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Biomedical subjects

R Arnon

Publications and source records attributed to R Arnon.

At least 91 records · Page 5Linked to original sources
PubMed1993

Immunogenicity and efficacy of oral or intranasal Shigella flexneri 2a and Shigella sonnei proteosome-lipopolysaccharide vaccines in animal models.

Immunity against shigellosis has been shown to correlate with the presence of antibodies specific for Shigella lipopolysaccharide (LPS). We here propose a new candidate vaccine for shigellosis composed of purified Shigella flexneri 2a or Shigella sonnei LPS hydrophobically complexed with group C type 2b Neisseria meningitidis outer membrane protein proteosomes. Immunization of mice either orally or intranasally with this complex induced specific homologous anti-LPS antibodies in both intestinal and respiratory secretions as well as in sera. Strong anamnestic responses were found after two or three immunizations. LPS alone, alkaline-detoxified LPS, or alkaline-detoxified LPS complexed with proteosomes was not effective. Oral or intranasal immunization of guinea pigs with two or more doses of this proteosome-LPS vaccine elicited homologous protection against Shigella keratoconjunctivitis (Serény test). These data demonstrate that proteosomes can be used as an effective mucosal vaccine delivery system and that orally or intranasally administered acellular vaccines can protect against Shigella infections.

Administration, Intranasal↗
PubMed1993

On the existence of suppressor cells.

Immunological suppression is one of the important aspects which govern the regulation of the immune response. Clonal deletion, clonal anergy and the activity of suppressor cells were proposed as mechanisms leading to this phenomenon. In this review we provide evidence for the existence of suppressor (Ts) cells and their role in autoimmunity in general and particularly in the system of experimental allergic encephalomyelitis (EAE). Ts cell lines and clones that downregulate in-vivo the autoimmune response are described. These results, as well as other recent advances in the understanding of Ts cells regulatory mechanisms and the molecular structures recognized by these cells, lead to the conclusion that Ts cells do exist and that they constitute a distinctive cell type in regard to their function and specificity.

Animals↗
PubMed1993

[Secondary achalasia].

Achalasia is usually a primary disorder of esophageal motility, but has been described in association with other pathological processes, such as malignancy. A 79-year-old man with achalasia secondary to gastric adenocarcinoma is presented. The differential diagnosis of secondary achalasia includes infectious and infiltrative disease and neuropathy, but mainly malignant diseases. The clinical criteria found for achalasia secondary to malignancy included older age at diagnosis, brief duration of symptoms, and weight loss. While upper gastrointestinal x-rays and computerized tomographic scanning may be helpful, the most reliable diagnostic tool is esophago-gastro-duodenoscopy. This is a terminal disease with short life expectancy. Yet making the correct diagnosis can save the patient from futile treatment with muscle relaxants and endoscopic balloon dilatation, the accepted therapeutic measures in primary achalasia.

Adenocarcinoma↗
PubMed1993

Acute upper gastrointestinal bleeding in Jerusalem 1988-91: causes, characteristics and relation to nonsteroidal anti-inflammatory drugs.

We analyzed 321 consecutive episodes of community-based acute upper gastrointestinal bleeding admitted to the Hadassah University Hospital in Jerusalem during 1988-91. Of these 71% were in males aged 56.2 +/- 1.2 years (mean +/- SE) and 29% were in females (67.9 +/- 1.7 years, P < 0.001). The main diagnoses were duodenal ulcer (39.5%), gastric ulcer (16.9%), esophageal varices (10.0%), erosive gastritis (8.2%) and esophagitis (7.5%). The distribution of these diagnoses differed significantly between the genders (P = 0.0003). In males the prevalence of duodenal ulcer and of esophageal varices was higher, and that of gastric ulcer and esophagitis lower, than in females. Gastric ulcer patients were oldest, were the least likely to have received anti-ulcer medications prior to admission, and had the highest levels of urea and the lowest levels of hemoglobin on admission. Use of nonsteroidal anti-inflammatory drugs increased significantly with age and was reported in 35% of the cases (aspirin in doses < 1.0 g/day in 21%, nonsalicylate anti-inflammatory agents in 11%, aspirin plus other anti-inflammatory drugs in 3%). Use of systemic corticosteroids was reported in 4%. The most distinctive features of the population with acute upper gastrointestinal bleeding in the present study compared to other series were the significantly higher proportion of duodenal ulcers and the lower proportion of Mallory-Weiss tears.

Acute Disease↗
PubMed1992

Cytotoxicity of streptavidin-blocked biotinyl-ricin is retrieved by in vitro immunotargeting via biotinyl monoclonal antibody.

The streptavidin-biotin system has been used to immunotarget whole ricin to tumor cells in a system that overcomes ricin-nonspecific cytotoxicity. Biotin was linked to ricin via a disulfide-containing reagent, sulfosuccinimidyl-2-(biotinamido)ethyl-1,3'-dithiopropionate. The product, biotinyl-S,S-ricin (b-ricin), retained most of its in vitro cytotoxic activity against human epidermoid carcinoma (KB) cells. Complexing b-ricin to streptavidin resulted in greater than 99% loss of its cellular toxicity which is associated with loss of cell-binding activity. The streptavidin-b-ricin complex could, however, be targeted to KB cells via the biotinylated monoclonal antibody 108 which is specific to the epidermal growth factor receptor overexpressed on KB cells. The complex did not regain its activity if the specific antibody was not biotinylated or if the biotinylated antibody was of a different specificity. Streptavidin is thus used to block b-ricin, presumably due to a steric restraint of the streptavidin on the ricin B-chain, and to bridge it to biotinyl antibody recognizing the target cell. Avidin could not replace streptavidin in this system since a complex between b-ricin and avidin retained a major part (60%) of ricin cytotoxic activity. This is attributed to the nonspecific binding of avidin to cells in vitro, including the KB cells. It is suggested that b-ricin is blocked by both streptavidin and avidin, but once the complex gains access to the cell surface, its cytotoxic activity is specifically retrieved.

Avidin↗
PubMed1992

Synthetic copolymer 1 inhibits human T-cell lines specific for myelin basic protein.

Copolymer 1 (Cop 1) is a synthetic basic random copolymer of amino acids that has been shown to be effective in suppression of experimental allergic encephalomyelitis and has been proposed as a candidate drug for multiple sclerosis. Cop 1 is immunologically cross reactive with myelin basic protein (BP) and was shown to inhibit murine BP-specific T-cell lines of various H-2 restrictions. In the present study these findings were extended to include human T-cell lines. Cop 1 competitively inhibited the proliferative responses and interleukin 2 secretion of six BP-specific T-cell lines and 13 clones with several DR restrictions and epitope specificities. Conversely, BP inhibited--albeit to a lesser extent--the response of all the Cop 1-specific T-cell lines and clones, irrespective of their DR restrictions. Another random copolymer of tyrosine, glutamic acid, and alanine, denoted TGA, had no effect on these lines. Neither Cop 1 nor BP inhibited the response of lines and clones specific for purified protein derivative. Cop 1 and BP exerted their cross-inhibitory effects only in the presence of antigen-presenting cells. These results suggest that Cop 1 can compete with BP for the binding to human major histocompatibility complex molecules. In view of recent studies implicating BP reactivity in multiple sclerosis, these findings suggest a possible mechanism for the beneficial effect of Cop 1 in this disease.

Antigen-Presenting Cells↗
PubMed1992

Synthetic recombinant vaccine expressing influenza haemagglutinin epitope in Salmonella flagellin leads to partial protection in mice.

The influenza virus haemagglutinin epitope 91-108, which is a conserved amino acid sequence in all type A H3 strains, was expressed in Salmonella flagellin, to evaluate its potential as a vaccine. For that purpose, a synthetic oligonucleotide comprising 54 bases coding for the corresponding sequence was inserted into the plasmid pLS408 and transformed into Escherichia coli JM101. Colonies containing the recombinant plasmid were used to transform Salmonella typhimurium LB5000 and were then transduced to a flagellin negative 'live vaccine' aroA mutant of Salmonella dublin. Rabbits immunized either with the live recombinant S. dublin or with the flagellin isolated from it, showed significant levels of IgG response against the synthetic peptide 91-108 as well as against the intact A/Texas/77 influenza virus. Mice immunized with the same preparations developed influenza-specific IgG antibodies in the blood and secreted IgA antibodies in their lungs. Furthermore, these mice showed about 50% protection against challenge infection with the virus. The most successful results were achieved by intranasal immunization with the isolated recombinant flagellin, when employed without the aid of adjuvant.

Amino Acid Sequence↗
PubMed1992

Synthetic approaches to vaccines for infectious and autoimmune diseases.

The development is outlined of some synthetic vaccines against infectious diseases, in particular cholera, shigella and influenza. In the last case, use of the synthetic adjuvant MDP in combination with a haemagglutinin peptide has led to a synthetic vaccine with built-in adjuvanticity. The production of vaccines both by chemical synthesis and genetic engineering is described. The successful use of the synthetic amino acid copolymer COP-1 as an immunomodulatory vaccine to suppress the onset of allergic encephalomyelitis in experimental animals has led to clinical trials with patients suffering from exacerbating remitting multiple sclerosis. T-cell vaccination is an alternative approach to immunization against autoimmune diseases.

Adjuvants, Immunologic↗
PubMed1992

Effect of the dosing interval on myelotoxicity and survival in mice treated by cytarabine.

Many antineoplastic drugs are cell-cycle-phase-specific. These drugs are often highly toxic to the host, as they have the potential to impair replication, not only in the cancer cells, but also in the normal tissues. Using mathematical models it has been shown how selectivity of these drugs can be increased by exploiting the relatively large variability in cell-cycle parameters of the neoplasia. These models predict that toxicity to the host of cell-cycle-phase-specific drugs can be minimised if the dosing interval is an integer multiple of the average intermitotic interval of the susceptible host cells. Experimental evidence supporting this prediction is presented in this work. Our results show that a constant duration of the dosing interval yields higher survival rates in mice treated by cytarabine, as compared with random dosing intervals. Minimal myelotoxicity is exerted when the dosing interval is an exact multiple of the inter-mitotic time of bone marrow stem cells and erythroid progenitors (i.e. 7 h). Survival is significantly lower in mice treated every 8 h, or its multiple, as compared with that of mice treated at a 7 h or 10 h dosing interval.

Animals↗
PubMed1992

Synthetic peptides as vaccines.

The use of synthetic peptides as an alternative approach to vaccination is currently being pursued. This is particularly true for viral and parasitic diseases in which no vaccines are yet available, most notably the acquired immune deficiency syndrome.

Adjuvants, Immunologic↗
PubMed1992

Structural basis of antigenic specificity and design of new vaccines.

This manuscript describes the design of new vaccines based on synthetic peptides. To this end, we first analyze the structural basis of antigenic reactivity and specificity and the various types of epitopes that form the mosaics of macromolecular antigens, as well as the regulatory mechanisms involved in immune recognition. A distinction is made between sequential or continuous epitopes, and discontinuous or conformational ones, which are the majority of epitopes in globular proteins. In this context it is of particular interest to identify epitopes reacting with B cells and T cells, respectively, or with cytotoxic T cells, in association with the major histocompatibility cell-surface antigens, and the role of these interactions in protective immunity. Identification of such epitopes in proteins of viral, bacterial, or parasitic organisms led to the synthesis of peptides, which when used in conjunction with appropriate carriers and/or adjuvants induced neutralizing antibodies. Particular examples are described, including: bacterial epitopes and mainly those of toxins of diphtheria, cholera, and shigella, leading not only to neutralizing antibodies but also to protective immunity against the deleterious effects of the respective toxins; parasite epitopes, such as those leading to anti-malaria vaccine, based on either the sporozoite or the merozoite stage antigens; viral epitopes leading to protective immunity, with special emphasis on influenza virus where induction of CTL is crucial; and finally, synthetic peptide vaccines against HIV, which should lead to broad specificity protective immunity while avoiding the risks of a vaccine based on the infectious agent. The rapid recent progress in this field, as described in this review, increases the prospect of constructing successful synthetic peptide vaccines in the not too distant future.

Adjuvants, Immunologic↗
PubMed1992

Peptide binding to class I molecules of the major histocompatibility complex on the surface of living target cells.

Molecules encoded by the class I major histocompatibility genes bind short (nonameric) peptides produced by intracellular proteolysis of antigens. These complexes formed intracellularly are then expressed on membranes of target cells and recognized by the antigen receptor of cytolytic T cells. No binding of externally added peptides could so far be monitored directly on the antigen presenting cells, although cytotoxicity experiments and indirect binding assays provided evidence for its existence. Here we report experiments where specific binding to class I molecules, of externally added peptides, has been monitored on living cells. N-terminal biotin-labelled Kd-restricted peptides (residues 147-155, residues 147-158, and an analogue lacking the arginine at position 156, derived from the sequence of the influenza A virus nucleoprotein) were incubated with murine H-2Kd mastocytoma cells (line P815) at 4 degrees C. The binding on surface of live, intact cells was then demonstrated fluorometrically via the interaction of a streptavidin-phycoerythrin conjugate with the biotin-labelled peptides. Thus, this binding does not involve processing, and its specificity in terms of peptide structure was established by competition with the respective unmodified peptides. The specificity of binding to class I molecules was demonstrated by blocking experiments using monoclonal antibodies specific for H-2Kd. Finally, a correlation was observed between the results of peptide binding measurements and those of cytotoxicity assays.

Amino Acid Sequence↗
PubMed1992

Seasonal fluctuations in acute upper gastrointestinal bleeding: lack of effect of nonsteroidal anti-inflammatory drugs.

The seasonal pattern of community-based acute bleeding from the upper gastrointestinal (UGI) tract was studied prospectively in 1988-1991. Out of 3343 emergency admissions to the Departments of General Surgery, 321 (9.6%) were due to acute UGI bleeding. There was a significant monthly variation in the total number of admissions, as well as in the number of admissions due to acute UGI bleeding (p < 0.0001). However, there was no correlation between the two. Significant seasonal fluctuations were noted both in the absolute number of admissions due to acute UGI bleeding and in the percentage of UGI bleeding admissions of the total number of admissions to the Departments of General Surgery (p = 0.0002). During summer (July through September), the incidence declined significantly to a nadir of 5.5% of total number of admissions in July. The seasonal fluctuation correlated closely with the incidence of duodenal ulcer, but not with that of gastric ulcer. The seasonal pattern was consistent both in patients who had used aspirin or other nonsteroidal anti-inflammatory drugs as well as in those who had not.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1992

Effects of heat-exercise stress, NBC clothing, and pyridostigmine treatment on psychomotor and subjective measures of performance.

This study investigated the effects of pyridostigmine pretreatment, NBC protective gear, and heat-exercise exposure on psychomotor performance and subjective sensations in eight healthy male volunteers. Exercise in heat enhanced performance of vertical addition (+7.3%, p less than 0.001) but prolonged the reaction time (+4.4%, p less than 0.01). The effects of pyridostigmine, protective gear, and the interactions between the various stressors were not significant. Cognitive performance was not dependent on body core temperature. Multiple complaints of subjective discomfort arose from wearing the protective garment. The results suggest the existence of a significant subjective discomfort but an absence of major cognitive decrements in a multiple-stresses state of chemical warfare alertness.

Exercise↗
PubMed1991

Cross-reactions and specificities of monoclonal antibodies against myelin basic protein and against the synthetic copolymer 1.

Antibody cross-reactivity is here demonstrated between basic protein (BP), the encephalitogenic molecule of myelin, and copolymer 1 (Cop 1), the synthetic amino acid copolymer, which has a suppressive effect on experimental allergic encephalomyelitis and is effective in reducing the number of relapses in exacerbating-remitting multiple sclerosis. This cross-reactivity is conclusively established using mouse monoclonal antibodies (mAbs). About a third of anti-rat BP mAbs and most of anti-mouse BP mAbs cross-reacted with Cop 1. This cross-reactivity could be demonstrated with anti-BP mAbs of different specificities. In addition, several anti-Cop 1 hybridomas cross-reacted with BP. This cross-reactivity was verified in several assay systems, including competitive inhibition experiments. Moreover, some anti-BP mAbs and anti-Cop 1 mAbs reacted in a heteroclitic manner and favored the cross-reactive antigen over the immunogen. In contrast to the mAbs, no cross-reactivity could be demonstrated with the antisera of immunized mice. This observation may reflect the different B-cell populations expressed in the mAb response as compared to the polyclonal response. Thus, the use of mAbs has uncovered specificities that are not evident in antisera and has revealed pronounced cross-reactivity between BP and Cop 1 at the B-cell level. These results further establish the immunological interrelationships between Cop 1 and BP, demonstrated earlier at the T-cell level.

Animals↗