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Biomedical subjects

E Raz

Publications and source records attributed to E Raz.

At least 73 records · Page 4Linked to original sources
PubMed1995

Transforming growth factor-beta gene therapy ameliorates experimental colitis in rats.

OBJECTIVE: To modulate experimental colitis by the direct intramuscular injection of cDNA expression vector encoding transforming growth factor-beta 1. METHODS: Colitis was induced in rats by the intracolonic administration of 0.25 ml 50% ethanol containing 30 mg trinitrobenzene sulfonic acid. Three and 10 days later the rats were injected intramuscularly with 200 micrograms transforming growth factor-beta 1 cDNA subcloned to the pRSV expression vector (pRSVTGF-beta 1). Control rats were injected with pRSVP2. The rats were sacrificed 2 weeks after trinitrobenzene sulfonic acid treatment and a 10 cm long distal colonic segment was resected, weighted, the lesion area measured, sections obtained for histology and the mucosa extracted for determination of myeloperoxidase activity and leukotriene generation. RESULTS: In pRSVP2-treated rats (n = 17) the colon was inflamed and ulcerated with many adhesions to adjacent structures; the pRSVTGF-beta 1-treated rats (n = 21) had minimal swelling and inflammation in the colon. On histological examination 50% of the pRSVTGF-beta 1-treated rats had minimal or no ulceration, whereas 83% of the pRSVP2-treated rats had a maximal damage score. In pRSVTG-beta 1-treated rats the lesion area and wet weight were 21 and 52.5%, respectively, of the values for pRSVP2-treated rats (P < 0.05). The amelioration of tissue injury was accompanied by a significant decrease in mucosal leukotriene C4 generation. CONCLUSIONS: Direct intramuscular transforming growth factor-beta 1 gene delivery effectively ameliorates trinitrobenzene sulfonic acid-induced colitis, suggesting that gene therapy with immunosuppressive cytokines may be a novel approach for the treatment of inflammatory bowel disease.

Animals↗
PubMed1994

Intradermal gene immunization: the possible role of DNA uptake in the induction of cellular immunity to viruses.

The skin and mucous membranes are the anatomical sites were most viruses are first encountered by the immune system. Previous experiments have suggested that striated muscle cells are unique among mammalian cell types in their capacity to take up and express free DNA in the absence of a viral vector or physical carrier. However, we have found that mice injected into the superficial skin with free (naked) plasmid DNA encoding the influenza nucleoprotein gene had discrete foci of epidermal and dermal cells, including cells with dendritic morphology, that contained immunoreactive nucleoprotein antigen. A single intradermal administration of 0.3-15 micrograms of free plasmid DNA induced anti-nucleoprotein-specific antibody and cytotoxic T lymphocytes that persisted for at least 68-70 weeks after vaccination. Intradermal gene administration induced higher antibody titers than did direct gene injection into skeletal muscle and did not cause local inflammation or necrosis. Compared with control animals, the gene-injected mice were resistant to challenge with a heterologous strain of influenza virus. These results indicate that the cells of the skin can take up and express free foreign DNA and induce cellular and humoral immune responses against the encoded protein. We suggest that DNA uptake by the skin-associated lymphoid tissues may play a role in the induction of cytotoxic T cells against viruses and other intracellular pathogens.

Amino Acid Sequence↗
PubMed1994

Regression of Kaposi's sarcoma after intravenous immunoglobulin treatment for polymyositis.

The authors report on the case of a patient with polymyositis who was given immunosuppressive therapy and then developed Kaposi's sarcoma. Subsequently, the polymyositis was treated with high dose intravenous immunoglobulin, and the Kaposi's sarcoma regressed abruptly. The association between these two diseases and the beneficial effect of intravenous immunoglobulin on Kaposi's sarcoma are discussed.

Humans↗
PubMed1994

Evidence for intrathecal synthesis of autoantibodies in systemic lupus erythematosus with neurological involvement.

The diagnosis of systemic lupus erythematosus (SLE) in a patient who presents with isolated central nervous system (CNS) abnormalities, is a difficult clinical challenge. The pathogenesis of such CNS involvement in SLE is unknown. Twelve patients with active SLE were examined for serum and cerebrospinal fluid (CSF) autoantibodies and compared with 21 patients with headache. Four of six patients with SLE and active CNS presentation had CSF autoantibodies while none of the other SLE patients and the controls had autoantibodies. We describe these four patients in whom immunological work-up revealed CSF antinuclear, anti-DNA, anti-SSA/Ro, anti-SSB/La and antineuronal autoantibodies. A newly devised antibody activity index provided means to demonstrate that the CSF autoantibodies in these patients were produced intrathecally. Beyond the importance of our finding of the potential role of autoantibodies in the pathogenesis of CNS damage in SLE, we propose that CSF analysis for autoantibodies should become an essential part of the diagnostic work-up in autoimmune diseases with CNS involvement.

Adolescent↗
PubMed1993

Induction of antibodies to a kappa V region by gene immunization.

Direct gene transfer into muscle can lead to sustained gene expression at the injected sites. Here we tested the ability of in vivo gene transfection to immunize mice against an isolated human IgV region. The Humkv325 germline kappa L chain V gene encodes the kappa L chain in V regions of several human IgM autoantibodies and is used frequently in chronic lymphocytic leukemia. This gene was inserted into a mammalian expression vector, pREP7, to produce pREVk3. Mice injected i.m. with pREVk3 produced antibodies against the V region of Glo, a human monoclonal IgM paraprotein whose kappa L chain is encoded by Humkv325. Co-injection of an expression vector encoding IL-2 enhanced anti-Glo antibody production fivefold and induced a localized delayed hypersensitivity reaction. Antibody production also was induced when vectors encoding Humkv325 and IL-2 were injected s.c. These experiments demonstrate that gene immunization vectors can stimulate immune responses to antibody V region determinants.

Animals↗
PubMed1993

Systemic immunological effects of cytokine genes injected into skeletal muscle.

Somatic gene therapy is an interesting approach for the delivery of cytokines for prolonged periods. The present experiments show that direct injections into mouse skeletal muscle of cDNA expression vectors encoding interleukin 2 (IL-2), IL-4, or type beta 1 transforming growth factor (TGF-beta 1) induce biological effects characteristic of these cytokines in vivo. Mice injected intramuscularly with a vector encoding IL-2 had enhanced humoral and cellular immune responses to an exogenous antigen, transferrin, that was delivered at a separate site. These IL-2 effects were abolished by coadministration of a vector directing synthesis of TGF-beta 1. The TGF-beta 1 vector by itself depressed the anti-transferrin antibody response and caused an 8-fold increase in plasma TGF-beta 1 activity. The TGF-beta 1 plasmid injection did not cause muscle infiltration with monocytes or neutrophils and there was no evidence for fibrotic changes. Muscle injection with a cDNA encoding IL-4 selectively increased IgG1 levels but did not alter the cellular immune response to transferrin. In lupus-prone mice (MRL/lpr/lpr), injection with IL-2 expression vectors increased and TGF-beta 1 vectors decreased auto-antibodies to chromatin. These results demonstrate that intramuscular injection of cytokine genes, in the absence of infectious viral vectors, can regulate humoral and cellular immune responses in vivo.

Animals↗
PubMed1993

Complete heart block and seizures in an adult with systemic lupus erythematosus. A possible pathophysiologic role for anti-SS-A/Ro and anti-SS-B/La autoantibodies.

OBJECTIVE: To determine the serum autoantibody profile in an adult patient with systemic lupus erythematosus manifested by complete heart block (CHB) and seizures, and to investigate the source of autoantibodies found in the patient's cerebrospinal fluid (CSF). METHODS: The serum and CSF autoantibody profiles were determined by serologic testing and Western blot studies. An antibody activity index was devised to determine the source of the autoantibodies found in the CSF. RESULTS: The patient's serum contained anti-SS-A (52 kd and 60 kd), anti-SS-B, anti-U1 RNP, and anti-Sm autoantibodies. Studies of her CSF, however, revealed only anti-SS-A and anti-SS-B autoantibodies, with a high antibody activity index. CONCLUSION: The finding of anti-SS-A (52 kd and 60 kd) and anti-SS-B autoantibodies was similar to reported findings in congenital CHB. Intrathecal synthesis of anti-SS-A and anti-SS-B was the source of autoantibodies found in the CSF. This patient's symptoms may be pathophysiologically linked to an immune reaction between the anti-SS-A and anti-SS-B autoantibodies and neural tissue in the brain and heart.

Adult↗
PubMed1993

Cross-reactions of anti-DNA autoantibodies with cell surface proteins.

Anti-DNA autoantibodies are thought to play a major role in the pathogenesis of systemic lupus erythematosus. However, the mechanism(s) by which they participate in tissue and organ damage is not well understood. It has been suggested that these antibodies combine with DNA or DNA-histone complexes to produce circulating immune complexes which may deposit in various tissues. Alternatively, anti-DNA autoantibodies could interact directly with tissue components by way of immunological cross-reaction. In this study we have used a panel of mouse monoclonal autoantibodies with anti-nuclear specificity and measured their binding to membrane proteins of several tissues and cell lines. We show that the anti-DNA antibodies, but not anti-RNA or anti-histone antibodies bind to membrane proteins of molecular weights 102, 80, 42, 35 and 31 kDa, which are expressed in different combinations on several cell types. The binding of anti-DNA antibodies to these cell surface proteins was not affected by DNase treatment of the target cells, was increased by DNase treatment of the antibody preparations and was completely inhibited by DNA, indicating a true cross-reaction and not an indirect interaction of antibody and membrane proteins through a DNA bridge. Our results suggest that direct binding of anti-DNA autoantibodies to cell surface membrane proteins may play an important role in the induction of the pleomorphic tissue damage in systemic lupus erythematosus.

Animals↗
PubMed1993

Establishment of ventral cell fates in the Drosophila embryonic ectoderm requires DER, the EGF receptor homolog.

The embryonic ectoderm in Drosophila displays a highly organized arrangement of specific structures along the dorsal-ventral axis. To establish this characteristic design, cells must receive instructive cues regarding their position. We present evidence that during stages 8-9 of embryonic development, the Drosophila EGF receptor homolog (DER) is essential for determining the identity of cells within the ventral ectoderm. In the absence of DER activity at this phase, alterations in cell fate are observed: Ventral cells acquire more dorsal fates, as visualized by the expression profile of specific markers. The ventralizing effect of DER appears to function later than that of the dorsalizing dpp pathway, and the spatial overlap between them is minimal. A model for the determination of cell fates along the dorsal-ventral axis involving the two pathways is presented. Some aspects of the mutant ectodermal and CNS phenotypes of the DER locus (faint little ball, flb) resemble the phenotype of mutations from the spitz group. Synergistic interactions between flb and spitz or Star mutations suggest that these genes participate in a common signaling pathway.

Animals↗
PubMed1992

Dissection of the faint little ball (flb) phenotype: determination of the development of the Drosophila central nervous system by early interactions in the ectoderm.

The complex embryonic phenotype of mutations in the faint little ball (flb) locus, encoding the Drosophila EGF receptor homolog (DER), was dissected by temperature shifts of a temperature-sensitive allele. We show that the phenotype can be resolved into at least five components, which are temporally and spatially distinct. Most notably, the central nervous system (CNS) phenotype is determined at two separate phases. A severe collapse results from early defects in the DER-expressing ectodermal cells from which neuroblasts and midline glial cells deaminate. We thus suggest that DER activity is crucial for interactions that occur in the ectoderm at an early stage, and determine the fate of neuronal and glial cell lineages. This finding explains how a severe CNS phenotype is generated in flb embryos, in spite of the absence of expression of the protein in neuronal cells. In a second phase, during germ band retraction, the flb function is required specifically in the three pairs of midline glial cells (MG). In the absence of a functional DER protein, these cells die or fail to differentiate correctly, resulting in a fused commissure phenotype.

Animals↗
PubMed1991

Interallelic complementation among DER/flb alleles: implications for the mechanism of signal transduction by receptor-tyrosine kinases.

The large number of available embryonic lethal alleles in the Drosophila EGF receptor homolog (DER)/faint little ball locus allowed us to test the possibility of positive or negative interactions among different DER alleles. These interactions were monitored by examining the embryonic cuticular phenotypes of different heteroallelic combinations. Several positive interactions were identified, while negative interactions were restricted to a single allele. This is the first example of positive interactions within the same cell type among alleles of a receptor tyrosine kinase gene. The basis for these interactions is likely to arise from the mechanism of signal transduction by receptor tyrosine kinases, which involves receptor aggregation. A combination of two different DER mutant proteins defective in temporally distinct stages of the signal transduction process, may thus form a functional heterodimer. The mutation sites in four alleles showing positive interactions were localized. They identify regions within the protein which are likely to be important for these temporally distinct signal transduction processes.

Alleles↗
PubMed1990

Effects of perfusion pressure and renal flow upon albumin excretion in isolated perfused kidneys.

To explore the effects of renal hemodynamics upon urinary albumin excretion, sequential changes in perfusion pressure and/or flow were performed in isolated perfused rat kidneys. Elevation of perfusion pressure from 90 to 130 mm Hg increased renal flow from 48.9 +/- 1.1 to 54.3 +/- 1.4 ml/min and glomerular filtration rate (GFR) from 0.37 +/- 0.03 to 0.81 +/- 0.06 ml/min (p less than 0.001). Despite more than a doubling in GFR, albumin excretion remained unchanged (from 252 +/- 53 to 167 +/- 36 micrograms/min, p not significant), resulting in a decreased fractional clearance of albumin (theta) from 0.009 +/- 0.002 to 0.004 +/- 0.005 ml/min (p less than 0.01). To dissociate the effects of flow from those of pressure, angiotensin II was infused to decrease renal flow from 49.9 +/- 0.6 to 38.7 +/- 0.6 ml/min (p less than 0.001), while keeping perfusion pressure constant at 96 +/- 1 mm Hg. Although GFR was essentially unchanged (from 0.59 +/- 0.02 to 0.65 +/- 0.05 ml/min, p not significant), albumin excretion increased from 68 +/- 8 to 151 +/- 21 micrograms/min (p less than 0.001) and theta rose from 0.002 +/- 0.000 to 0.005 +/- 0.001 (p less than 0.02). Whole kidney hemodynamics acutely affect renal excretion of albumin in isolated kidneys.

Albuminuria↗
PubMed1990

Localization of the DER/flb protein in embryos: implications on the faint little ball lethal phenotype.

Antibodies were raised against the Drosophila EGF receptor homolog (DER) and used for immunohistochemical analyses of Drosophila embryos. We found that DER is localized in a wide array of embryonic tissues, displaying a dynamic pattern of expression. DER appears to be expressed in all cells at the cellular blastoderm and gastrula stages. In extended-germ-band embryos, it is found predominantly in the mesoderm and the head. Finally, in retracted-germ-band embryos, DER immunoreactivity is most pronounced at sites of somatic muscle attachments and along the ventral midline of the CNS. We have thus observed that DER is expressed in the diverse tissues which are affected in the DER faint little ball (flb) embryonic lethal phenotype. The different pattern and extent of expression in each tissue suggests that the disparate aspects of the flb phenotype may result from different mechanisms of DER function. To understand the basis for the CNS phenotype of DER/flb mutants, we have closely followed the collapse of the CNS in mutant embryos. Our observations on the evolution of the final CNS phenotype, in combination with the temporo-spatial pattern of appearance of DER in the ventral neuroepithelium, suggest that this receptor participates in the second phase of neuron-glia interactions, namely in stabilization of the ladder-like CNS scaffolding formed by outgrowth of pioneer axonal processes along the glial pre-pattern.

Animals↗