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Biomedical subjects

M Fattal-German

Publications and source records attributed to M Fattal-German.

At least 19 recordsLinked to original sources
PubMed2000

T cell deletion and unresponsiveness induced by intrathymic injection of staphylococcal enterotoxin B.

Intrathymic injection of alloantigens appears to be the most efficient route to induce alterations of T cell reactivity. In the present study, we explored the modifications of Vbeta8.1, 8.2 T cell population and T cell reactivity in the thymus and in the spleen induced by intrathymic injection of staphylococcal enterotoxin B to adult mice. Vbeta8 antigen expression was investigated by flow cytometry analysis. T Cell reactivity was studied in vitro by the proliferative response to SEB. SEB induced a significant reduction in the percentage of mature Vbeta8+ T cells in the thymus (days 7-14), and in the spleen (days 7-28). Interestingly, this depletion occurs in the CD4- CD8+ cells in the thymus whereas in the CD4+ CD8- cells in the spleen. In parallel, the proliferative response to SEB but not to SEA was significantly decreased in the thymus on days 7 and 14, and in the spleen from day 7 to day 28. Moreover, this unresponsiveness was more pronounced in the spleen than in the thymus. Anergy was SEB-specific and fully reversed by exogenous IL-2. SEB injected intrathymically induced significantly more pronounced and more durable T cell alterations than intraperitoneal and subcutaneous injections. This may be related to the observation that after i.t. injection, SEB was detected both at a higher amount and for a longer period in the central and peripheral compartments. Our results clearly demonstrate that the intrathymic route is definitely the most efficient to induce not only thymic but also peripheral pivotal immune alterations in our model.

Animals↗
PubMed1998

Expression and modulation of ICAM-1, TNF-alpha and RANTES in human alveolar macrophages from lung-transplant recipients in vitro.

Alveolar macrophages (AMs) play a central role in pulmonary inflammation in response to local stimuli. As a model for investigating anti-inflammatory drugs, we studied the effects of the cyclohexadepsipeptide antibiotic, fusafungine, and that of the glucocorticoid dexamethasone on the expression of ICAM-1, TNF-alpha and RANTES, induced in vitro by rIFN-gamma in human AMs freshly isolated from bronchoalveolar lavage fluid (BAL) obtained in lung-transplanted patients. ICAM-1 antigen expression, induced on AMs after 24 h of culture, was significantly inhibited by fusafungine in a concentration-dependent manner, as measured by flow cytometry analysis using an anti-CD54 monoclonal antibody. TNF-alpha production, but not RANTES release (measured by ELISA), was significantly inhibited. mRNA studies, by means of polymerase chain reaction amplification of complementary deoxyribonucleic acids (RT-PCR), showed no significant modification of mRNA levels, suggesting that fusafungine acts mainly at a post-transcriptional level. In the same conditions, dexamethasone significantly inhibited the release both of TNF-alpha and RANTES by AMs, mainly acting at the mRNA level, but had no effect on ICAM-1 expression. Assessment of the cellular and molecular targets of anti-inflammatory drugs in this model of human AM activation should lead to more appropriate treatment of inflammatory process of the respiratory tract. By virtue of its anti-inflammatory effects on alveolar macrophages, combined with its antibacterial properties, fusafungine should prove particularly suitable for local treatment of bacterial infections of the respiratory tract.

Aerosols↗
PubMed1996

Expression of ICAM-1 and TNF alpha in human alveolar macrophages from lung-transplant recipients.

Local activation of macrophages may play an important role in the immune process of pulmonary infections and in the inflammatory response of lung allograft rejection. To document macrophage activation within human lung allografts displaying various complications, we have investigated ICAM-1 expression in freshly isolated alveolar macrophages (AM) from lung-transplant recipients by immunocytofluorimetric analysis, and rIFN gamma induced in vitro by ELISA. A total of 21 bronchoalveolar lavage fluids (BAL) from 13 transplanted patients displaying no complication, acute rejection, bacterial/fungal infection, or CMV infection entered the study. ICAM-1 was expressed at a higher level in rejecting patients. Surprisingly, TNF alpha release from AM upon in vitro activation was significantly decreased during rejection. Furthermore, we have studied the effects of the glucocorticoid dexamethasone, the key drug for the treatment of allograft rejection, on the expression of ICAM-1 and TNF alpha induced in vitro in AM, at the levels of protein production and of transcription. Whereas dexamethasone did not influence ICAM-1 expression in AM, it downregulated TNF alpha production at least in part at the transcriptional level. Our results suggest strongly that the anti-inflammatory effects of corticosteroids are not related to ICAM-1 modulation on human AM but to the downregulation of the proinflammatory cytokine TNF alpha that is produced early in the inflammatory process. Moreover, our model of human AM activation induced in vitro by rIFN gamma appears a useful tool for in vitro investigation of the cellular and molecular targets of anti-inflammatory drugs for a more appropriate use.

Bronchoalveolar Lavage Fluid↗
PubMed1996

Modulation of ICAM-1 expression in human alveolar macrophages in vitro.

Modulation of intercellular adhesion molecule-1 (ICAM-1) expression may be a basic mechanism by which alveolar macrophages (AMs) regulate the inflammatory process in the lung in response to local stimuli. As a model for studying the anti-inflammatory activity of drugs on human AMs, we investigated the effects of fusafungine, an antibiotic for local use by aerosol with anti-inflammatory properties, and that of the glucocorticoid dexamethasone, on ICAM-1 expression induced in vitro by recombinant interferon-gamma (rIFN-gamma). ICAM-1 protein expression was studied on AMs by means of flow cytometry with an anti-CD54 monoclonal antibody; messenger ribonucleic acid (mRNA) levels were determined by reverse transcriptase-polymerase chain reaction (RT-PCR). ICAM-1 was expressed before culture on 21% of bronchoalveolar lavage (BAL) cells, with low intensity. Culture for 24 h with rIFN-gamma resulted in a significant increase in ICAM-1 protein expression (82% of cells were strongly positive). Fusafungine significantly inhibited rIFN-gamma-induced ICAM-1-protein expression on AMs in a concentration-dependent fashion. The mechanism of ICAM-1 downregulation was mainly post-transcriptional, but also partly transcriptional. By contrast, dexamethasone did not influence rIFN-gamma-induced ICAM-1 expression. This in vitro model using human AMs should prove useful for investigating the cellular and molecular targets of anti-inflammatory drugs.

Aerosols↗
PubMed1995

[Expression of intercellular adhesion molecule 1 (ICAM-1) on human alveolar macrophages].

Modulation of intercellular adhesion molecule 1 (ICAM-1) expression on alveolar macrophages (AM) may be one of the the basic mechanisms by which AM regulate the course of inflammatory response during pulmonary allograft rejection and infectious processes by mediating macrophage-lymphocyte interactions. As a model for studying anti-inflammatory activity of drugs on AM, we have investigated the effect of fusafungine, a local antibiotic which displays also anti-inflammatory properties, on the regulation of ICAM-1 membrane expression induced in vitro by stimulating AM from lung-transplant recipients. We have studied ICAM-1 membrane expression by immunocytofluorometric analysis using the anti-CD54 monoclonal antibody. The ICAM-1 molecule was expressed on 10 to 47% of freshly isolated AM, depending on the clinical status of the patients. After 24 hr cultivation with 250 U/ml gamma-IFN, the percentage of ICAM-1+ AM s increased to more than 90%. When added with the stimulating agent, fusafungine could inhibit the induction of ICAM-1 membrane expression, up to 90% of inhibition at 8 microgram/ml. However, once ICAM-1 was induced after 24 hr cultivation upon stimulation, fusafungine could not afford any reversion. On going investigations on mRNA for ICAM-1 should indicate whether fusafungine acts at the transcriptional level. These results clearly demonstrate the capacity of fusafungine to down-regulate ICAM-1 expression on AM upon activation. This approach could represent a useful tool for in vitro study of drug efficacy upon inflammatory processes of the respiratory mucasa.

Aerosols↗
PubMed1994

Emergence of inflammatory alveolar macrophages during rejection or infection after lung transplantation.

Local activation of macrophages may play an important role in immune complications following lung transplantation. To document such a phenomenon, we have investigated the possible changes of alveolar macrophage surface antigen expression after lung transplantation. Using immunocytofluorometry, we have analyzed the phenotype of alveolar macrophages from 41 bronchoalveolar lavage fluids obtained from 19 lung transplant recipients displaying various complications. The strong expression of HLA-DR observed on almost all alveolar macrophages was similar among groups I (no complication), II (minimal acute rejection), and III (mild to severe acute rejection), but was enhanced in group IV (bronchial infection) (P < 0.03). We observed no significant variation in the monocyte lineage CD14 antigen expression among the 4 groups, and about 83% of alveolar macrophages expressed this marker strongly. Membrane expression of the 27E10 antigen that characterizes infiltrating macrophages in acute inflammatory lesions was significantly higher during mild to severe rejection episodes than in controls (P < 0.02) and during bronchial infections (P < 0.05) but not during minimal rejection. Double staining experiments confirmed that 27E10-positive cells in groups III and IV belonged to the macrophage lineage. In addition, the expression of the 27E10 antigen on cultured alveolar macrophages was found to be increased after stimulation by bacterial lipopolysaccharide or IFN-gamma. These results indicate that a particular alveolar macrophage subpopulation is activated during immune events after lung transplantation. This population, recognized by the 27E10 mAb, might be involved in cytokine production during severe acute rejection and infection episodes.

Adolescent↗
PubMed1994

Particular phenotypic profile of blood lymphocytes during obliterative bronchiolitis syndrome following lung transplantation.

Bronchiolitis obliterans syndrome (OBS) remains the major complication in long-term survivors with heart-lung transplants, occurring in up to 50% of patients who survived the first year postsurgery. Until now, a significant decrease in small airway flow parameters has represented the most sensitive index for the detection of early OBS. Using immunocytofluorometric analysis, in a prospective study we have analysed the phenotype of peripheral blood lymphocyte effector and regulatory subsets in seven patients with inactive well-established OBS as compared with lung transplant recipients without any complication. We found a particular phenotypic profile during well-established OBS characterized by: (1) the disappearance of the CD19+ B cell population despite normal or increased immunoglobulin blood levels; (2) a marked decrease in the CD4+/CD8+ ratio; (3) a dramatic increase in phenotypic cytotoxic effector T cells CD8+S6F1+high and CD3+CD4-CD8-; (4) a dramatic increase in the CD4+CD29+/CD4+CD45RA+ ratio associated with the loss of the phenotypic suppressor/inducer CD4+CD45RA+T cells. The results of this preliminary study suggest that, using this selected combination of lymphocyte membrane markers, sequential phenotyping could be useful in the noninvasive follow-up of lung transplant recipients. The predictive value of this phenotypic profile for the early diagnosis of OBS is under investigation.

Adolescent↗
PubMed1993

[Phenotype profile of blood lymphocytes in bronchiolitis obliterans after lung transplantation].

Bronchiolitis obliterans (BO) remains the major complication in long-term survivors with lung transplants, occurring in up to 30% of them. As a non-invasive follow-up of lung recipients, we studied the phenotype of peripheral blood lymphocyte subsets. Using a flow cytometric analysis, we could define a specific pattern during BO. The most important findings were 1) disappearance of the CD19+ B cell population, despite normal or increased immunoglobulin blood levels; 2) marked decrease of the CD4+/CD8+ ratio; 3) dramatic increase in phenotypic cytotoxic effector T cells CD8+S6F1+ (MHC Class I-restricted allocytotoxicity) and CD3+CD4-CD8- (MHC Class I-non restricted allocytotoxicity); 4) marked increase of the CD4+CD29+ (helper/inducer T cell) to CD4+CD45RA+ (suppressor/inducer T cell) ratio associated with the loss of phenotypic suppressor/inducer CD4+CD45RA+ T cells. Moreover, we have shown that the maintenance triple immunosuppressive regimen that consisted of cyclosporin, prednisolone and azathioprine, did not affect the relative distribution of lymphocyte subsets, except for the CD3+CD4-CD8- cytotoxic subset that was slightly decreased under therapy. Thus, using a selected combination of lymphocyte membrane antigens, sequential prospective testing should be useful in the non-invasive follow-up of lung-transplanted patients to predict and halt the progressive course towards BO.

Adolescent↗
PubMed1992

Induction of various cytokines in mice and activation of the complement system in rats as a part of the mechanism of action of the Corynebacterium granulosum-derived P40 immunomodulator.

The capacity of the Corynebacterium granulosum-derived P40 immunomodulator to induce in mice the formation of various cytokines IFN, IL-1, IL-2, alpha-TNF as well as to activate the complement system in rats was investigated. The results showed that P40 injected by the intravenous route was capable of inducing the formation of all four cytokines. High levels of IFN were measured 2 h after P40 stimulation and were still present at 24 h. The kinetic study of IL-1, IL-2 and alpha-TNF induction showed that it was a biphasic phenomenon. The patterns of IL-1 and alpha-TNF induction were quite comparable, whereas the release of IL-2 was delayed with respect to that of IL-1 and alpha-TNF. Oral administration of P40 to rats strongly activated the alternative pathway of the complement system. It was concluded that most of the non-specific effects of P40 on the immune system are likely to be mediated by its capacity to induce cytokine formation and to activate the complement system.

Adjuvants, Immunologic↗
PubMed1992

Assessment of the anti-viral effect of a short-term oral treatment of mice with live Saccharomyces cerevisiae cells.

For assessing the efficacy of antiviral treatments, influenza and herpes virus HSV-1 infections of varying degrees of severity have been produced. The infections proved to be reproducible with respect to both their course and death rate. These infections also exhibited a course slow enough to permit the assessment of treatments under conditions mimicking human infections and lent themselves to the choice of the best adapted strategy to treat an infection. A short-term oral treatment with live cells of S. cerevisiae was efficacious in protecting mice against mild influenza infection and partly but significantly against severe infection. On the other hand, it did not afford significant protection towards either mild or severe HSV-1 infections, but it significantly potentiated the effectiveness of the antiviral drug vidarabin. S. cerevisiae treatment induced the synthesis of IFN alpha but not that of TNF alpha.

Adjuvants, Immunologic↗
PubMed1992

Standardized mouse infection models as a way of evaluating the potency of anti-infectious agents.

Standardized bacterial and viral mouse infection models have been developed. Infections with extracellular bacteria (K. pneumoniae, S. pneumoniae, S. pyogenes A) were produced by either of two routes: via the intravenous route (i.v.) resulting in septicaemia and the intranasal route (i.n.) giving infections confined to the respiratory apparatus. Infections with intracellular bacteria (L. monocytogenes, S. typhimurium) were produced only by the i.v. route. Two types of viral infection, mild and severe, were produced. Infection with influenza virus was by aerosol and herpes virus HSV-1 by the intraperitoneal route. All infection models produced under strictly controlled conditions were shown to be characterized by a remarkable reproducibility regarding both the pattern of development and death rate. The infection models lend themselves to estimation of the efficacy of a drug as well as the designing of new therapeutic strategies.

Animals↗
PubMed1992

[Immunocompetence in the elderly].

Ageing is associated with a progressive decline of the immune systems, characterized by impaired T cells and changes in the antigenic repertory related to both the humoral and cell-mediated immune responses. The major alterations have been demonstrated in the T cells which undergo functional changes, such as a decrease in precursor frequencies of helper and cytotoxic T-cells, and accumulation of T cells which does not respond to activators. In general, T cell-dependent, cell-mediated responses decline with age. The elderly are at great risk for low consumption of proteins and of several micronutrients, such as zinc or vitamins C, E and B6 which play a critical role in the maintenance of normal immune function. As a consequence, the incidence of inflammatory and infectious disease, auto-immune disorders, cutaneous pathological changes, and skin cancers increases. Morbidity and mortality rates due to tetanus, pulmonary infections and influenza remain high in elderly populations. Depressing the rate of immunosenescence and restoring a normal immunocompetence in the elderly may involve improved nutrition through proteins, micronutrients and vitamins, and should deal with the economic and psychosocial problems of the elderly. Vaccinations against tetanus, pneumococcus and influenza proved to be efficacious and well-tolerated. Consequently, they should be applied systematically to non protected elderly individuals.

Aged↗
PubMed1991

Pneumococcal vaccination of elderly individuals.

Pneumococcal infections are still a cause of high morbidity and mortality in elderly populations. Since antibiotics are not wholly effective, vaccination should be performed. The response to pneumococcal vaccination of a limited group of elderly persons aged 60 to 90 years was studied. The sera of most individuals were found to contain antipneumococcal antibodies prior to vaccination. Vaccination resulted in antibody level increases in sera of all subjects except two. On the basis of antibody levels, 19 out of 20 vaccinees proved to be protected after vaccination. Combination of vaccination with a non-specific immunostimulation enhanced the antibody response.

Aged↗
PubMed1991

[The usefulness of vaccination in elderly persons].

The antitetanus, antipneumococcal and antiinfluenza immune status, as well as the efficacy of vaccination have been evaluated in the elderly. Ages of the studied populations ranged from 60 to 98 years. Before vaccination, only half of the tested population was found to be protected against tetanus. Immunization resulted in 80% coverage of this population. Prior to antipneumococcal vaccination, 32% of the tested sera did not contain a "potentially" protective antibody titre. Vaccination resulted in 100% seroconversion. It was verified that 100% of tested sera contained antibodies (greater than 10 U.H.A./ml) directed to the former Singapore antigen and 99.2% and 66.7%, respectively, to the newly immerged Shanghaï and Yamagata antigens (present in the administered vaccine). Following vaccination, 100% of the sera exhibited antibody titres higher than 10 U.H.A./ml to the Singapore and Shanghaï antigens, and 90.5% to the Yamagata antigen. It can be concluded from the reported results that antitetanus, antipneumococcal and antiinfluenza vaccinations should be systematically given to all individuals beyond 60 years of age, since these vaccinations are innocuous and confer extended vaccinal coverage.

Aged↗
PubMed1991

Usefulness of influenza vaccination in the elderly.

Since influenza morbidity and mortality are high in the elderly, the usefulness of vaccination has been evaluated. One hundred and twenty-six older persons aged 60-90 yr were given a vaccine consisting of the 3 antigens Singapore, Shanghaï and Yamagata, the latter 2 being new antigens. Antibody levels for each of the antigens were determined by ELISA calibrated in HA units prior to and 1 month after vaccination. Before vaccination, antibodies to Shanghaï and Singapore antigens were found in practically all sera tested, and antibodies to Yamagata antigen in only 66% of sera. After vaccination, significant levels of antibodies to all 3 antigens were found in sera tested. Thus, it was observed that influenza vaccination proved to be effective in the elderly. The elderly should be immunized against influenza, since this is a safe and efficacious preventive measure. In addition, vaccination should limit the spreading of influenza in nursing homes.

Aged↗
PubMed1990

A dot-ELISA for the detection of IgG antibodies to mumps and varicella viruses.

An enzyme-linked immunosorbent assay using nitrocellulose strips (dot-ELISA) for the routine laboratory detection of IgG antibodies to mumps and varicella viruses is described. The virus antigens are dotted onto nitrocellulose strips, and the dotted strips are incubated with the sera to be tested. The bound antibodies are revealed using enzyme-labeled antihuman IgG antibodies. Reliable results are obtained when the assay is carried out at 37 degrees C. The reported data indicate that the dot-ELISA can reliably be used for the detection of IgG antibodies to mumps and varicella viruses in human sera.

Antibodies, Viral↗
PubMed1990

A dot-ELISA intended for the specific and simultaneous detection of antibodies directed to antigens derived from Toxoplasma gondii, rubella virus, cytomegalovirus, and type 1 and type 2 herpesviruses.

A procedure for the routine and simultaneous laboratory detection of IgG antibodies produced in humans in the course of various infectious diseases is described. The procedure, based on dot-enzyme-linked immunosorbent assay (ELISA), used single nitrocellulose strips onto which several antigens were dotted in close proximity. Optimal conditions were specified that allowed the unequivocal and simultaneous detection of IgG antibodies specifically directed against Toxoplasma gondii, rubella virus, cytomegalovirus, and herpes simplex virus type 1 and type 2 antigens. This technique has proved to be simultaneously specific, sensitive, and reliable, and it has been applied to prenatal screening of sera from pregnant women. It is suggested that this technique should also be used for the screening of large numbers of sera under field trial conditions.

Animals↗