelial cells (EC). The antibodies directly activated primary cultures of human bone marrow microvascular EC (HBMEC) and SV40 immortalized HBMEC (TrHBMEC) only in the presence of PF4, but did not activate macrovascular human umbilical vein EC (HUVEC) under the same conditions. These antibodies were found to bind to TrHBMEC through the F(ab)(2) portion of the anti-PF4/heparin IgG. TrHBMEC activation was characterized by an augmented release of IL-6, von Willebrand factor, soluble thrombomodulin, and by an elevated expression of the adhesion molecules P-selectin, E-selectin and vascular cellular endothelial molecule-I to different degrees. Enhanced monocyte adhesion to PF4/heparin antibody-treated TrHBMEC (33-72% adhesion) was also observed. None of these effects occurred with unstimulated HUVEC. However, pre-treatment of HUVEC with tumor necrosis factor-alpha resulted in the same changes observed with microvascular EC exposed to the HIT antibodies. Our findings indicate that anti-PF4/heparin antibodies directly activate microvascular EC while interaction with macrovascular EC requires pre-activation. These results may explain some of the specific clinical manifestations in HIT.

Aged↗
PubMed2002

Efficacy of IVIG affinity-purified anti-double-stranded DNA anti-idiotypic antibodies in the treatment of an experimental murine model of systemic lupus erythematosus.

Since the idiotypic network is an important mechanism for controlling the immune repertoire, we tested anti-idiotypic modulation employing concentrated specific natural polyclonal anti-double-stranded (ds) DNA anti-idiotypic antibodies obtained from a commercial IVIG in the treatment of experimental systemic lupus erythematosus (SLE). Specific natural polyclonal anti-dsDNA anti-idiotypic antibodies (IVIG-ID) were affinity purified from IVIG on an anti-dsDNA-Sepharose column constructed from anti-dsDNA idiotypes (ID) affinity purified from 55 patients with active SLE. NZB/W F(1) mice were treated i.v. with 3 weekly injections of IVIG-ID (2 mg/kg/injection) or regular IVIG (400 mg/kg/injection) both before (age 8 weeks) and after developing anti-dsDNA antibodies at the age of 21-22 weeks. The IVIG-ID-treated mice showed a decline in the titer of anti-dsDNA antibodies during the treatment, reaching maximum suppression 1 week after the last injection. A significant difference in the proteinuria level in the IVIG-ID-treated group compared to the control group was observed. Immunohistology showed different patterns of IgG deposition, with mesangial and capillary wall deposits in controls and in the IVIG-treated group, but only mesangial deposits in the IVIG-ID-treated group. The survival time of the IVIG-ID-treated group was longer than the IVIG-treated group. Treatment with concentrated specific anti-dsDNA anti-ID prepared from commercial IVIG is more effective in suppressing the humoral reaction and clinical signs of SLE than native IVIG. These results point to the considerable regulatory role of anti-ID in the mechanism of action of IVIG in SLE.

Animals↗
PubMed2002

Autoantibodies to cardiolipin and beta-2-glycoprotein-I in coronary artery disease patients with and without hypertension.

BACKGROUND: Autoantibodies to cardiolipin (aCL) and beta2-glycoprotein-I (beta2GPI) are considered proatherogenic. Elevated levels of both antibodies have been reported in hypertension. Nonetheless, there are no data regarding an association between these autoantibodies and hypertension in coronary artery disease. METHODS: The levels of aCL and anti-beta2GPI antibodies were measured in patients having coronary artery disease with (n = 82) or without (n = 36) hypertension, in association with other major risk factors for coronary artery disease. RESULTS: The levels of aCL and anti-beta2GPI antibodies were (OD at 405 nm) 0.23 +/- 0.14 and 0.22 +/- 0.12 in the normal blood pressure group, as opposed to 0.24 +/- 0.12 and 0.20 +/- 0.12 in the hypertensive group, respectively (p = 0.67; 0.42). No significant difference in either antibody levels was found between hypertensive patients with normal and abnormal blood pressure measurements. The presence of additional risk factors did not affect antibody levels in normotensive patients. However, in the hypertensive group, the presence of smoking was associated with significantly decreased anti-beta2GPI antibody levels, whereas no change was found in aCL. Further, patients who had hypertension, smoking and hypercholesterolemia, had significantly decreased anti-beta2GPI antibody levels compared with patients without any of these risk factors (0.13 +/- 0.04 versus 0.23 +/- 0.13, respectively; p = 0.02). CONCLUSION: Hypertension is not associated with modification of aCL and anti-beta2GPI antibody levels in coronary artery disease patients. However, there are elevated anti-beta2GPI antibody levels in patients without conventional risk factors compared with patients with these risk factors.

Anticoagulants↗
PubMed2002

Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome.

The antiphospholipid syndrome (APS) is characterized by the presence of pathogenic autoantibodies against beta2-glycoprotein-I (beta2GPI). The factors causing production of anti-beta2GPI remain unidentified, but an association with infectious agents has been reported. Recently, we identified a hexapeptide (TLRVYK) that is recognized specifically by a pathogenic anti-beta2GPI mAb. In the present study we evaluated the APS-related pathogenic potential of microbial pathogens carrying sequences related to this hexapeptide. Mice immunized with a panel of microbial preparations were studied for the development of anti-beta2GPI autoantibodies. IgG specific to the TLRVYK peptide were affinity purified from the immunized mice and passively infused intravenously into naive mice at day 0 of pregnancy. APS parameters were evaluated in the infused mice on day 15 of pregnancy. Following immunization, high titers of antipeptide [TLRVYK] anti-beta2GPI Ab's were observed in mice immunized with Haemophilus influenzae, Neisseria gonorrhoeae, or tetanus toxoid. The specificity of binding to the corresponding target molecules was confirmed by competition and immunoblot assays. Naive mice infused with the affinity-purified antipeptide Ab's had significant thrombocytopenia, prolonged activated partial thromboplastin time and elevated percentage of fetal loss, similar to a control group of mice immunized with a pathogenic anti-beta2GPI mAb. Our study establishes a mechanism of molecular mimicry in experimental APS, demonstrating that bacterial peptides homologous with beta2GPI induce pathogenic anti-beta2GPI Ab's along with APS manifestations.

Animals↗
PubMed2002

[Fibrotic diseases].

Fibrosis is a pathologic process, which includes scar formation and over production of extracellular matrix, by the connective tissue, as a response to tissue damage. The molecular process is not different from normal formation of connective tissue and extracellular matrix in the normal organs. The context, the environment and the over production make the difference. Fibrosis formation includes interaction between many cell types and cytokines, and when the balance becomes profibrotic, there is fibrosis formation. Major profibrotic agents are type 2 CD4 positive lymphocytes, CD40 receptor and ligand interaction, and the following cytokines: IL-4, transforming growth factor b, platelet derived growth factor. The major antifibrotic agent is interferon gamma. Pathologies include: in the skin pathologic scarring as colloid and hypertrophic scar, cirrhosis of liver and gallbladder, in the heart and the kidneys, pulmonary and bone-marrow fibrosis, and scleroderma. Scleroderma is chronic connective tissue disease, expressed clinically by systemic sclerosis and diffuses fibrosis of the skin and viscera. This is a progressive degenerative disorder of the blood vessels, skin, lungs, kidneys, heart and GI tract and for this reason this disease plays a major role in fibrosis research. Fibrosis is considered an irreversible process, at least clinically, and is usually treated by anti-inflammatory and immunosuppressive agents. This kind of therapy was not proven successful and sometimes it harms more than cures. Many patients suffer from fibrotic diseases and the aim is to develop anti-fibrotic agents, targeted to the pathologic molecular process. Progressing step by step in this issue has direct clinic affect.

Cytokines↗
PubMedDate not supplied

Autoantibodies and prediction of reproductive failure.

PROBLEM: To determine which autoantibodies are associated with reproductive failure. METHOD OF STUDY: Sera from 269 patients with autoimmune disease and/or reproductive failure were analyzed for anti-phospholipid (aPL), anti-annexin-V, anti-lactoferrin, anti-thyroglobulin, anti-thyroid peroxidase, anti-prothrombin, anti-nuclear, and anti-saccharomycetes cerevisiae antibodies (ASCA), by enzyme-linked immunosorbent assay. Patients were classified as: recurrent pregnancy loss (RPL), infertility, and autoimmune diseases. The results were compared with those of 120 healthy volunteers. RESULTS: In autoimmune diseases, the prevalence of anti-prothrombin, anti-annexin, anti-phospholipid and anti-nuclear antibodies was significantly higher than in the control group, OR 11.0 [CI, 3.5-35.2], 33 [CI, 7.2-174.2], 13 [CI, 1.4-309.7], and 16.1 [CI 2.4-122], respectively. In infertility, the antibodies with significantly higher levels than controls were: aPL OR, 5.11 [CI 1.2-25.4], and anti-prothrombin antibodies, OR, 5.15 [CI, 2.1-12.7]. In RPL, ASCA, anti-prothrombin and aPL were more prevalent than in controls, OR 3.9 [CI, 1.5-10.6], 5.4 [CI, 2.4-12.5] and 4.8[CI, 1.2-22.2] for each antibody, respectively. Anti-prothrombin antibodies and aPL were more significantly associated with late pregnancy losses than early losses. CONCLUSION: ASCA antibodies have not previously been described in RPL. Nor are anti-prothrombin antibodies usually assessed in infertility or RPL. If these results are confirmed in further studies, these antibodies might be assessed routinely in reproductive failure.

Abortion, Spontaneous↗