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Biomedical subjects

A Achour

Publications and source records attributed to A Achour.

At least 55 records · Page 3Linked to original sources
PubMed1998

A three-dimensional model of the Fas/APO-1 molecule: cross-reactivity of anti-Fas antibodies explained by structural mimicry of antigenic sites.

Fas/APO-1 is a member of the tumor necrosis factor (TNF)/nerve growth factor receptor family. This cell surface protein, when associated with the Fas/APO-1 ligand or specific mAb, elicits an apoptotic response in susceptible cells via an oligomerization of its intracellular domains, termed the'death domains'. We have previously mapped the epitopes of a panel of Fas/APO-1-reactive mAb to a series of linear portions of the Fas/APO-1 molecule. In order to gain a greater understanding of the mode of interaction of these antibodies with the Fas/APO-1 antigen, we constructed a homology-based model of the extracellular portion of the molecule, based on the crystallographic coordinates of the TNF type I receptor. The model clearly demonstrates that the antibodies do not identically mimic the endogenous ligand to achieve their effect, but probably act in an analogous manner by recruiting Fas/APO-1 molecules into clusters which may lead to oligomerization of 'death domains'. Moreover, the apparent cross-reactivity observed for the monoclonal anti-Fas antibodies between different linear regions of the Fas/APO-1 molecule was found to be due, most likely, to the structural mimicry of these epitopes. Reduction of the Fas/APO-1-derived cross-reactive peptides by dithiothreitol completely abrogated their antigenic reactivity with the anti-Fas mAb CH-11, thus indicating that the establishment of intrapeptide disulfide bonds is critical for antigenic reactivity.

Amino Acid Sequence↗
PubMed1998

Investigations into the cross-reactivity of rabbit antibodies raised against nonhomologous pairs of synthetic peptides derived from HIV-1 gp120 proteins.

The immunological cross-reactivity of several peptides with specific pattern-property characteristics related to the epitopes of human immunodeficiency virus type 1 (HIV-1) gp160/ 120 envelope proteins has been investigated. Proteins with similar primary structures can be expected to show functional or topographic similarities, such as specific epitopes which may cross-react with antibodies derived from the immunisation of animals with other members of the same protein family. These structure-function characteristics may be revealed as periodicities derived from presentations based on the discrete Fourier transformation of the distributions of various physico-chemical amino acid descriptors, constituting the polypeptide backbone and amino acid side-chains of the protein molecule. Such approaches, for example, have permitted prediction of periodicities corresponding to secondary structural motifs, including amphipathic alpha-helices and beta-sheets, within protein sequences, and have helped to clarify potential binding sites for ligands, substrates or cofactors with interacting macromolecules. Based on this approach, characteristic periodicities have been identified which represent common Fourier transform spectral properties of the envelope (ENV) gp160/120 glycoproteins from a range of HIV-1 isolates. In addition, similar periodicities have been detected as components of the discrete Fourier transform representation of the corresponding amino acid descriptors of the CD4 binding domain of gp120. Accordingly, we have synthesised several peptides having periodic characteristics in their discrete Fourier transform representations similar to these HIV-1 proteins. These nonhomologous synthetic peptides induced cross-reactive antibodies in New Zealand White rabbits. Polyclonal antibodies raised to one of these peptides reacted with HIV-1 ENV gp120-related proteins, as determined by enzyme-linked immunosorbent assay and Western blotting techniques. These findings provide further evidence for a role of immunological cross-reactivity and molecular biomimicry in the development of peptide-based vaccines directed against viral or bacterial pathogens.

Animals↗
PubMed1998

Restoration of immune response by a cationic amphiphilic drug (AY 9944) in vitro: a new approach To chemotherapy against human immunodeficiency virus type 1.

AY 9944 [AY; trans-1,4-bis(chlorobenzylaminomethyl)-cyclohexane dihydrochloride], an inhibitor of sterol synthesis, was found to help restore the normal mitogenic responses and cytokine profiles of peripheral mononuclear cells (PBMCs) from AIDS patients in vitro. Compared to untreated cells, the human immunodeficiency virus type 1 (HIV-1)-infected PBMCs precultured in the presence of AY exhibited a normal rate of either mitogen-induced or recall- and superantigen-induced proliferation. After 2 weeks in the presence of the drug, the percentage of dead CD4(+) cells in HIV-1-infected cultures was comparable to that observed in uninfected cultures, while over the same time interval it increased by three- to fivefold in HIV-1-infected cultures maintained in the absence of AY. AY also stimulated by 2- to 12-fold interleukin-12 (IL-12) and (gamma interferon production. For IL-12, this effect appears to be related to an increase in corresponding IL-12 p35 and IL-12 p40 mRNA levels. Moreover, AY restored the expression of the IL-2 receptor, which was severely impaired in HIV-1-infected PBMCs. Although the drug has no direct antiviral effect (it does not significantly inhibit reverse transcriptase activity measured in vitro), it might be considered a potential therapeutic agent for HIV-infected patients, in that it may correct viral infection-related immune system defects by indirectly enhancing the level of resistance to HIV and opportunistic infections.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Potentialization of IL-2 effects on immune cells by oyster extract (JCOE) in normal and HIV-infected individuals.

Peripheral blood mononuclear cells (PBMCs) are physiologically activated by interleukin (IL)-2. We found that oyster extract (JCOE) currently used as a functional nutrient enhanced in vitro the IL-2 dependent activation as measured by cell count. 3H-thymidine uptake and up-regulation of a IL-2 receptor. In human immunodeficiency virus (HIV) seropositive individuals, this oyster extract-induced effect was marked in asymptomatic individuals with quasi-normal CD4 cell counts, but was weakly reflected in acquired immunodeficiency syndrome (AIDS) patients.

Animals↗
PubMed1996

Lymphoproliferative response to synthetic V3 loop P18 peptide and HIV-1 envelope glycoprotein among individuals immunized with gp160 candidate vaccines.

Because T-cell responses are critical for defense against viral infections, the synthetic P18 peptide (RIQRGPGRAFVTIGK) and active component of gp160 protein has previously been shown to induce cytotoxic and helper T-lymphocyte responses. In order to further define the T-helper cells, responses which are known to play a role in enhancing the immunological response to foreign antigen, we studied the response of individuals immunized with HIV gp160 candidate vaccines. We investigated the proliferative cellular response of peripheral blood mononuclear cells (PBMC) derived from individuals immunized with gp160 antigens in three different protocols. We found a PBMC proliferative response to synthetic P18 peptide in healthy immunized individuals induced by gp160 antigen with or without vaccinia virus. There was correlation between the proliferative response to P18 peptide and other antigens such as HIV-like proteins and gp160 molecule. HLA-DR typing revealed the possible presentation of P18 peptide by several different class II molecules. Since these class II molecules occur frequently in the general population, P18 peptide appears to contain broadly reactive epitopes and thus is presented by multiple HLA class II molecules. Due to its broad reactivity P18 peptide is one of the candidates for inclusion as a subunit vaccine against HIV-1.

AIDS Vaccines↗
PubMed1996

Induction of anti-gp160 cytotoxic T cells cross-reacting with various V3 loop P18 peptides in human immunodeficiency virus type 1 envelope-immunized individuals.

Cytotoxic T lymphocytes (CTL) may be important to prevent cell-to-cell transmission of human immunodeficiency virus type 1 (HIV-1), the agent responsible for AIDS. In this study, we investigated the epitope specificity of CTLs induced in individuals immunized against the virus envelope glycoprotein gp160. The determinant of HIV-1 gp160 for the stimulation of CTL is located in a region of high sequence variability among HIV-1 isolates, the so-called V3 loop P18. Using a panel of P18 peptides, we compared the CTL specificities of cells from two individuals immunized with vaccinia virus recombinants expressing the envelope glycoproteins from two different strains of HIV-1, IIIB and SIMI. For this purpose, CTLs specific for the IIIB P18 peptide (RIQRGPGRAFVTIGK) were compared with CTLs for the site from the SIMI isolate (TLHMGPKRAFYATGD). The results indicate that in contrast to CD8+ CTLs induced by the glycoprotein from strain IIIB, CD8+ CTLs induced by strain SIMI strongly cross-reacted with targets presenting P18 peptides as well as envelope proteins from the divergent MN and RF isolates but failed to cross-react with targets that presented the IIIB peptide. These data have implications for the design of an HIV vaccine.

AIDS Vaccines↗
PubMed1996

[Level of cardiovascular risk factors in the urban and rural populations of Cap-Bon: Tunisia].

Cardiovascular risk factors were studied in a random sample from the urban and rural population of the Cap-Bon, including 692 men and women, aged 35-50 years. In this sample, including 56 % urban dwellers, the mean total cholesterol was higher in urban areas (4.64 mmol/l) than in rural areas (4.16 mmol/l). In urban areas 10.2 % of the subjects had values above 6.2 mmol/l compared with 6.6 % in rural areas. Obesity was much more frequent among women (35.2 % versus 26.3 %) but less frequent among men (16.0 % versus 5.4 %) in urban and rural areas. Diabetes was found in 8.8 % of men and 10.4 % of women in urban areas, and only 0.8 % and 3.9 % in rural areas. Hypertension was found in 13.8 % of women and 11.6 % of men in urban areas, 13.3 % and 4.0 % in rural areas (13.3 %). Cigarette smoking was found in 60.7 % of men in urban areas and 75.8 % in rural areas (p < 0.05).

Adult↗
PubMed1995

Foodstuffs and human blood contamination by the mycotoxin ochratoxin A: correlation with chronic interstitial nephropathy in Tunisia.

Ochratoxin A (OTA) has been detected in high amounts in human blood samples collected in nephrology departments in Tunisia from nephropathy patients under dialysis, especially those categorised as having a chronic interstitial nephropathy of unknown aetiology. These represent 12-26.1% of all chronic renal failure patients. To clarify the situation, food and blood samples were collected from nephropathy patients and controls, (with no familial case of nephropathy). The OTA assay showed very different scales of OTA food and blood contamination from 0.1 to 16.6 micrograms/kg and 0.1-2.3 ng/ml, respectively, in controls and healthy individuals and 0.3-46 830 micrograms/kg for food and 0.7-1136 ng/ml for blood in nephropathy patients. The disease seems related to OTA blood levels and food contaminations, since the control group was significantly different from the nephropathy group (p < 0.005) for both food and blood ochratoxin A contamination. Combined with data published already, the results emphasize the likely endemic aspect of this OTA-related nephropathy occurring in Tunisia and possibly in other countries of northern Africa. This nephropathy is very similar to Balkan endemic nephropathy.

Chronic Disease↗
PubMed1995

Altered MHC class I presented peptide repertoire is not sufficient to induce NK cell mediated F1-hybrid resistance.

Murine NK cells are known to mediate F1-hybrid anti-parental graft rejection responses. This phenomenon has been linked to the MHC, and in particular, to the alpha 1/alpha 2 domains of the MHC class I molecules. Here, we have addressed the role of MHC class I bound peptides in NK cell mediated F1-hybrid anti-parental rejection by studying the resistance of F1-hybrids between B6 and different bm mutant strains to B6-derived RBL-5 lymphoma cell line. Tumor development occurred at a similar frequency in all combinations of (B6 x bm)F1 mice and control B6 mice. These results suggest that absence of a specific MHC class I presented peptide repertoire on grafted cells is not sufficient to induce NK cell mediated F1-hybrid anti-parental rejection responses.

Animals↗
PubMed1995

Automat and BLAST: comparison of two protein sequence similarity search programs.

Since the early 1980s, protein/DNA sequence similarity search has become of major importance to biologists, and the need for fast and efficient tools grows with the size of databanks. Two programs use the strategy of finite state deterministic automatons to accomplish these searches. One of these two is BLAST, which is now widely used, and the other Automat, which has just been published. The differences and similarities in their basic principles, their use and their performances are analysed in this paper in order to allow optimal use of these important softwares.

Algorithms↗
PubMed1995

Ochratoxin A in human blood in relation to nephropathy in Tunisia.

The determination of ochratoxin A (OTA) in human blood in Tunisian populations is underway. The range of contamination is between 0.7 to 7.8 ng ml-1 for the general population and 12 to 55 ng ml-1 for people suffering from chronic renal failure. It appears that 21 to 64% of people suffering from nephropathy are OTA positive with a detection limit of 1ng ml-1. This situation prompted us to search for possible association of OTA contamination and nephropathy resembling Balkan endemic nephropathy. The classification of the ill population into chronic interstitial nephropathy (CIN), chronic glomerular nephropathy (CGN), chronic vascular nephropathy (CVN) and others, indicated that the largest is the CIN group which is significantly different from the other groups, and from the control (P < 0.005). Furthermore, it presented the highest OTA mean values (25 to 59 ng ml-1) compared with the control, CGN, CVN and other groups (6 to 18 ng ml-1) according to the designated region in Tunisia. The rural population seems to be more exposed to ochratoxins in Tunisia, as has been previously reported in the Balkans and Western Europe. Altogether, these results emphasise that in Tunisia an endemic ochratoxin-related nephropathy is probably occurring.

Adult↗
PubMed1995

Are CD4 and Fas peptide identities of gp120 relevant to the molecular basis of AIDS pathogenesis?

The release of virions from HIV-1-infected CD4 cells, although occurring readily as a result of immune activation, does not appear to be the only mechanism mediating T-cell loss in AIDS. Three other interacting HIV-1-induced immune disorders in association with viral release (the source of gp120 molecules) may also account for the constitutive T-cell depletion and functional immune suppression: 1. gp120-induced CD4(+) cell anergy, which can be reproduced in cultures of immune activated normal T-cells in the presence of gp120 or gp120 peptide containing the SLWDQ sequence identity to the CD4 molecule; 2. overproduction of IFNalpha and gamma, 3. activation-driven apoptosis of non infected T-cells. Apoptosis of T-cells could also be: 1. induced by effector components - particularly CTL and lymphotoxins produced by helper T-cells of the anti-Fas autoimmune reaction triggered by gp120 epitopes shared with the Fas/APO-1 molecule; 2. enhanced by IFN overproduction. These molecular mechanisms stress the importance in the progression to AIDS of both the viral load and HIV-induced cytokine dysregulation, including overproduction of IFNalpha, which should be considered as targets in the development of strategies for AIDS prophylaxis and immunotherapy.

Journal Article↗
PubMed1995

"Kinoids": the basis for anticytokine immunization and their use in HIV infection.

HIV infection is characterized, at least in part, by the dysregulation of the cytokine network. Both IFN gamma and IFN alpha are occasionally overproduced. These cytokines could participate in the HIV-induced immunosuppression. To enable a HIV-infected organism to promote an immune reaction against the virus, the immune competence should tentatively be restored by counteracting the overproduction of IFN alpha because of its well known antiproliferative properties. For this purpose, IFN alpha was chemically converted into a biologically inactive, but still immunogenic product, which we termed "kinoid", reminiscent of that of bacterial toxins which have been transformed into toxoids for vaccination. The "kinoid" derived from IFN alpha showed to be well tolerated and immunogenic, since its administration to experimental animals and humans should result in no untoward reactions, while eliciting the production of anti-IFN alpha antibodies. Active "kinoid" immunization should permit to counteract the overproduction of the corresponding cytokine when involved in pathogenesis. Another alternative, although less attractive than active anti-kinoid vaccination, is passive immunization by administering anti-kinoid antibodies. Biological antagonists of cytokine, as well as gene therapy should also be taken into consideration.

Acquired Immunodeficiency Syndrome↗
PubMed1995

HIV-1 soluble antigens induced CD8+ cytotoxic T-cell responses in an immunized individual.

In an attempt to determine whether immunization of healthy HIV-1 seronegative individuals with a soluble gp160 candidate vaccine could induce an anti-HIV specific immune response, volunteers were immunized by two injections of a water-in-oil emulsion containing a mixture of gp160 antigen together with selected peptides. Following immunization, lymphocytes were collected and stimulated in vitro with autologous HIV-1-infected cells. The results showed that immunization with soluble HIV-1 envelope was able to generate CD3+ CD8+ CTLs directed to gp160 antigen. The CTL response was restricted to class I molecule HLA-A2. The CTL response was comparable to that elicited by immunization with HIV-1-envelope recombinant vaccinia virus.

AIDS Vaccines↗
PubMed1995

Which nutrient supplements for optimal HIV-1 production by cultured human lymphocytes?

Under standard conditions, all established cell-lines of HIV-1-infected lymphocytes are cultured in a medium containing a high percentage of serum. We have found that whilst partial or total serum depletion impedes their cell growth, it dramatically increases their virus production. Serial subcultures in serum-depleted medium are necessary to insure permanent cell growth and a relatively high reverse transcriptase activity. Following optimization of culture conditions, both HIV-infected and uninfected H9 cells have been regularly grown in a new protein-free medium. Such chemically defined culture conditions were required to detect the effect of minor components, such as vitamins, on host cell-virus interactions.

Blood Proteins↗
PubMed1995

Cytotoxic T lymphocytes specific for the synthetic VEINCTR peptide, a sequence found within the Fas molecule and env gp120 in the blood of HIV-1 seropositive individuals.

We have previously identified a VEINCTR peptide common to both the Fasmolecule and HIV-1 gp120. Here we report the characterization in PBMCs from HIV-1-infected individuals of a CD8+ class I restricted CTL activity directed towards this peptide. The peptide is highly conserved in various HIV-1 strains, being located at amino acid 287-293 (VEINCTR), within an epitope known as cell T epitope on the env protein of human immunodeficiency virus type-1. Cell cultures were obtained by polyclonal activation using autologous blast cells and CTL lines generated from frozen peripheral blood lymphocytes of HIV-1 seropositive donors by stimulation with the peptide and recombinant interleukin-2. The env-specific CTL turned out to kill autologous target cells infected with a recombinant vaccinia virus containing the env gene of HIV-1 or pulsed with peptide. Specificity was determined using shorter peptides. The CTL activity was directed against autologous target cells presenting the heptapeptide which is site located in the Fas molecule, known to be functionally involved in T-cell apoptosis.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Syngeneic adoptive transfer of anti-human immunodeficiency virus (HIV-1)-primed lymphocytes from a vaccinated HIV-seronegative individual to his HIV-1-infected identical twin.

Immunotherapy by adoptive transfer of lymphocytes was attempted in identical twins, one who was virus-free and the other who was infected with human immunodeficiency virus-1 (HIV-1), at the stage of acquired immunodeficiency syndrome. The noninfected twin was vaccinated by priming with a recombinant vaccinia virus expressing the envelope glycoprotein of one of his brother's viruses and boosting with the same purified gp160 adsorbed on alum. Vaccination elicited major histocompatibility complex class I-restricted CD8+ cytolytic T lymphocytes specific for HIV-1, but no antibody response. The diseased brother, a 38-year-old homosexual who had developed repeated opportunistic infections since 1990 and had a CD4+ count reduced to practically zero, was treated by infusions of lymphocytes collected from the vaccinated brother by lymphopheresis. After a first transfer of the whole lymphocyte population, no changes were observed in the clinical status and biologic or virologic parameters. A second transfer was then applied with activation of the cells with purified envelope glycoprotein before infusion. The outcome of the treatment was an increase in total lymphocytes, in CD4+ and activated CD8+ DR+ cell counts, and in proliferative responses to HIV antigens. A marked but transient 3-log increase in cellular and plasmatic virus loads was also observed after the second adoptive transfer. These observations will be considered with attention to improve the future adoptive transfer protocols, especially in patients with severe CD4+ depletion.

Acquired Immunodeficiency Syndrome↗