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Biomedical subjects

N Lahat

Publications and source records attributed to N Lahat.

At least 37 records · Page 2Linked to original sources
PubMed1998

Treatment of multiple sclerosis with copolymer-1 (Copaxone): implicating mechanisms of Th1 to Th2/Th3 immune-deviation.

The synthetic polypeptide copolymer-1 (Cop-1; Copaxone; Glatiramer Acetate) has been recently approved as an effective treatment in relapsing multiple sclerosis (MS). A large body of evidence demonstrates that Cop-1 induces active suppression of CNS-inflammatory disease in animal models. However, Cop-1-mediated suppressor mechanisms have not yet been elucidated in humans. A 12-month open study following clinical and immunological parameters of ten relapsing MS patients treated with Cop-1 is presented. Relapse rates and disability scores (EDSS) were evaluated prior to and after 12 months of treatment. The immunological parameters assessed prior to and at 3 months' interval during treatment included serum levels of soluble IL-2 receptor (sIL-2R) and IL-10 as well as leukocyte cytokine mRNA expression of TNF alpha, IL-4 and TGF-beta. Copaxone treatment was found to lead to a significant reduction in the mean annual relapse rate (from 1.4 prior to treatment to 0.6 during treatment) and stabilization of disability in 90% of the patients. The treatment was accompanied by an elevation of serum IL-10 levels, suppression of the pro-inflammatory cytokine TNF alpha mRNA, and an elevation of the anti-inflammatory cytokines TGF-beta and IL-4 mRNAs in PBLs. These results suggest that the beneficial clinical effects of Copaxone in MS patients may be attributed to changes in activation of T cell subsets and a shift from Th1 to Th2/Th3 cytokine profile, probably leading to Cop-1-driven mechanisms of bystander suppression.

Adult↗
PubMed1998

Increased prevalence of autoantibodies in celiac disease.

Several features suggest an immune mechanism operates in celiac disease. Information on the autoantibody repertoire in this condition is lacking. The purpose of the study was to investigate the reactivity of celiac patients sera to various autoantigens widely distributed in the human intestine. Seventy children, celiacs and controls, were evaluated for serum autoantibodies using ELISA and immunofluorescence. Celiac patients had increased prevalence of serum anti-single-stranded DNA (14%), anti-double-stranded DNA (23%), anti-cardiolipin (14%), and anti-endomysial autoantibodies (63%). The relevance of this finding on the extraintestinal manifestations of celiac disease or the coexistence of autoimmune conditions and celiac disease remains to be determined.

Autoantibodies↗
PubMed1998

mRNA cytokine profile in peripheral blood cells from chronic hepatitis C virus (HCV)-infected patients: effects of interferon-alpha (IFN-alpha) treatment.

Natural immune responses, both cellular and humoral, are not capable of terminating HCV infection in most patients. A role has been suggested for peripheral blood leucocytes (PBL) in viral persistence and clinical implications, as these cells may serve as a viral reservoir and at the same time may be inadequate active participants in antiviral immune reactions. IFN-alpha administration, although only partially successful, is currently the main therapy available for chronic HCV patients. In addition to its antiviral effects, IFN-alpha regulates the function of cytokines, their receptors and other molecules of immune importance. The aim of this study was to determine cytokine mRNA expression in PBL derived from chronic HCV patients prior to and at termination of IFN-alpha treatment. HCV RNA was still observed in sera of most patients (10 out of 14 treated patients) at termination of treatment. In pretreated patients mRNA expression of Th2 (IL-4, IL-6 and IL-10) and Th3 (transforming growth factor-beta (TGF-beta)) was observed in only a low percentage of PBL samples from patients, similar to controls. IFN-alpha treatment led to an elevation in the number of samples expressing these cytokines (significant for IL-4, IL-6, IL-10, tumour necrosis factor-alpha (TNF-alpha) and TGF-beta), accompanied by reduction in liver enzymes but in serum viral load in only approximately 30% of patients. Expression of TNF-alpha and TNF-beta mRNA was observed in samples from patients but not controls, while no differences were observed for mRNA of classical Th1 cytokines (IL-2 and IFN-gamma) between patients before or during treatment as well as controls. The cytokine mRNA profile following IFN-alpha treatment points to an anti-inflammatory response which does not appear to be involved in termination of the viral infection. The PBL cytokine profile observed in this study may explain the failure of the immune system to eradicate HCV chronic infection and suggests that early treatment in the acute phase of disease with agents that stimulate cytotoxic immune type 1 responses may lead to eradication of HCV infection.

Antiviral Agents↗
PubMed1998

Regulation of HLA-DR and costimulatory B7 molecules in human thyroid carcinoma cells: differential binding of transcription factors to the HLA-DRalpha promoter.

The consequence of autoantigen presentation by thyroid cells is dependent on the magnitude of expression of both HLA class II antigens (mainly HLA-DR) and costimulatory molecules, such as B7 (CD80 and CD86). Autoimmune thyrocytes are induced to express HLA-DR by interferon-gamma (IFN-gamma). The costimulatory signal leading to autoantibody production or cytotoxic T-cell immune response could be provided by antigen presenting cells (APCs) attracted to the thyroid by the primary autoimmune stimulus. Malignant thyrocytes can express HLA-DR antigens either constitutively, as a result of a nonimmunologic stimulus, or on induction with IFN-gamma after triggering of an immune response. However, their ability to express B7 molecules, which may determine enhanced antitumoral immune response mainly in the absence of intrathyroidal macrophages, has not yet been studied. The regulation of HLA-DR gene expression in APCs, such as B cells, is mediated by a series of short DNA consensus sequences located in the promoter, termed the W, X, and Y boxes, which bind several known transcription factors. We have previously characterized the expression of HLA-DR in four human thyroid carcinoma cell lines and found differences between constitutive and high- or moderate-induced expression of the protein and mRNA. Evaluation of B7 expression on the surface of thyroid cancer cells and understanding the mechanisms of HLA-DR gene expression may help in designing efficient immune response to thyroid tumors. Using the electrophoretic mobility shift assay (EMSA), we have demonstrated differences between the four thyroid cell lines in the binding of transcription factors to each of the three boxes. The binding to the promoter in each of the cell lines resulted in a single band, probably representing a complex of proteins formed via protein-protein interactions. Using flow cytometry we have shown that the B7 molecule was absent in the four thyroid cell lines and could not be induced by IFN-gamma. The absence of surface B7 molecules from the malignant thyroid cells may lead to either suppression of antitumoral cytotoxic T cell response or demand the cooperation of infiltrating APCs to favor immune response. Differences previously found in HLA-DR expression in the four human malignant thyroid cell lines may be explained by the variation in the binding of transcription factors to the boxes in the HLA-DRalpha promoter. The binding patterns of nuclear proteins derived from the four thyroid cell lines or from the B lymphocyte cell line--Raji--to each of the boxes or to the whole promoter exhibit similarities, thus suggesting similar DNA-protein interactions.

Carcinoma↗
PubMed1997

Three different GB virus C/hepatitis G virus genotypes. Phylogenetic analysis and a genotyping assay based on restriction fragment length polymorphism.

The 5'-untranslated region (5'-UTR) sequences of 33 GB virus C/hepatitis G virus (GBV-C/HGV) obtained from different geographic areas were determined through reverse-transcription polymerase chain reaction and dideoxy chain termination sequencing, the alignment of sequences, the estimation of the number of nucleotide substitution per site, and construction of phylogenetic trees. The 5'-UTR of GBV-HGV was found to be heterogeneous, with 70.9-99.5% homology. Three distinct phylogenetic branches were observed consistently in all phylogenetic trees. GBV-C is the prototype for one, HGV for another, and there is a new branch which consisted of GBV-C/HGV isolates from Asia. Genotype-specific restriction sites for the restriction enzymes, ScrFI and BsmFI, were identified, and a simple restriction fragment polymorphism analysis was developed for genotyping. These data provide evidence that GBV-C/HGV consists of three different genotypes. Our simple genotyping assay will also provide a tool for epidemiological studies of GBV-C/HGV infection.

Base Sequence↗
PubMed1997

Interferon-beta and -gamma, but not tumor necrosis factor-alpha, demonstrate immunoregulatory effects on carcinoma cell lines infected with human papillomavirus.

BACKGROUND: Mechanisms whereby cells infected with human papillomavirus (HPV) escape immune surveillance, ultimately leading to invasive cervical carcinoma, may involve changes in local cytokine production, loss of responsiveness to cytokines, and alterations in the expression of immune-regulatory molecules such as histocompatibility-related leukocyte antigen (HLA) Class 1 and 2 and ICAM-I. This study examined the separate and combined effects of immune-activating cytokines, interferon (IFN)-gamma, IFN-beta, and tumor necrosis factor (TNF)-alpha, on the expression of these molecules. METHODS: Membrane protein expression and cellular mRNA levels were analyzed in cervical carcinoma-derived cell lines, SiHa and CaSki (with low and high HPV16 copy number, respectively), after exposure to cytokines. RESULTS: Both cell lines demonstrated constitutive expression of HLA Class 1 but not HLA Class 2 membrane antigens. IFN-gamma and -beta induced changes in Class 1 mRNA levels but not in membrane molecule expression. IFN-gamma induced dose-dependent expression of Class 2 membrane and mRNA molecules in both cell lines (more pronounced in SiHa than in CaSki cells), which was antagonized by IFN-beta. Constitutive ICAM-I membrane expression was observed only on CaSki cells, although ICAM-I mRNA was expressed in both cell lines. IFN-gamma up-regulated the membrane expression of this molecule, whereas IFN-beta led to its suppression. Differential modulation of ICAM-I mRNA was observed in both cell lines. A lack of response to TNF-alpha was observed throughout the experiments. CONCLUSIONS: The findings of this study point to possible mechanisms leading to suppression of local immune response in the pathogenesis of HPV-associated neoplasia. They also emphasize the complexity of developing an efficient cytokine therapy for patients with premalignant cervical disease.

Adjuvants, Immunologic↗
PubMed1997

Vestibulodynia--a subset of vulvar vestibulitis or a novel syndrome?

OBJECTIVE: Our purpose was to recognize special features of women with both vestibulitis and constant vulvar pain (vestibulodynia) and to determine whether vestibulodynia is a separate disease entity or a subset of vestibulitis. STUDY DESIGN: Ninety-one women with severe vulvar vestibulitis underwent perineoplasty by a single surgeon during 1992 to 1995. Twenty-five (27%) of them who had vestibulodynia were compared with 66 (73%) who had dyspareunia alone. With univariate and then multivariate analysis, the two groups were compared with regard to demographic, social, and medical variables, the presence of human papillomavirus deoxyribonucleic acid, physical findings in the vestibule, and surgical outcome. RESULTS: The vestibulodynia and vestibulitis groups differed in age (30.5 +/- 10.6 years vs 24.7 +/- 6.2 years respectively), as well as in marital status (married, 44% vs 18%, respectively), nonuse of contraception (20% vs 1%, respectively), presence of human papillomavirus deoxyribonucleic acid in the vestibule (80% vs 48%, respectively), and failure of surgical treatment (incomplete response rate, 64% vs 2%, respectively). With multivariate analysis, patients with human papillomavirus deoxyribonucleic acid present in the vestibule have an odds ratio of 5.44 (95% confidence interval, 1.45 to 20.33) of belonging to the group with vestibulodynia, whereas dysuria and age have odds ratios of 3.70 (95% confidence interval 1.09 to 12.55) and 1.14 (95% confidence interval 1.04 to 1.24), respectively. CONCLUSIONS: Vestibulodynia is a unique syndrome in that it affects women who are older than those who have vestibulitis alone and it is associated with human papillomavirus deoxyribonucleic acid, dysuria, and a higher surgical failure rate than that for vestibulitis.

Adolescent↗
PubMed1997

Desialylated and deglycosylated human chorionic gonadotropin are superagonists of native human chorionic gonadotropin in human thyroid follicles.

Highly purified human chorionic gonadotropin (hCG) interacts with the thyrotropin (TSH) receptor and stimulates triiodothyronine (T3) secretion, iodide uptake and organification, and cyclic adenosine monophosphate (cAMP) formation in human thyroid follicles. Because of interest in the role of the carbohydrate component in the structure-function relationships of hCG we undertook to deplete hCG of its sialic acid or carbohydrate residues and assess the thyrotropic activity of the carbohydrate-modified forms. For this purpose, we used our assay system consisting of human thyroid follicles cultured and suspended in collagen gel in serum-free medium. Under these conditions, the cells are organized as follicular three-dimensional structures with normal polarity, enabling enhanced responsiveness to hormonal stimulation, and T3 secretion can be measured as a response parameter. Desialylated (ds)-hCG and deglycosylated (dg)-hCG dose-dependently stimulated T3 secretion, iodide uptake and organification, and in each case did so with about twice the intrinsic activity of native hCG. Indeed, removal of the sialic acid or carbohydrate residues from native hCG transformed it into a thyroid stimulator that elicited a maximal response in terms of iodide uptake, organification and T3 secretion by human thyroid follicles as high as TSH and almost twice as high as native hCG. Not only were ds-hCG and dg-hCG more intrinsically active than hCG, they were more than five times as potent. As with hCG, both ds-hCG and dg-hCG managed to elicit such responses in human thyrocytes while evoking minimal amounts of cAMP, illustrating the concept of cAMP superfluity and highlighting the potential pitfalls of using cAMP as a measure of hormonal bioactivity. hCG, and to a greater extent ds-hCG and dg-hCG, inhibited, as did TSH, gamma-interferon-induced human leukocyte antigen-DR (HLA-DR) expression in human thyrocytes, again reflecting the intrinsic thyrotropic activity of native hCG and its variants depleted of sialic acid or carbohydrate residues. In conclusion, this is the first report on the thyrotropic activity of ds-hCG and dg-hCG using the physiologically relevant hormonal end-point response, thyroid hormone secretion. The study was conducted in a serum-free culture system of human thyroid follicles and shows that removal of the sialic acid or carbohydrate residues from native hCG transform hCG variants into thyroid stimulating superagonists. The hCG variants inhibited, as did TSH, gamma-interferon-induced HLA-DR expression.

Asialoglycoproteins↗
PubMed1997

Severe vulvar vestibulitis. Relation to HPV infection.

OBJECTIVE: To determine whether patients with human papillomavirus (HPV)-associated vestibulitis present differently from patients with HPV-negative disease and whether the presence of HPV is a predictor of the outcome of surgical treatment by perineoplasty. STUDY DESIGN: Thirty-eight women with severe vulvar vestibulitis who underwent surgical perineoplasty were found to have HPV DNA in the vestibule by polymerase chain reaction. Thirty-six other women with severe vestibulitis had no HPV DNA in the surgical specimen. The two groups were compared with regard to demographic, social and medical variables as well as physical findings in the vestibule and response to operative treatment. RESULTS: Both groups were found to be similar in respect to age (mean 25.9 +/- 7.93 versus 25.47 +/- 5.8, respectively), parity, education, smoking habits, contraceptive use, presence of primary vestibulitis, presence of dysuria and involvement of the whole vestibule (both anterior and posterior). More unmarried than married women were infected with HPV (P < .002). There was no significant correlation between the presence of HPV and the outcome of surgical treatment (P < .6, relative risk = 0.9, 95% confidence interval = 0.5-1.5). CONCLUSION: Although HPV DNA was found in more than half of women with vestibulitis, it appears to play no role in the presentation or response to surgical therapy for vulvar vestibulitis.

Adolescent↗
PubMed1996

Immunoregulatory effects of interferon-beta and interacting cytokines on human vascular endothelial cells. Implications for multiple sclerosis autoimmune diseases.

The mechanism(s) of action responsible for the anti-inflammatory effects mediated by interferon (IFN)-beta are still elusive although suggestions include anti-viral effects, the enhancement of natural killer (NK) or suppressor T cell activity and opposition to the effects of inflammatory cytokines. As vascular endothelial cells are active participants in inflammatory and demyelinating processes, we decided to examine the effects of IFN-beta on the expression of major histocompatibility complex (MHC) gene products and intercellular adhesion molecule (ICAM)-1 on human vascular endothelial cells (ECs). Human umbilical ECs demonstrated constitutive expression of ICAM-1 and MHC class I molecules but did not express MHC class II molecules. Basal expression of ICAM-1 molecules was enhanced by TNF alpha and to a lesser extent by IFN-beta, but was not affected by IFN-gamma. MHC class I expression on ECs was enhanced by IFN-beta, IFN-gamma, and tumor necrosis factor (TNF)-alpha. Furthermore, a synergistic effect was observed to combinations of these interacting cytokines. Incubation of ECs with IFN-gamma, but not IFN-beta, induced class II expression in a dose dependent manner. Moreover, co-incubation of ECs with IFN-beta and IFN-gamma resulted in significant down-regulation of class II molecules expression which was directly dependent on IFN-beta concentration. Northern blot analysis of DR alpha and Beta 2-microglobulin mRNA expression suggested that cytokine-mediated regulation of MHC molecules is at the transcriptional level, while modulation of ICAM-1 expression appears to be at the transcriptional as well as post-transcriptional level. Thus, our study demonstrated that IFN-beta and interacting cytokines exert complex immunoregulatory effects on endothelial cells with differential modulatory effects on various cell surface markers. Understanding the biological significance of these immunomodulatory effects mediated by IFN-beta may have important implications for cytokine-based strategies in the treatment of inflammatory and autoimmune diseases.

Autoimmune Diseases↗
PubMed1996

Polymerase chain reaction search for viral etiology of vulvar vestibulitis syndrome.

OBJECTIVE: Our purpose was to assess the prevalence of infections by human papillomavirus, herpes simplex virus, and cytomegalovirus among women with severe vulvar vestibulitis. STUDY DESIGN: Eighty-six women referred for dyspareunia and diagnosed as having severe vestibulitis underwent perineoplasty, including surgical removal of the sensitive vestibule. Controls included 25 age-matched patients without dyspareunia undergoing vaginal operations for various benign causes or undergoing repair of an episiotomy. Polymerase chain reaction analysis was carried out to determine the presence of viral genes. RESULTS: The prevalence of herpes simplex virus and cytomegalovirus among the subjects tested was nil, whereas human papillomavirus was detected in 46 cases (54%). The human papillomavirus present was not of types 6, 11, 16, 18, or 33. Only one woman of the 25 asymptomatic controls (4%) had human papillomavirus deoxyribonucleic acid in the vestibule (p < 0.001). CONCLUSION: Our data provide support for the idea that vulvar vestibulitis is associated with human papillomavirus deoxyribonucleic acid in more than half of cases.

Adolescent↗
PubMed1995

Sebaceous adenomas, squamous cell carcinoma and skin infections in a patient with carcinoma of the colon, rectum and bladder.

Sebaceous adenomas and squamous cell carcinoma developed in a male patient in addition to viral, mycotic and bacterial infections, several years after the removal of three malignant tumors from his lower gastrointestinal and urinary tract. Skin tests with trichophytin, candidin, and mixed bacteria were negative. Various aspects regarding cutaneous changes associated with colorectal and bladder carcinomas are discussed.

Adenocarcinoma, Mucinous↗
PubMed1995

T cell receptor repertoire in the peripheral blood and intestinal mucosa of coeliac patients.

The alpha beta and gamma delta T cell receptor (TCR) repertoire in the peripheral blood and intestinal mucosa of six coeliac and six age-matched controls was analysed by reverse transcription and polymerase chain reaction (PCR). No TCR alpha and gamma delta restriction was observed in coeliacs and controls. However, V gamma 3 was expressed only in coeliac peripheral and intestinal T cells. V delta 2 was strongly expressed in coeliacs and scarcely transcribed in control cells. The unique expression of these gamma delta TCR in coeliac patients suggests that V gamma 3 and perhaps V delta 2 TCR-bearing lymphocytes may play a role in the pathogenesis of coeliac disease.

Celiac Disease↗
PubMed1995

Exposure to hyperbaric oxygen induces tumour necrosis factor-alpha (TNF-alpha) secretion from rat macrophages.

We investigated the secretion of TNF-alpha by monocytes and macrophages derived from the peripheral blood, spleen, and lungs after a single exposure to a therapeutic profile of hyperbaric oxygen (HBO). Rats were exposed for 90 min to either 100% oxygen at 0.28 MPa (2.8 atmospheres absolute) or air. Immediately after exposure, mononuclear cells were isolated from blood, spleen, and lungs and cultured for 18 h. The secretion of TNF-alpha from the cultured monocytes/macrophages was determined with and without stimulation with lipopolysaccharide (LPS). Exposure to hyperbaric oxygen induced a significant increase in the spontaneous ex vivo secretion of TNF-alpha (without LPS) by mononuclear cells from the blood, spleen, and lung (P < 0.05 from air controls). Stimulation with LPS after exposure to HBO induced a significant increase in TNF-alpha secretion by lung and spleen macrophages compared with air controls (P < 0.05). However, absolute TNF-alpha levels were not significantly higher than those achieved 'spontaneously' in macrophages exposed to HBO without LPS. Stimulation with LPS induced a marked increase in secretion of TNF-alpha from blood monocytes after exposure to air, but not after exposure to HBO. These results provide evidence in support of a role played by TNF-alpha in mediating HBO effects on different tissues and their immune responses.

Animals↗
PubMed1994

Coincidence of vitiligo and Paget's bone disease in a patient.

Paget's bone disease developed in a patient with vitiligo. Scrupulous physical examination excluded further systemic or cutaneous involvement. The immunological workup revealed a reversed CD4/CD8 ratio due to a very low CD4 cell percentage and almost negligible responses to PHA as well as Con A, T cell mitogens. The pathogenic significance of these results, which point to phenotypic and functional T cell defects, is discussed.

Aged↗
PubMed1994

Effect of hyperbaric oxygen on tissue distribution of mononuclear cell subsets in the rat.

In a previous study we found a significant temporary decrease in the ratio of CD4/CD8 (helper, inducer/suppressor, cytotoxic) T lymphocytes in the peripheral blood of healthy human volunteers after exposure to a single commonly used profile of hyperbaric oxygen (HBO). The transient nature of the changes suggested redistribution of T-cell subsets. The purpose of the present study was to verify such a redistribution and to locate possible target organs in an animal model. A single exposure of rats to HBO (0.28 MPa) induced a highly significant rapid decrease in the CD4/CD8 ratio in peripheral blood count (P < 0.0001), confirming our previous findings in humans. HBO also induced a significant increase in the CD4/CD8 ratio in the lungs and lymph nodes (P < 0.001) and a significant decrease in the ratio in the spleen (P < 0.01). Furthermore, exposure to HBO induced a significant increase in T cells bearing surface interleukin-2 receptors in the blood, spleen, lungs, and lymph glands (P < 0.001) and a significant decrease in T cells expressing alpha beta-receptors in the lungs (P < 0.001) and lymph glands (P < 0.05). Our findings suggest rapid T-cell activation after a brief exposure to HBO, with shifts of CD4 and CD8 subsets and variations in T-cell receptor type. These rapid changes in the parameters of cell-mediated immunity may represent the activation of protective mechanisms against the toxic effect of oxygen or the early stages of pulmonary oxygen toxicity.

Animals↗
PubMed1994

Selection of human TcR V gene families in autologous mixed lymphocyte reactions: relevance to autoimmune immunopathology.

We have postulated that in vivo autologous mixed lymphocyte reactions (AMLRs) are one mechanism in the development of the intrathyroidal lymphocytic infiltration of human autoimmune thyroid disease. Such a mechanism would explain the significant numbers of self-reactive T cells present in thyroid infiltrates as evidenced by cloning studies. However, infiltrating T cells in a variety of autoimmune disease including autoimmune thyroid disease, demonstrate bias in their use of T cell receptor (TcR) V gene families. In order to examine whether such TcR V gene bias may occur secondary to non-antigen specific in vivo AMLRs rather than secondary to specific autoantigen driven mechanisms we have examined the human TcR repertoire after prolonged AMLRs in vitro. Using 5 healthy donors in 1, 2 and 3 weeks AMLRs we showed stimulation indices of 3.1-6.5 after 3 weeks. The hTcR V alpha and V beta gene repertoire was assessed using the PCR technique and revealed an almost complete repertoire of V gene families at the beginning of the studies while at the end of 3 weeks a mean of only 5.2 V alpha genes were transcribed. Less restriction was seen in the hTcR V beta repertoire with a mean of 9 V beta genes used. These data demonstrate that the AMLR is able to mimic the marked bias in hTcR V gene family use seen within the inflammatory infiltrates of autoimmune diseases.

Adult↗