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Biomedical subjects

L P Nicod

Publications and source records attributed to L P Nicod.

At least 19 recordsLinked to original sources
PubMed2004

Development of a quantitative TaqMan RT-PCR for respiratory syncytial virus.

Respiratory syncytial virus (RSV) is a ubiquitous RNA virus of the family Paramyxoviridae that may interfere with graft tolerance and with other interstitial lung diseases. The low viral titre observed in the immunodeficient transplanted patients requires a highly sensitive detection method. Although different tests already exist for the detection of RSV, reverse transcription-polymerase chain reaction (RT-PCR) has been shown to have the best sensitivity. In this study, a SYBR Green assay was established for the detection of RSV A and RSV B in a common screening test, and two quantitative TaqMan RT-PCRs were developed to quantify both RSV subgroups separately. Standard dilutions obtained from RSV cell infections were included in each test, and the assay was normalised using a housekeeping gene. RSV was found in 16% of the transplanted patients tested. The quantitative TaqMan assay is fast, reproducible, specific and very sensitive, and could facilitate considerably the detection of RSV virus. This would in-turn facilitate studies on the role of RSV in graft rejection.

Benzothiazoles↗
PubMed2003

[Research in pneumology since 100 years].

Pulmonology during the last century has early on benefited from outstanding morphologic, anatomic and physiologic descriptions which have allowed the comprehension of pulmonary mechanic and gas exchanges. On these bases invasive and non-invasive ventilations have been initiated. With the discovery of antibiotics and antituberculosis treatments, the mortality related to infections diseases has markedly decreased in the young ages in countries having access to them. Biotechnology should soon improve the treatment not only of vascular but also interstitial diseases. Surgery remains the cornerstone for the treatment of limited cancer. Lung transplantation and lately thromboendarterectomy are becoming of more widespread usage.

Biomedical Research↗
PubMed2001

Early chimerism of macrophages and lymphocytes in lung transplant recipients is predictive of graft tolerance.

BACKGROUND: The persistence of donor cells derived from the graft (chimerism) has been documented in various tissues after organ transplantation. It was suggested that stable chimerism might reflect a state of donor-specific tolerance. Chimerism of macrophages and lymphocytes were studied over time after lung transplantation as well as its impact on graft tolerance. MATERIAL AND METHODS: Macrophages and lymphocytes were purified from bronchoalveolar lavage sequentially obtained from 24 patients between 1 and 41 months posttransplantation (20, 22, 24, and 17 patients at, respectively, 1, 3, 6, and 12 months). DNA was extracted from these cells and their recipient-donor origin was evaluated by PCR amplification of highly polymorphic DNA regions (minisatellites). RESULTS: We show that the remaining donor cells over the first month vary from 10 up to 50% and 5 up to 55% for lymphocytes and macrophages respectively (+/-2 SD). All patients presented some chimerism up to the 6th postoperative month. Good correlation was observed between the residual amount of donor lymphocytes and macrophages during the first 3 months (P<0.001). Patients with at least 30% donor lymphocytes at 1 month after transplantation had less rejections (> or =stage II) in the follow up (P=0.0007). The same observation is true for donor macrophages although to lower extend (P=0.02). The chimerism lost its predictive value beyond 3 months. CONCLUSIONS: These data demonstrate that a level of chimerism above 30% of either donor lymphocytes or macrophages at 1 month is related to a better state of graft tolerance. However, chimerism decreases markedly beyond 3 months and has then no predictive value.

Adolescent↗
PubMed2001

Evaluation of phagocytic activity in human monocyte-derived dendritic cells.

Dendritic cells play a central role in initiation of primary T lymphocyte responses to foreign antigens. Their potency in antigen presentation vis-à-vis reported low or lack of ability to phagocytize particulate matter has limited our understanding of the role that they play in inducing immunity to particulate antigens. One hypothesis is that dendritic cells may possess a high phagocytic capacity when immature and located in peripheral tissues, which they lose on maturation. Our goal was to characterize the phagocytic capacity in human immature dendritic cells. The phagocytic capacity of human monocyte-derived immature dendritic cells was studied by morphological and morphometric means, and compared to that of professional phagocytes, human alveolar macrophages, their progenitors, the peripheral blood monocytes, and mature dendritic cells. Phagocytic index (proportion of phagocytic cells) was decreased by 42.8% (immature dendritic cells) and 74.2% (mature dendritic cells) with respect to monocytes. Similarly, the phagocytic index was decreased by 46.5% (immature dendritic cells) and 75.9% (mature dendritic cells) with respect to macrophages. Volume density of phagocytized particles was decreased by 76.1% (immature dendritic cells) and 96.7% (mature dendritic cells) with respect to the monocytes. However, volume density was decreased by 34.3% (immature dendritic cells) and 91% (mature dendritic cells) with respect to alveolar macrophages. These results show that human monocyte-derived immature dendritic cells possess a phagocytic capacity that is lower than that of peripheral blood monocytes and alveolar macrophages but higher than that of mature dendritic cells.

Cells, Cultured↗
PubMed2001

Human lung tissue macrophages, but not alveolar macrophages, express matrix metalloproteinases after direct contact with activated T lymphocytes.

Human alveolar macrophages (AM) and lung tissue macrophages (LTM) have a distinct localization in the cellular environment. We studied their response to direct contact with activated T lymphocytes in terms of the production of interstitial collagenase (MMP-1), 92-kD gelatinase (MMP-9), and of TIMP-1, one of the counter-regulatory tissue inhibitors of metalloproteinases. Either AM obtained by bronchoalveolar lavage or LTM obtained by mincing and digestion of lung tissue were exposed for 48 h to plasma membranes of T lymphocytes previously activated with phorbol myristate acetate and phytohemagglutinin for 24 h. Membranes of activated T cells strongly induced the production of MMP-1, MMP-9, and TIMP-1 exclusively in LTM but not in AM, whereas membranes from unstimulated T cells failed to induce the release of MMPs. Both populations of mononuclear phagocytes spontaneously released only small amounts of MMPs and TIMP-1. Similar results were obtained when MMP and TIMP-1 expression was analyzed at pretranslational and biosynthetic levels, respectively. Blockade experiments with cytokine antagonists revealed the involvement of T-cell membrane-associated interleukin-1 and tumor necrosis factor-alpha in MMP production by LTM upon contact with T cells. These data suggest that the ability of lung macrophages to produce MMPs after direct contact with activated T cells is related to the difference in phenotype of mononuclear phagocytes and cell localization. In addition, these observations indicate that cell-cell contact represents an important biological mechanism in potentiating the inflammatory response of mononuclear phagocytes in the lungs.

CD40 Ligand↗
PubMed2001

Fungal infections in transplant recipients.

Fungi are ubiquitous and the respiratory tract is exposed to aerosolized spores of both fungi that are "pathogenic" even in the normal host, such as Cryptococus neoformans, and those that are "opportunistic", such as Candida and Aspergillus species, among others. Although these latter species may occasionally form fungal balls or induce allergic phenomena in the normal host, they produce more invasive diseases in immunosuppressed patients. Among these diseases, pseudomembranous aspergillosis has recently been described. The diagnostic approach to these entities, and, in particular, the thin dividing line between colonization and infection are addressed, along with the diagnostic value of the various procedures. New prophylactic regimens are reviewed such as the possibility of using amphotericin aerosols in combination with systemic azole administration. The authors would emphasize the importance of restoring lung defences by not only decreasing immunosuppressive regimens but also considering the use of newly available recombinant cytokines such as growth factors, to reduce neutropenia, for instance, in addition to antifungal drugs when infection is diagnosed. However, immunomodulation procedures are far from being well established.

Humans↗
PubMed2001

Genetic background of attenuated Salmonella typhimurium has profound influence on infection and cytokine patterns in human dendritic cells.

Salmonella typhimurium (ST) can cause infection in man, and attenuated strains are under consideration as live vaccine vectors. However, little is known about the interaction of ST with human dendritic cells (DC). Here, we compared the consequences of exposure of human, monocyte-derived DC with different attenuated strains of ST. Infection was observed with all four strains tested (wild type, PhoP-, PhoPc, and AroA), but the PhoPc strain was by far the most efficient. Intracellular persistence of wild type and PhoP- was longer than that of PhoPc and AroA, both of which were largely eliminated within 24 h. Most DC survived infection by the attenuated strains, although apoptosis was observed in a fraction of the exposed cells. All strains induced DC maturation, independent from the extent of infection. Although all strains stimulated secretion of TNF-alpha and IL-12 strongly, PhoPc induced significantly less IL-10 than the other three strains and as much as 10 times less IL-10 than heat-killed PhoPc, suggesting that this mutant suppressed the secretion of IL-10 by the DC. These data indicate that infectivity, bacterial elimination, and cytokine secretion in human DC are controlled by the genetic background of ST.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗
PubMed2000

New strategies against an old plague: genetically engineered tuberculosis vaccines.

The failure of BCG vaccination to control the global tuberculosis epidemic and the spread of multidrug resistance underline the need for a better vaccine. Recent advances in molecular microbiology, gene therapy, and, last but not least, immunobiology, provide a rational basis for the development of more efficient vaccines against tuberculosis. The complete sequencing of the M. tuberculosis genome marked a turning point in tuberculosis vaccine research. The advent of genetic vaccination with either naked DNA, live recombinant, or artificial vaccine vectors holds out great promise of more efficient immunisation, in particular against intracellular pathogens such as M. tuberculosis. Our new understanding of how the immune response is orchestrated by dendritic cells makes it possible to design vaccines which specifically exploit the functions of these antigen presenting cells. Yet M. tuberculosis has kept many of its secrets, and although functional genomics, molecular medicine and immunotherapy are evolving rapidly, much empiric search and discovery are needed until the "captain of all these men of death" gives up his ghost to biotechnology.

BCG Vaccine↗
PubMed2000

Matrix metalloproteinases correlate with alveolar-capillary permeability alteration in lung ischemia-reperfusion injury.

BACKGROUND: Matrix metalloproteinases (MMPs) are able to degrade the endothelial basal lamina and increase vascular permeability. METHODS: In a porcine model of isolated-reperfused lung, we studied the alveolar-capillary permeability and the zymographic expression of MMP-9 and MMP-2 in the bronchoalveolar lavage fluid of lungs submitted ex vivo to ischemia in three preservation solutions [modified Euro-Collins (EC), low-potassium-dextran, modified-blood]. Twenty-two pigs were randomly divided into three groups according to the preservation solution used. One lung of each pig was rapidly reperfused and analyzed (control lung) although the other lung was reperfused and analyzed after 8 hr of ischemia (ischemic lung). RESULTS: Alveolar-capillary permeability, evaluated by the transferrin leak index, was increased after 8 hr of ischemia compared with controls in the three groups, but was significantly higher in the modified EC group. In the EC group, after 8 hr of ischemia, both proMMP-9 and MMP-9 increased significantly (8.8- and 22-fold, respectively) compared with controls and this increase correlated with the transferrin leak index. Neither proMMP-9 nor MMP-9 increased with the other two preservation solutions. The MMP-2 increase after ischemia was smaller and was also restricted to the EC group. CONCLUSION: MMP expression is enhanced during lung ischemia-reperfusion, especially in the presence of EC and this phenomenon correlates with the alteration of alveolar-capillary permeability.

Animals↗
PubMed2000

[Indications for lung transplantation in advanced cystic fibrosis].

Lung transplantation has become a valid therapeutic option for cystic fibrosis patients with end-stage lung disease. The indication for transplantation does not rely on strict criteria only but must be evaluated case by case. In particular, the dynamics of the clinical course need to be considered with regard to impaired physical performance, recurrent infections, decline in pulmonary function and weight loss. Important risk factors are a poor nutritional status, osteoporosis, liver involvement, previous pleurodesis and the occurrence of multiresistant bacteria. Management and assessment of cystic fibrosis patients for lung transplantation is complex. Therefore patients should be referred to specialised centres at an early stage.

Bacterial Infections↗
PubMed2000

Bone mineral density in lung-transplant recipients before and after graft: prevention of lumbar spine post-transplantation-accelerated bone loss by pamidronate.

BACKGROUND: Lung-transplant recipients are at risk of osteoporosis. They may have low bone mass even before posttransplantation immunosuppressive therapy. We studied bone mineral density (BMD) before and after lung transplantation and compared the efficacy of antiresorptive therapies to calcium and vitamin D supplementation. METHODS: Areal BMD was assessed in 42 patients awaiting lung transplantation and measured again after surgery at 6 (n = 29), and at 12 months (n = 20). Nineteen patients received antiresorptive therapy (30 mg pamidronate IV every 3 months (n = 14), or hormonal replacement therapy (n = 5)), and 10 patients received only calcium and vitamin D supplements. RESULTS: Mean age- and gender-adjusted lumbar spine (LS) and femoral neck (FN) BMD was significantly decreased prior to transplantation (- 0.6 +/- 0.2, p< 0.01, and - 1.5 +/- 0.2 standard deviation, p < 0.001, respectively). At that time, 29% were osteoporotic (T-score < - 2.5 below the peak bone mass), while 55% were below - 1.0 T-score. Antiresorptive therapy decreased the rate of LS bone loss during the first 6 months and led to a significant increase of BMD at 1 year, with LS changes of + 0.2 +/- 0.1 vs - 0.4 +/- 0.1 Z-score in the calcium-vitamin D group (p< 0.002), and + 0.2 +/- 0.1 vs - 0.04 +/- 0.1 for FN (NS). One out of 20 patients experienced clinically evident fractures during antiresorptive therapy, and 3 out of 12 in the calcium-vitamin D group. CONCLUSION: A significant proportion of patients awaiting lung transplantation was osteoporotic or osteopenic. Antiresorptive therapy (pamidronate or hormone-replacement therapy (HRT)) prevented accelerated LS bone loss after graft.

Adolescent↗
PubMed2000

Antigen presentation in the lung: dendritic cells and macrophages.

Antigen presentation is a required prime event before T-cell activation can occur. Cells which constitutively express major histocompatibility antigen class I or II are responsible for presenting antigens. These are essentially alveolar macrophages (AM) residing mostly in the air spaces, and dendritic cells (DC), which create a tight surveillance network just below the epithelial cells of the airways and in the loose connective tissue around the vessels or in the pleura. AM are poor antigen presenting cells compared to DC. AM when encountering foreign particles or organisms may, however, influence the degree of activity or maturation of neighbouring DC, by releasing cytokines. Thus, we will describe how the innate immune processes may influence specific immunity and perhaps Th1 and Th2 differentiation. Following the description of the differences in phenotype and functions of AM and DC, we will provide data showing that in some pathological conditions, such as sarcoidosis, AM can acquire some specificities of DC.

Dendritic Cells↗
PubMed1999

Improvement of drug-induced chronic renal failure in lung transplantation.

BACKGROUND: Nephrotoxicity is a frequently encountered adverse effect of calcineurin inhibitors (cyclosporine and tacrolimus)-combined immunosuppressive regimens. METHODS: We have compared the glomerular filtration rate in 14 patients who underwent lung transplantation, before and after replacement of azathioprine by mycophenolate mofetil and reduction of associated calcineurin inhibitors doses. RESULTS: After a mean follow-up of 16+/-4 months with the modified immunosuppressive regimen, the mean glomerular filtration rate increased by 20% with no change in lung function. CONCLUSION: By its strong immunosuppressive effect, mycophenolate mofetil allows the decrease of associated calcineurin inhibitor doses, with subsequent improvement of renal function without jeopardizing the transplanted lung.

Calcineurin Inhibitors↗
PubMed1999

Pre-emptive therapy with azoles in lung transplant patients. Geneva Lung Transplantation Group.

Pulmonary fungal infection is diagnosed in up to 15-25% of lung transplant recipients and frequently bears a fatal outcome. This prospective uncontrolled study addresses the efficacy and safety of pre-emptive azole therapy against fungal infection in these patients. Fluconazole or itraconazole have been systematically used according to reported fungus sensitivity after the discovery of fungi in lower respiratory tract samples. Patients were treated until the bronchial suture was normal and the cultures of the following bronchoscopy remained negative. Fungi were found post-transplantation in the lower respiratory tract specimens of 26 out of 31 (84%) patients, predominantly Candida albicans (20 patients) and Aspergillus fumigatus (16 patients). Mycelia characteristic of Candida spp. or Aspergillus spp. were found in necrotic tissue at the bronchial suture of nine patients. The mean duration of the 38 treatments was 3.6+/-2.6 months (range, 0.5-12 months). After a median follow-up of 16 (range, 0-48) months, two cases of extended ulcerative and pseudo membranous Aspergillus fumigatus bronchitis were observed and healed under itraconazole treatment. In conclusion, pre-emptive azole therapy may be effective and well-tolerated in lung transplant patients where fungi are found in the airways or pleura.

Adult↗