Effects of cyclosporine A monotherapy on the incidence of rejection and infection episodes in heart transplant patients.
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Communicable Diseases↗
Biomedical subjects
A Fischer
Publications and source records attributed to A Fischer.
Genetic effects on immunity.
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Journal Article↗
Mendelian susceptibility to mycobacterial infection in man.
Selective susceptibility to poorly pathogenic mycobacteria, such as bacille Calmette-Guérin vaccine and environmental non-tuberculous mycobacteria, has long been suspected to be a mendelian disorder but its molecular basis has remained elusive. Recently, recessive mutations in the interferon-gamma-receptor receptor ligand-binding chain, interferon-gamma-receptor signalling chain, IL-12 p40 subunit and IL-12-receptor beta 1 chain genes have been identified in a number of patients with disseminated mycobacterial infection. Although genetically distinct, these conditions are immunologically related and highlight the essential role of interferon-gamma-mediated immunity in the control of mycobacteria in man.
Genetic Predisposition to Disease↗
Prevention of EBV-induced B-lymphoproliferative disorder by ex vivo marrow B-cell depletion in HLA-phenoidentical or non-identical T-depleted bone marrow transplantation.
HLA-mismatched bone marrow transplantation (BMT) is hampered by three major complications: graft rejection, acute graft-versus-host disease (aGVHD) and delayed immune reconstitution. Infusion of anti-LFA1 plus anti-CD2 monoclonal antibodies (MAb), combined with ex-vivo T-cell depletion of the graft, was efficient in preventing graft rejection and aGVHD. Nevertheless, disease-free survival was limited by the high frequency of lethal infections, including EBV-induced lymphoproliferative disease (BLPD), which originates mostly from donor B cells, with an incidence of 5-30%. To decrease the rate of this complication, ex-vivo B-cell depletion was attempted. This study compares a group of 19 patients who received a T- and B-cell-depleted marrow from an HLA-mismatched related donor with a retrospective control group of 19 patients, who had received T-cell-depleted marrow by the same method. The level of T-cell depletion was similar in the two groups. For B-cell depletion, two different methods were compared. The median number of B cells infused in the study group was 0.46/kg. Engraftment and aGVHD incidence were similar in the two groups. No EBV donor-derived BPLD occurred in the study group, compared with seven in the control group, four of whom died because of EBV-BPLD. Event-free survival was significantly different between the two groups. We conclude that ex-vivo B-cell depletion of the graft may be a useful means of preventing EBV-BPLD, and warrants further study on a larger group of patients.
B-Lymphocytes↗
Mite control with low temperature washing-II. Elimination of living mites on clothing.
BACKGROUND: Allergens produced by mites are one of the principal causes of allergic disease. House dust mites can be found in significant numbers living in textile garments, and therefore development of optimal washing conditions for delicate textiles represents an important aim for domestic mite control. OBJECTIVES: Investigation of methods to eliminate house dust mites from clothing under low temperature washing conditions. METHODS: Domestic house dust mites Dermatophagoides farinae were cultured on garments under favourable conditions. The breeding success was monitored in terms of population and distribution using the free-mite Mobility Test. The mite containing garments were washed at low temperature with different commercial detergents in the presence or absence of a mite control additive containing 0.03% benzyl benzoate, and the numbers of mites surviving the washing process were assessed using the Heat Escape Method. RESULTS: The successful culture of mites in textile garments led to mite numbers of a total of at least 9000 to 10000 mites in 10 garments (Mobility Test). After washing in a domestic washing machine with detergents alone approximately 6000 remaining mites were detected in 10 garment halfs (Heat Escape Method). In contrast, mite control by the application of the same detergents together with an additive achieved a reduction to almost 50 mites. This is an additional reduction in mite numbers of 99.2%. CONCLUSIONS: It is possible to achieve mite control in delicate garments by washing at low temperature in the presence of a mite control additive providing a final concentration of 0.03% benzyl benzoate.
Allergens↗
A causative relationship between mutant IFNgR1 alleles and impaired cellular response to IFNgamma in a compound heterozygous child.
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Alleles↗
Invasive pulmonary infection due to Scedosporium apiospermum in two children with chronic granulomatous disease.
Scedosporium apiospermum is an opportunistic fungus in humans. The incidence of S. apiospermum infection in patients with acquired neutropenia (e.g., patients receiving chemotherapy and bone marrow transplant recipients) is steadily increasing. S. apiospermum has poor in vitro susceptibility to "conventional" antifungal agents, rendering the management of infections complex. Patients with chronic granulomatous disease (CGD) are highly susceptible to fungal infections, which are mostly due to Aspergillus species. We describe two children with CGD and invasive pulmonary infection due to S. apiospermum. Both patients were treated with antifungal therapy including azole derivatives (itraconazole or voriconazole) and surgical resection of infected tissues. These cases highlight that scedosporium infection can closely mimic aspergillus infection and should be considered in any case in which there is a failure to respond to appropriate "conventional" antifungal therapy. We also suggest that the emergence of this pathogen may have been favored by long-term use of amphotericin B in both patients.
Adolescent↗
Genetic and molecular definition of complementation group D in MHC class II deficiency.
Four complementation groups, A, B, C and D, have been described among cell lines defective in the coordinate expression of MHC class II genes. These include cell lines established from patients affected with MHC class II deficiency and experimentally generated mutant cell lines. Group D, in contrast to the other groups, was for a long time represented only by the 6.1.6 mutant cell line. The gene responsible for the defect in this group, RFXAP , recently was cloned and found to be mutated in the 6.1.6 cell line and in three patients. Here we report fusion experiments in several new HLA class II-deficient patients, completing the classification of the majority of known patients into the four complementation groups. Patients from five unrelated families were classified in complementation group D, while nine others fall into complementation groups A and B. None of the patients defined a new complementation group. Full correction of MHC class II expression was obtained in cells from patients belonging to group D by transfection with the RFXAP cDNA. The RFXAP coding region was found to be mutated in all patients. Mutations were found to be recurrent since only three different mutations have been found in the eight unrelated families reported to date.
Antigens, Differentiation, B-Lymphocyte↗
Binding of CD4 ligands induces tyrosine phosphorylation of phosphatidylinositol-3 kinase p110 subunit.
We have previously reported that different putative CD4 ligands (anti-CD4 antibody, gp160 from HIV, synthetic peptides analogous to the residues 35-46 of HLA class II beta1 chain and residues 134-148 of HLA class II beta2 chain) down-regulate LFA-1-dependent adhesion between CD4+ T cells and HLA class II+ B cells, and also activate p56lck and the phosphatidylinositol-3 kinase (PI3-kinase) associated with the CD4-p56lck complex. It was demonstrated that the latter activation was dependent on the CD4-p56lck association. Since these results suggest a relationship between p56lck and PI3-kinase, we investigated whether PI3-kinase was tyrosine phosphorylated after CD4 binding and whether this phosphorylation was also dependent on the CD4-p56lck association. We show herein that CD4 binding increased tyrosine phosphorylation of the catalytic subunit p110 of PI3-kinase but not of the p85 subunit. Association between p56lck and PI3-kinase was constitutive, and was not modified after CD4 binding. In contrast, p110 tyrosine phosphorylation was inducible, transient and dependent on the CD4-p56lck association. The role of the tyrosine phosphorylation of p110-PI3-kinase following ligand binding to CD4 is unknown. We speculate that this event could link the activation of p56lck and of PI3-kinase after CD4 binding.
Amino Acid Sequence↗
Differential CD4-dependent inhibition of JNK but not Erk-2 activities in human naive and memory CD4+ T cell populations.
CD4 ligand binding to the CD4 molecules has been shown to inhibit T cell proliferation and IL-2 transcription and synthesis. We have recently shown that this inhibition correlated with a CD4-mediated inhibition of the kinase Erk-2 and c-Jun-N-terminal kinases (JNK) which play a key role in IL-2 transcription. Moreover, we have previously reported that antigen-independent adhesion of CD45RObright/CD4+ T cells to B cells is negatively regulated by CD4 ligands, whereas that of CD45RAbright/CD4+ naive T cells is not. Other groups have described, in murine models, a differential sensitivity of memory and naive T cells to CD4-mediated inhibitory effects on T cell activation. The aim of the present report was to study the sensitivity of the naive and memory CD4+ T cell populations to the CD4-mediated inhibition of Erk-2 and JNK activation. Our data show that preincubation with anti-CD4 mAb, of the CD45RAbright/CD4+ naive and the CD45RObright/CD4+ memory human T cell populations, induces inhibition of both Erk-2 phosphorylation and Erk-2 activation by phorbol ester or anti-CD3 mAb. In contrast, CD3 mediated JNK activation was inhibited in the memory but not in the naive CD4+ T cell population, whereas JNK activation by phorbol ester or phorbol esters plus Ca2+ ionophore was inhibited by anti-CD4 mAb in both T cell populations. These data further demonstrate a differential sensitivity of naive and memory CD4+ T cell populations to the CD4-mediated negative signaling.
Antibodies, Monoclonal↗
Nitric oxide synthase in the innervation of the human nasal mucosa: correlation with neuropeptides and tyrosine hydroxylase.
Nitric oxide (NO) is a powerful mediator in the central and peripheral nervous system. In the present study the authors have examined the human nasal mucosa innervation for the presence of the neuronal isoform of the NO-generating enzyme, NO-synthase (NOS), and its correlation with other neuronal mediators and markers by means of double-labeling immunohistochemistry. NOS-immunoreactive nerve fibers were observed to be numerously present around glands and venous sinusoids and, less frequently, around small arteries and veins. Few fibers were seen in the lamina propria. NOS appeared to be frequently colocalized in nerve fibers with vasoactive intestinal peptide and, occasionally, with substance P and tyrosine hydroxylase, a marker for catecholamine biosynthesis. These findings suggest that neurally released NO is an important regulatory mediator of glandular secretion and blood flow in the nasal mucosa.
Adult↗
Identification of a novel cis-acting element for fibroblast-specific transcription of the FSP1 gene.
The FSP1 gene encodes a filament-binding S100 protein with paired EF hands that is specifically expressed in fibroblasts. This led us to look for cis-acting elements in the FSP1 promoter that might engage nuclear transcription factors unique to fibroblasts. The first exon of FSP1 is noncoding, therefore, a series of luciferase reporter minigenes were created containing varying lengths of 5'-flanking sequence, the first intron, and the noncoding region of the second exon. A position and promoter-dependent proximal element between -187 and -88 bp was shown to be active in fibroblasts but not in epithelium. Sequence in the first intron from +777 to +964 had an enhancing effect that was not cell type specific. Hsv TK reporter constructs driven by this promoter/intron cassette in transgenic mice were coexpressed appropriately with FSP1 in tissue fibroblasts. Gel mobility shift competitor assays identified a novel domain, FTS-1 (fibroblast transcription site-1; TTGAT from -177 to -173 bp), that specifically interacts with nuclear extracts from fibroblasts. The necessity of this binding site was confirmed by site-specific mutagenesis. Database searches also turned up putative FTS-1 sites in the early promoter regions of other fibroblast expressed proteins, including the alpha1 and alpha2(I), and alpha1(III) collagens and the alphaSM-actin gene. We hypothesize that the selective engagement of FTS-1 elements may contribute to the mesenchymal phenotype of fibroblasts and perhaps other dedifferentiated cells.
3T3 Cells↗
Localization of heme oxygenase-2 immunoreactivity to parasympathetic ganglia of human and guinea-pig airways.
Carbon monoxide (CO), an activator of soluble guanylate cyclase and generated enzymatically by heme oxygenase-2 (HO-2), is thought to function as an intra- and intercellular neurotransmitter in the central and peripheral nervous system. In the present study, the distribution of HO-2 in airway nerves from both humans and guinea pigs was assessed. HO-2 was found in all neuronal perikarya of the intrinsic ganglia of guinea-pig airways and in all ganglion nerve cell bodies localized to the trachea and bronchi of humans. By contrast, nerve fibers innervating the smooth muscle, lamina propria, and epithelium of the airways in both species were devoid of HO-2 immunoreactivity. HO-1, the inducible isoform of heme oxygenase, was not found in airway nerves. The pattern of distribution of HO-2 observed suggests that CO might serve as a modulator of synaptic neurotransmission in the lung and airways rather than as a bona fide neurotransmitter in the smooth muscle, vasculature, or glands. Consistent with this hypothesis, 8-bromo-cyclic guanosine monophosphate (cGMP) (30 microM), a stable, pharmacologically active analog of cGMP, markedly inhibited vagally-mediated cholinergic contractions of the isolated guinea-pig trachea. In subsequent studies, however, neither inhibiting heme oxygenase with zinc protoporphyrin-IX (30 microM) nor inhibiting the soluble isoform of guanylate cyclase with ODQ (3 microM) had measurable effects on vagally-mediated cholinergic contractions of the trachea. These results indicate that CO could play a modulatory role in efferent (parasympathetic) synaptic neurotransmission in the airways, but under normal conditions may not be activated to an appreciable extent during periods of elevated vagal activity.
Animals↗
Patients with a malignant tumor have more extended thrombosis than patients without.
Changes in the coagulability or rheology of the blood are supposed to cause an increased frequency of thrombosis in patients with a malignant tumor. These procoagulopathic disorders may not only increase the frequency of thrombosis but may also enlarge the extent of the thrombosis. The authors retrospectively analyzed, therefore, the extension of thrombosis in patients with and without a malignant tumor. From 1991 to 1995 in the University Hospital Essen 489 consecutive cases of thrombosis were diagnosed. The diagnosis was made by color Doppler sonography or phlebography; 230 patients (47%) suffered from a malignant tumor (110 men, 120 women). To exclude the influence of the patient's age on the extension of the thrombosis the authors distinguished three different age groups. In the tumor group aged from 21 to 40 years they found 10 large (iliacal, femoral, and crural veins), six medium (femoral and crural veins), and four small thromboses (crural veins). In the tumor group aged from 41 to 60 years they found 38 large, 24 medium, and 27 small thromboses. In the group without a tumor aged from 21 to 40 years they found seven large, 13 medium, and 28 small thromboses, and in the group aged from 41 to 60 years, 12 large, 29 medium, and 41 small thromboses. The difference between the two groups supports the assumption that in patients suffering from a malignant tumor, thromboses tend to be more extended than in patients without a malignant tumor.
Adult↗
Sulfamidase deficiency in a family of Dachshunds: a canine model of mucopolysaccharidosis IIIA (Sanfilippo A).
Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo A, McKusick 25290) was diagnosed in two adult wire-haired Dachshund littermates. Clinical and pathologic features paralleled the human disorder; both dogs exhibited progressive neurologic disease without apparent somatic involvement. Pelvic limb ataxia was observed when the dogs were 3 y old and progressed gradually within 1-2 y to severe generalized spinocerebellar ataxia. Mentation remained normal throughout the course of the disease. A mucopolysaccharide storage disorder was indicated in both dogs by positive toluidine blue spot tests of urine. The diagnosis of MPS IIIA was confirmed by documentation of urinary excretion and tissue accumulation of heparan sulfate and decreased sulfamidase activity in fibroblasts and hepatic tissue. Mild cerebral cortical atrophy and dilation of the lateral ventricles were grossly evident in both dogs. Light microscopically, fibroblasts, hepatocytes, and renal tubular epithelial cells were vacuolated. Within the nervous system, cerebellar Purkinje cells, neurons of brainstem nuclei, ventral and dorsal horns, and dorsal ganglia were distended with brightly autofluorescent, periodic acid-Schiff-positive, sudanophilic material. Ultrastructurally, visceral storage presented as membrane-bound vacuoles with finely granular, variably electron-lucent contents. Neuronal storage appeared as membranous concentric whorls, lamellated parallel membrane stacks, or electron-dense lipid-like globules. This represents the first reported animal disease homolog of the human Sanfilippo A syndrome.
Animals↗
Pharmacological analysis of the tachykinin receptors that mediate activation of nonadrenergic, noncholinergic relaxant nerves that innervate guinea pig trachealis.
Previous studies indicated that antidromic stimulation of capsaicin-sensitive vagal afferent fibers activated, via peripheral release of tachykinins, nonadrenergic, noncholinergic parasympathetic ganglion neurons that mediate relaxations of guinea pig trachealis. On the basis of the effects of selective agonists and inhibition with a nonselective receptor antagonist (SR 48968), we speculated that tachykinin-mediated activation of neurokinin3 (NK3) receptors might be involved. Using the recently developed NK3-selective receptor antagonist SR 142801, we further assessed the role of NK3 receptors in these relaxant responses. Relaxations of the guinea pig trachea elicited by antidromic stimulation of capsaicin-sensitive vagal afferent nerves were markedly inhibited by 0.3 microM SR 142801 and were abolished by a combination of SR 142801 and either of the NK1-selective receptor antagonists SR 140333 and CP 99994 (0.3 microM each). The NK3 receptor antagonist had similar effects on the relaxant responses elicited by capsaicin and substance P, but it had no effect on relaxations of the trachealis elicited by electrical field stimulation of the postganglionic nerves that innervate the trachealis or by stimulation of the preganglionic parasympathetic vagal nerves that innervate the trachea. These results and the observation that the ganglion neurons that mediate these responses are densely innervated by substance P-containing nerve fibers lead us conclude that stimulation of capsaicin-sensitive visceral afferent fibers activates, upon peripheral release of tachykinins, nonadrenergic, noncholinergic inhibitory neurons innervating guinea pig trachealis via activation of both NK3 and NK1 receptors.
Animals↗
Nociceptin-induced inhibition of tachykinergic neurotransmission in guinea pig bronchus.
Nociceptin is a novel neuropeptide of the opioid peptide family recently identified as the endogenous ligand of the opioid receptor-like "orphan" receptor. Unlike other opioids, nociceptin has hyperalgesic effects in vivo. In the present study, nociceptin was found to inhibit electrical field stimulation-induced tachykinergic contractions of the guinea pig isolated bronchus preparation. The threshold effect was about 1 nM, and at 0.1 microM, nociceptin inhibited contractions evoked by 5-Hz stimulation by more than 50%. This inhibitory effect was found to be mediated by a prejunctional mechanism involving none of the classical (mu, delta and kappa) opioid receptors. Although the hypothesis that the effect of nociceptin was secondary to opioid receptor-like stimulation cannot be pharmacologically addressed, opioid receptor-like-receptor-mRNA was found to be expressed in the upper vagal sensory ganglion, where the cell bodies of the tachykinin-containing sensory neurons are located. Nociceptin immunoreactive nerve fibers in the airway wall, distinct from the tachykinin-containing fibers, were identified as an endogenous source of nociceptin. These data indicate that nociceptin may influence airway physiology by modulating tachykinergic neurotransmission.
Animals↗
[Allogeneic bone marrow transplantation in congenital erythropoietic porphyria. Gunther's disease].
INTRODUCTION: The congenital erythropoietic porphyria (Günther's disease) (CEP) is a rare autosomal recessively metabolic disease due to the deficit of uroporphyrinogen III cosynthetase, fourth enzyme of the porphyrin-heme biosynthesis. This disease is characterized by severe cutaneous photosensitivity with profound skin lesions, hemolytic anemia and excess of uroporphyrin I excretion. The vital prognosis is very bad and until now, no treatment seems to be efficient. Bone marrow transplantation seems to be able to correct the enzymatic deficit that causes the disease because it is located in the bone marrow. OBSERVATION: We report the case of a four and a half year old girl who received an allogeneic bone marrow transplantation (BMT) at the age of two. Despite an encouraging result, the first transplantation failed. A second allogeneic transplantation was attempted eight months later with the same HLA identical heterozygous donor and bone marrow engrafment succeeded. Twenty one months after the second bone marrow transplantation, clinical and biological results are still excellent. DISCUSSION: No classical treatment of CEP really proved its efficiency and no one was curative. CEP resulting from an homozygous deficiency in uroporphyrinogen III cosynthetase, enzyme that takes part in the porphyrin-heme biosynthesis which is principally located in the erythropoietic system of the bone marrow, substitution of this defective lineage by BMT was a very attractive treatment to correct this anomaly. The first bone marrow transplantation attempted on an affected child in 1990 in Manchester failed because the patient died of infections complications. After the failure of the first transplantation, our little patient is now healed twenty one months after the second BMT and biochemical anomalies are corrected. If a long follow up is necessary to appreciate the long-term efficiency of this treatment, allogenic bone marrow transplantation seems to cure Günther's disease and must be proposed as the treatment of this affection.
Bone Marrow Transplantation↗