Intraperitoneal injection of CD4+ T cells induces CD5 B cells. Implications for a regulatory role of CD5 B cells in experimental autoimmune encephalomyelitis.
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Animals↗
Biomedical subjects
D Lehmann
Publications and source records attributed to D Lehmann.
Prevention of experimental autoimmune encephalomyelitis and induction of tolerance with acute immunosuppression followed by syngeneic bone marrow transplantation.
Experimental autoimmune encephalomyelitis (EAE) is an inducible autoimmune disease widely used as a model of the acute/relapsing stage of multiple sclerosis. In the present study we examined the effect of acute immunosuppression induced by total body irradiation (TBI) (900 to 1100 centigray (cGy)) or by a single high dose of cyclophosphamide (CY) (300 mg/kg), followed by syngeneic bone marrow transplantation (SBMT), on the development of EAE in SJL/J mice. EAE was induced in SJL/J mice by immunization with spinal cord homogenate in adjuvant. Treatment with TBI (900 cGy) and SBMT on day 6 postimmunization caused a delayed onset and a marked reduction in the incidence and severity of EAE. A higher dose of irradiation (1100 cGy) or the administration of CY followed by SBMT completely abrogated the development of paralysis. None of the 21 mice treated with CY and SBMT, and only 1 of 7 mice treated with TBI (1100 cGy) and SBMT developed clinical signs of EAE during a period of 3 months. Furthermore, mice treated with CY and SBMT became resistant to rechallenge with the same encephalitogenic inoculum. In addition, the lymphocytes obtained from these mice did not proliferate in vitro in response to myelin basic protein or tuberculin-purified protein derivative, unlike lymphocytes from immunized but untreated animals. This absence of reactivity was not associated with alterations in the proportion of the L3T4 and Lyt-2 T-cell subsets nor with a loss in T cell competence as evidenced by the full response of lymphocytes to the T cell mitogen Con A and to a nonrelevant Ag (OVA). Our results indicate that the elimination of effector lymphocytes either by myeloablative doses of CY or ionizing irradiation followed by rescue with SBMT inhibits the development of the autoimmune process in EAE and leads to induction of tolerance to the immunizing Ag by newly developing lymphocytes. This approach of combining immunoablation and reconstitution with autologous bone marrow transplantation may be applicable in the treatment of life-threatening neurologic autoimmune diseases.
Animals↗
Randomized double blind trial of Ambroxol for the treatment of respiratory distress syndrome.
In order to test the ability of Ambroxol to improve the clinical course of respiratory distress syndrome and to reduce the incidence of complications a multicentre, randomized, placebo-controlled double-blind trial was conducted. Entry was limited to infants with a birth weight below 1500 g. A total of 179 neonates were enrolled, but 31 were later excluded because they had other diseases. Of the remaining 148 babies, 74 received Ambroxol (birth weight 1190 +/- 216 g; gestational age 29.1 +/- 1.9 weeks) and 74 placebo (birth weight 1168 +/- 216 g; gestational age 28.9 +/- 1.9 weeks). In the Ambroxol group 23 (31%) and in the placebo group 27 (37%) infants died during the first 5 months of life. In 28 day-survivors Ambroxol was able to significantly improve the PaO2/FiO2 ratio, mean airway pressure, phospholipid profile of tracheal effluent and pulmonary mechanics of spontaneously breathing infants. In addition, the incidences of bronchopulmonary dysplasia (29% vs 54%), intraventricular haemorrhage (25% vs 44%) and postnatally acquired pneumonia (15% vs 36%) were significantly reduced in the Ambroxol group as compared to the control group. No adverse events attributed to the Ambroxol treatment were reported.
Ambroxol↗
Localization of the sources of EEG delta, theta, alpha and beta frequency bands using the FFT dipole approximation.
FFT dipole approximation and 3-dimensional dipole modelling were used to determine the locations of the equivalent dipole model sources of the delta, theta, alpha, beta-1 and beta-2 frequency bands in 13 normal subjects during resting. From each subject, 2 successive data sets were analysed, each consisting of 10 epochs of 2 sec randomly collected during 30 min. ANOVAs showed that over subjects, the source locations of EEG frequency bands differed significantly in the vertical and antero-posterior dimensions. Results of data set 2 confirmed those of data set 1. The source of delta was deepest and most anterior, theta more posterior and less deep, alpha most posterior and highest on the vertical dimension, beta-1 deeper and slightly more anterior than alpha, and beta-2 again more anterior and deeper than beta-1. Thus, the depth of source location was not linearly related to temporal frequency. The sources of all 5 bands were oriented in the sagittal direction; delta mean fields had steeper gradients anteriorly, alpha and beta-1 posteriorly. The power map for any frequency was well described by a single phase angle. The results indicate that the different EEG frequency bands during a given EEG epoch are generated by neural populations in different brain locations.
Adult↗
Chronic-relapsing experimental autoimmune encephalomyelitis (CR-EAE): treatment and induction of tolerance, with high dose cyclophosphamide followed by syngeneic bone marrow transplantation.
We examined the effect of acute immunosuppression with high dose cyclophosphamide (CY), followed by syngeneic T-cell-depleted bone marrow transplantation (SBMT) on chronic-relapsing autoimmune encephalomyelitis (CR-EAE) induced in SJL/J mice by immunization with mouse spinal cord homogenate (MSCH) in adjuvant. Treatment of mice on day 9 post immunization, before the appearance of clinical signs of the disease, delayed the onset of paralysis, but did not affect its clinical course. Treatment on day 2-3 after the first clinical signs led to complete regression of the disease. During a period of 3 months, only one of the 15 mice treated after the the onset of CR-EAE relapsed, as compared to a total of 21 relapses in the 15 untreated animals. A rechallenge with MSCH in adjuvant on day 78 after immunization induced a severe relapse in all untreated mice, with 78% mortality; in contrast, only 25% of mice treated with CY and SBMT relapsed when similarly rechallenged. Lymphocytes from mice treated with CY and SBMT showed reduced in vitro proliferative responses to myelin basic protein (GMBP) and PPD, even after the rechallenge with MSCH. Our results show that high dose CY for elimination of immunocompetent lymphocytes, followed by SBMT rescue, suppresses CR-EAE and induces tolerance to the immunizing antigens. These results may encourage attempts to apply a similar therapeutic principle in life-threatening human neurological autoimmune diseases.
Animals↗
42-channel potential map series to visual contrast and stereo stimuli: perceptual and cognitive event-related segments.
Event-related potential maps to perceptual (stimulus type) and cognitive (stimulus relevance) manipulations were studied in 12 healthy volunteers using 42-channel mapping. Perceptual manipulation used three types of visual stimuli: rectangles constituted by: (1) contrast; (2) different densities of monocular Dynamic Random Dots (Flat DRD); and (3) different binocular disparities of Dynamic Random Dots (Stereo DRD). Cognitive manipulation within each stimulus type consisted of presenting the rectangles horizontally and vertically, one of the two with a probability of 33%, and requesting the subjects to count and thus attend to the 'rare' rectangles. Spatial characteristics of the maps were analyzed; this allowed conclusions about the generating sources. The map series were adaptively segmented using the minima points of the grand mean Global Field Power curve. Segment strength (Global Field Power) and segment landscape (locations of extreme potentials) were assessed. Stimulus type had effects from 78 to 310 ms, stimulus relevance was effective from 210 to 1000 ms. In the 78-174 ms segment, Stereo DRD and Flat DRD stimuli produced similar map landscapes, while contrast stimuli produced different map landscapes. Attended and ignored stimuli produced contrary effects on landscapes at 210-310 ms as compared to those at 310-546 ms, indicative of different neural populations activated by attention processes during these late event-related potential segments. Interaction between perceptual and cognitive manipulation occurred at 210-310 ms when perceiving stereo stimuli and attending to relevant monocular visible stimuli produced similar map landscapes, suggesting a common brain resource during this segment for automatic figure perception and voluntary attention. The observed functional differences of the segments contribute to the identification of global functional microstates of brain electric activity.
Adult↗
Delineation of tissue damage mechanisms in experimental autoimmune encephalomyelitis (EAE). I. Cell detachment and lysis induced by encephalitogenic CD4+ T lymphocytes.
Myelin basic protein (MBP) reactive CD4+ T lymphocytes, capable of inducing experimental autoimmune encephalomyelitis (EAE), were examined for their ability to damage target cells of central nervous system (CNS) origin. Damage was assessed by monitoring detachment of adherent astrocytes from substratum and astrocyte lysis. MBP-specific, but non-encephalitogenic CD4+ T cells mediated astrocyte detachment but not lysis. However, encephalitogenic CD4+ T cell lines were more efficient in causing astrocyte detachment and could also cause astrocyte lysis. The detachment and lytic activities of the MBP-reactive T cell lines tested were often independent of the presence of specific antigen, and were not restricted to syngeneic major histocompatibility (MHC) antigens. MBP often augmented the detaching and, if lytic, lytic activities of these T cells. The encephalitogenic CD4+ T cells also detached and lysed allogeneic 'bystander' fibroblasts in the presence of unlabelled syngeneic astrocytes, suggesting the involvement of a soluble mediator(s). Although MBP is essential for the initiation of EAE, the presence of MBP on cells of CNS origin, such as astrocytes and oligodendrocytes, does not appear to be necessary for their damage by MBP-specific CD4+ T cells. Immune CD4+ T cells, which penetrate the CNS, may disorganize brain tissue structure by lysing astrocytes directly and by damaging other brain cells indirectly by soluble mediators. Thus cellular detachment, in addition to cell lysis, mediated by MBP-specific CD4+ cells may contribute to EAE pathogenesis.
Animals↗
Bacterial agents protect against autoimmune disease. I. Mice pre-exposed to Bordetella pertussis or Mycobacterium tuberculosis are highly refractory to induction of experimental autoimmune encephalomyelitis.
Infectious agents have often been implicated in the etiology of autoimmune diseases. Here we show that bacteria may also play a role in resistance to autoimmune diseases. SJL/J and (SJL/J x BALB/c)F1 mice are genetically susceptible to induction of experimental autoimmune encephalomyelitis (EAE), a murine model for human demyelinating autoimmune diseases such as multiple sclerosis. We studied the effect of several bacteria on the development of EAE and found that exposure of SJL/J or (SJL/J x BALB/c)F1 mice to Mycobacterium tuberculosis or Bordetella pertussis consistently rendered mice highly refractory to subsequent induction of the disease. Other bacteria such as Escherichia coli, Shigella and Staphylococcus aureus were found to be less effective, or were protective only if specific immunization procedures were used. Furthermore, M. tuberculosis and B. pertussis were protective irrespective of the route of administration and minute amounts (as low as 0.5 micrograms) of M. tuberculosis were sufficient to protect EAE-susceptible mice against induction of the disease. Interestingly, these bacteria, which are commonly used to promote development of EAE, conferred the highest degree of protection against the disease. The M. tuberculosis-induced protection was found to be associated with active suppression mechanisms mediated by T lymphocytes capable of transferring protection to naive syngeneic mice. These findings indicate that certain bacteria may protect against the development of autoimmune diseases. These results also suggest the potential use for still-unidentified bacterial agents in the manipulation of certain autoimmune diseases.
Animals↗
Epidemiology of acute respiratory tract infections, especially those due to Haemophilus influenzae, in Papua New Guinean children.
Acute lower respiratory tract infections (ALRI) are the most common cause of death in Papua New Guinean children. Haemophilus influenzae and Streptococcus pneumoniae are almost universally carried in the nasopharynx from a young age and commonly cause disease. While most H. influenzae isolates from blood and cerebrospinal fluid are serotype b, other serotypeable and nonserotypeable H. influenzae are more frequently isolated in Papua New Guinea than in developed countries. Low levels of antipneumococcal antibody, malnutrition, and upper respiratory carriage of invasive pneumococcal serotypes are associated with increased risk of ALRI. An oral H. influenzae vaccine given to adults with chronic bronchitis reduced the bacterial load in sputum and may thereby help reduce transmission of bacteria in the community. The efficacy of conjugate H. influenzae type b vaccine in preventing pneumonia must be determined in developing countries; vaccines against other types of H. influenzae will also be needed to control pneumonia and meningitis.
Acute Disease↗
[Antimicrobial chemotherapy of infection in intensive care conditions].
Antimicrobiologic chemotherapy is a cornerstone in the modern concept of treatment of sepsis. It is supported by a number of measures of intensive care. Externally acquired infections followed by sepsis mainly affect immunocompromised patients. They represent the minority. On the other hand, nosocomial infections play a dominant role in intensive care units. Nosocomial pneumonias and infections caused by intravascular plastics or endoprotheses are the most important reasons of sepsis. Initial antimicrobiologic therapy considers both the infectious focus and the specific epidemiology and resistance of microorganisms present in the department: it comprises the drawing of 2 to 3 blood cultures, taking of urinary cultures, tracheal secretion, liquor and wound-swaps for microbiologic examination. A gramstaining of the preparation can be helpful. In case the focus of the sepsis is not known, the first step of treatment consists of a combination of piperacilline or cephalosporins with aminoglycosides. If the septic state does not improve within 48 hours, a glycopeptide should be added against staphylococci (second step). If the combination fails, imipenem/cilastatin and aminoglycosides are administered as the third step. Normally, the result of cultures and resistogram already are available by this time. Today aminoglycosides are preferably given once daily, the serum level is monitored, and the toxicity of aminoglycosides is thus diminished.
Anti-Bacterial Agents↗
[Evaluation of evoked potential or event-related potential mapping].
Strategies for the evaluation of EP and ERP maps are discussed. Spatial interpolation is presented. The reference does not change the landscape but the wave shapes, the baselines change the landscape but not the wave shapes. Electric strength of the map is assessed using Global Field Power, whereby non-ambivalent component latencies can be established. Map landscapes are compared using Global Dissimilarity. Maps are classified using extracted landscape descriptors: locations of minimal and maximal potential, locations of the centroids of the positive and negative map area, reduction to a three-dimensional model dipole source. Adaptive segmentation into echoes of stable landscape (functional microstates) based on landscape descriptors is discussed. Diagnostic and physiological-functional interpretation of the results ought to be distinguished.
Brain Mapping↗
Restricted T-cell receptor V beta gene usage by myelin basic protein-specific T-cell clones in multiple sclerosis: predominant genes vary in individuals.
Recent studies in experimental autoimmune encephalomyelitis as a model for multiple sclerosis (MS) have demonstrated limited heterogeneity in T-cell antigen receptors (TCR) specific for myelin basic protein (MBP). To investigate restricted beta-chain variable-region (V beta) gene usage in humans, we analyzed TCR gene rearrangements in two lines and 34 MBP-specific T-cell clones that were isolated from five MS patients and two healthy subjects. The T cells were characterized for their specificity to MBP epitopes and HLA-restricting molecules. We demonstrate here that MBP-specific T-cell clones from these different MS patients and healthy individuals, in contrast to T cells from rodents, display a more diverse V beta gene usage as evidenced by their TCR V beta gene rearrangements. However, the different MBP-specific T-cell clones isolated from each individual MS patient showed a common V beta gene usage, suggesting individual-specific TCR restriction. Out of 16 MBP-specific clones derived from a single MS patient, 12 clones (75%) utilized the V beta 15 gene for their TCR gene rearrangement. MBP-specific clones isolated from four other MS patients also showed a consistent tendency for a predominant, but different, TCR V beta gene rearrangement. These results suggest a TCR heterogeneity among MBP-specific T-cell clones from different individuals but a limited TCR V beta gene usage among MBP-specific T-cell clones of the same individual. The predominant V beta gene used by the MBP-specific T-cell clones studied here was not found to correlate with the epitope specificity of T cells or with their restricting HLA molecule. These findings may support the possibility of intervention with monoclonal antibodies to specific V beta gene products as an approach to immune therapy of MS but also imply the necessity for an individual-specific immunotherapeutic approach.
Base Sequence↗
Event-related potential components N1, P2 and P3 to rare and frequent stimuli in intellectually impaired neurological patients.
Event-related potentials (ERPs) and attention performance data were collected in an auditory odd-ball paradigm from 24 intellectually impaired neurological patients, and compared with normal controls (n = 19). For the ERP components N1, P2 and P3, reference-independent measures (latency, global field power, current density at Cz, location of extreme potential, centroid location) were determined for the target stimulus and for the preceding and the following two "frequent" stimuli. In 8 of the 45 measures obtained, patients and controls differed significantly. To target stimuli, patients had shorter N1 latency and smaller current density, more posterior P2 location and longer P3 latency; to immediately following "frequent" stimuli, longer P2 latency; and to preceding and both following "frequent" stimuli, smaller P2 current density. Attention performance was significantly worse for the 15 patients who scored on at least one of the eight ERP measures above normal range than for the other 9 patients. Decreased N1 latency to targets is viewed as failure to activate normal attentional capacity; changed P2 location suggests activation of deviant neuronal populations in response to targets; and increased post-target P2 latency suggests abnormal persistence of induced state change.
Adult↗
Effect of pneumococcal vaccine on morbidity from acute lower respiratory tract infections in Papua New Guinean children.
The effect of a 14-valent pneumococcal polysaccharide vaccine on morbidity from acute lower respiratory tract infection (ALRI) was determined in a randomized double-blind controlled trial in children under the age of 5 years living in the Paupa New Guinea highlands. The vaccine did not protect against mild ALRI. Vaccine efficacy in the study as a whole was 28% for moderate/severe ALRI, which was not statistically significant though consistent with the significant effect on mortality. Children entered the trial in five separate cohorts 4 months apart. The incidence of disease and vaccine efficacy varied between cohorts and with age. There was no vaccine effect in the first cohort, which had a much higher proportion of older children. The effect was greatest and statistically significant among those groups encountering an epidemic of moderate and severe ALRI at a young age. It was therefore in children at the most vulnerable age in times of greatest incidence of disease that the vaccine had its most potent effect. It is postulated that the efficacy of pneumococcal vaccine is dependent on the predominant invading serotypes in the period after vaccination, the age at which children develop immunocompetence to specific vaccine serotypes, and the levels of naturally acquired specific immunity already present in children at the time of vaccination, and that for all of these conditions there will be a cohort effect.
Acute Disease↗
Relationships between growth and acute lower-respiratory infections in children aged less than 5 y in a highland population of Papua New Guinea.
One hundred fifty-six children in the highlands of Papua New Guinea aged less than 5 y, studied for a total of 7019 child-weeks, had an incidence of 1.3 episodes per child-year of acute lower-respiratory-tract infections (ALRIs). There was a marked age trend with an incidence of almost three times this average for children aged less than 6 mo. Those with low weight-for-age or low height-for-age had a higher ALRI incidence rate, with no evidence of cutoffs above which nutritional status had no effect; there was no association between low weight-for-height and increased risk of ALRI. A slow weight gain was not a significant risk factor in the short term but weight gain was reduced during episodes of ALRI.
Aging↗
Antibodies to pneumococcal polysaccharides in pneumonia and response to pneumococcal vaccination in young children in Papua New Guinea.
Antibodies against pneumococcal polysaccharides were measured by ELISA in Papua New Guinean children with pneumonia aged 0-14 months, in age-matched healthy Papua New Guinean controls and in healthy expatriate children living in Papua New Guinea. At 0-5 months of age, the IgG antibody titres against six of the eight polysaccharides measured were significantly lower in pneumonia patients than in both control groups. Antibody titres in 6-14-month-old Papua New Guinean controls were significantly lower than in control Papua New Guineans aged 0-5 months for five of the eight polysaccharides tested. In the 6-14-months age group the antibody titre was significantly lower in pneumonia patients than in controls for only one polysaccharide. For seven of the eight serotypes tested, antibody levels in expatriate controls did not decline with age. Antibody responses of Papua New Guinean children aged 6-18 months to a 23-valent pneumococcal vaccine were serotype dependent. Fold increases in response to the vaccine were greatest for the IgA isotype. IgG antibody responses were greater than three fold to four of the eight serotypes tested.
Age Factors↗
Amikacin pharmacokinetics in patients receiving high-dose cancer chemotherapy.
We retrospectively analyzed amikacin pharmacokinetics in 28 patients (mean age, 47.4 +/- 13.6 years) who received high-dose chemotherapy during a neutropenic febrile episode. Patients received an experimental protocol of high-dose anticancer chemotherapy. Amikacin pharmacokinetic parameters were calculated from two or more concentrations in serum around a single dose by the method of Sawchuck and Zaske (J. Pharmacokinet. Biopharm. 4:183-195, 1976). Predicted parameters were calculated by using standard methods. The observed amikacin volume of distribution and clearance were significantly greater and the elimination half-life was longer than predicted (0.38 +/- 0.13 versus 0.25 liter/kg [P = 0.0001], 1.51 +/- 0.92 versus 1.17 +/- 0.38 liters/h/kg [P = 0.012], and 3.8 +/- 2.4 versus 2.9 +/- 1.1 h [P = 0.011], respectively). Multivariate analysis revealed that albumin correlated negatively and creatinine correlated positively with the volume of distribution and the elimination half-life. Creatinine and the percentage below the ideal body weight correlated negatively and hematocrit correlated positively with clearance. Administration of dosage regimens based on predicted pharmacokinetic parameters yielded subtherapeutic amikacin concentrations in serum in our patients. Because of the increased dosage requirements and the need for adequate antibiotic treatment in this population, we suggest guidelines for empiric dosing for patients with advanced cancer receiving intensive chemotherapy.
Adolescent↗
Reduction in the incidence of acute bronchitis by an oral Haemophilus influenzae vaccine in patients with chronic bronchitis in the highlands of Papua New Guinea.
Following the administration of a standardized questionnaire, 62 adult patients with chronic bronchitis were enrolled into a double-blind controlled trial of an oral killed Haemophilus influenzae vaccine in the highlands of Papua New Guinea. A 3-day course of vaccine or placebo was given monthly for 3 consecutive months. Participants were monitored weekly over 12 months for acute exacerbations; early morning sputum specimens were collected monthly and during acute exacerbations. Density of colonization by H. influenzae and H. parainfluenzae was determined by standard quantitative and semiquantitative techniques, and the latter method (quadrant score) was used to determine the density of growth of pneumococci. A total of 30 patients received vaccine and 32 placebo. The incidence rate of acute bronchitis in the vaccine group (0.011 episodes/person-weeks) was significantly lower than that in the placebo group (0.021 episodes/person-weeks), but there was no difference between the two groups in the incidence rates of more severe disease. Vaccine efficacy was maximal at times of peak incidence of disease. There was no evidence of a decline in vaccine efficacy for acute bronchitis over the 12-month follow-up period. The number of viable H. influenzae in the sputum declined in both vaccine and placebo groups over the 12-month follow-up period. The average concentration of H. influenzae in the vaccine group fell below that in the placebo group within 1 to 2 months after first immunization and remained so for 12 months, although the difference between the two groups narrowed during the follow-up period.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗