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Biomedical subjects

A Fischer

Publications and source records attributed to A Fischer.

At least 577 records · Page 32Linked to original sources
PubMed1991

Anti-B-cell monoclonal antibodies in the treatment of severe B-cell lymphoproliferative syndrome following bone marrow and organ transplantation.

BACKGROUND: The B-cell lymphoproliferative syndrome is an infrequent life-threatening complication of marrow or organ transplantation that is the consequence of profound immunosuppression. The results of treatment have been disappointing, although a small number of patients have been cured by chemoradiotherapy or antiviral agents after a reduction in the dosage of immunosuppressive therapy. We report here the results of treating this disorder with anti-B-cell antibodies. METHODS: Twenty-six patients in whom aggressive B-cell lymphoproliferative syndrome developed after bone marrow (n = 14) or organ (n = 12) transplantation received 0.2 mg of CD21-specific and of CD24-specific antibodies per kilogram of body weight for 10 consecutive days in an open, prospective, multicenter trial. RESULTS: The treatment was well tolerated. All patients had transient neutropenia, apparently because the CD24 molecule is also expressed on granulocytes. The treatment was ineffective in seven patients with monoclonal B-cell proliferation. In contrast, 16 patients with oligoclonal B-cell proliferation had complete remission. Systemic remission also occurred in two other patients with oligoclonal proliferation who had central nervous system involvement, although they subsequently died because of progression of the central nervous system disease. In one patient who died early, clonality was not determined. Of the 16 patients who had complete remission, 2 with persistent immunodeficiency due to graft (marrow) rejection or acute graft-versus-host disease had a relapse, and the 1 with graft-versus-host disease subsequently died. Eleven patients were alive and disease-free after a median follow-up of 35 months (5 of 14 marrow recipients and 6 of 12 organ recipients). Four other patients in complete remission died of unrelated causes 4 to 12 months after treatment. CONCLUSIONS: Intravenous administration of anti-B-cell antibodies may be effective in controlling diffuse, severe, oligoclonal B-cell proliferation not involving the central nervous system.

Adolescent↗
PubMed1991

[Primary immune deficiencies of B-lymphocytes].

Primary B-cell immunodeficiency is relatively frequent and may result in recurrent bacterial infections involving notably the respiratory tract, and in chronic severe enteroviral infections in patients with agammaglobulinaemia. Selective IgG2 isotype deficiency results in pneumococcal, Haemophilus influenzae and pseudomonal infections, since it is associated with defective production of antibodies that are specifically directed against bacterial capsular polysaccharides. Progress has recently been achieved in the determination of genetic and molecular bases of some of these immunodeficiencies. In X-linked agammaglobulinaemia, the abnormal gene has been located on the long arm of the X chromosome (Xq22-23); the intrinsic B-cell abnormality blocks differentiation at the pre-B stage, before the genes coding for light chain immunoglobulins are rearranged. There is now a strong suspicion that IgA deficiency, hypoglobulinaemia with variable expression and some selective IgG isotype deficiencies are three ways of expressing one single abnormality a genetic factor of which is located in the class III region of the HLA complex and perhaps also associated with HLA class II DQ. Treatment of deficient IgG production with intravenous immunoglobulin has thoroughly altered the prognosis of these diseases. Complete IgA deficiency carries a risk of accident by production of anti-IgA antibodies, which means that patients with isolated IgA deficiency should not be treated, that these antibodies should systematically be looked for in patients with IgA deficiency associated with partial deficiency of other immunoglobulins, and that these patients should be treated with IgA-free immunoglobulin preparations.

Adult↗
PubMed1991

Myeloma of the head of the pancreas. A case report.

A 45-year-old man was diagnosed with multiple myeloma, IgA-kappa, in 1975. Thirteen years later he presented with obstructive jaundice. Computed tomography (CT) showed a 6-cm mass in the head of the pancreas. Needle aspiration showed myeloma. The jaundice resolved after treatment with radiotherapy. Extraosseous involvement by myeloma is frequently found at autopsy but obstructive jaundice from myeloma of the head of the pancreas is quite rare. This atypical complication of myeloma may be related to the patient's long survival.

Biopsy, Needle↗
PubMed1991

Reduction of graft failure by a monoclonal antibody (anti-LFA-1 CD11a) after HLA nonidentical bone marrow transplantation in children with immunodeficiencies, osteopetrosis, and Fanconi's anemia: a European Group for Immunodeficiency/European Group for Bone Marrow Transplantation report.

Forty-six infants and children suffering from either inherited immunodeficiency disorders (Wiskott-Aldrich syndrome, functional T-cell immunodeficiency with or without HLA class II expression deficiency), malignant osteopetrosis, or Fanconi's anemia received HLA-nonidentical bone marrow transplantation (BMT) from related donors. Bone marrow was T-cell depleted to reduce the risk of graft-versus-host disease (GVHD). To prevent graft failure, a mouse monoclonal antibody specific for the CD11a-lymphocyte function-associated antigen 1 (LFA-1) molecule was infused into the patients. Eleven patients received five infusions of 0.1 mg/kg every other day from day -3 to +5. Thirty-five patients received 0.2 mg/kg daily from day -3 to +6. The overall sustained engraftment rate was 72% instead of 26.1% in a historical control group of 24 patients similarly treated except for the infusion of the anti-LFA-1 antibody. No late rejection occurred. The T-cell depletion method (E-rosetting or Campath IM plus complement) resulted in different rate of engraftment (83.3% v 57.9%, respectively, P = .05). Engraftment rate was slightly but not significantly influenced by the degree of HLA incompatibility between donor and recipient. Acute GVHD of grade II or more occurred in 35.5% of the patients and the rate of chronic GVHD was 12.9%. The overall actuarial survival rate with a functional graft is 47.3% with a mean follow-up of 28.0 months for patients with immunodeficiency and osteopetrosis, while none of the four patients with Fanconi's anemia survived. The development of full T-cell functions took on the average 6 months and of full B-cell functions 10 months. Significant infectious problems developed in the majority of the patients during the posttransplant course. Epstein-Barr virus-induced B-cell proliferative syndromes were observed in seven patients, six of whom had Wiskott-Aldrich syndrome. Correction of immunodeficiency was comparable in terms of kinetics and quality with that observed in patients with severe combined immunodeficiency undergoing HLA-nonidentical BMT. Correction of osteopetrosis appears not to be different from what has been observed after HLA-identical BMT. The in vivo use of an anti-CD11a-LFA-1 antibody as an additional immunosuppressive therapy in HLA-nonidentical BMT may thus promote engraftment and survival with correction of the primary disease in a significant number of patients with life-threatening immunodeficiency and osteopetrosis, but not with Fanconi's anemia.

Antibodies, Monoclonal↗
PubMed1991

Regulation of LFA-1-mediated T cell adhesion by CD4.

Heterotypic adhesion of T lymphocytes to monocytes, B lymphocytes, or other target cells is mainly mediated by LFA-1 and CD2 molecules. Low-affinity binding of resting T cells can be transiently up-regulated by cross-linking of CD3. We have previously found that binding of specific ligands to CD4 can down-regulate adhesion of resting T cells to B cells. We now show that the enhanced adhesiveness of CD4+ T cells induced by CD3 cross-linking using plastic-bound anti-CD3 antibody can also be inhibited by several CD4 ligands. i.e. anti-CD4 antibodies, the gp160 env protein of human immunodeficiency virus, as well as by putative CD4 ligands, i.e. synthetic peptides analogous to the gp160-binding site to CD4 (positions 418-434 and 449-464) and a 12-mer synthetic peptide (DR-12) analogous to positions 35-46 of HLA class II beta subunit and including the highly conserved Arg-Phe-Asp-Ser (RFDS) sequence. After CD3 cross-linking, maximal binding of T cells to HLA class II-positive and -negative B cells was similar, although binding to HLA class II-negative B cells was more prolonged. T cells that were passively induced to up-regulate adhesion by binding of a CD11a-specific antibody NKIL16, known to enhance LFA-1-dependent adhesiveness, were less sensitive to the inhibitory effect of the DR-12 peptide, whereas the inhibitory effects of gp160 were preserved. The kinetics of adhesion of NKIL16-pretreated T cells was not influenced by HLA class II expression at the B cell surface. Together, these results strongly suggest that CD4-HLA class II interaction may down-regulate low-affinity adhesion of resting T cells and, to some extent, high-affinity adhesion of T cells actively induced by CD3 cross-linking but not passively induced by an anti-CD11a antibody.

Adult↗
PubMed1991

Immunodeficiency with low expression of the T cell receptor/CD3 complex. Effect on T lymphocyte activation.

We report the consequences of low expression of the T cell receptor (TcR)/CD3 complex by T lymphocytes from a 4-year-old boy with a mild immunodeficiency. TcR/CD3 expression was found to be deficient on both resting and activated T cells, using both anti-CD3 and anti-TcR alpha/beta monoclonal antibodies. As shown by immunofluorescence and immunoprecipitation studies, residual expression (corresponding to about 10% of normal) was detectable on resting and activated TcR alpha/beta+ T cells. Other T cell membrane receptors were normally expressed. The functional consequences of this TcR/CD3 expression deficiency included an absence of T cell proliferation, interleukin 2 receptor expression and calcium flux following anti-CD3 and anti-CD2 antibody-triggered T cell activation. Antigen (tetanus toxoid, Candida and allogeneic cell)-induced proliferation was detectable. In contrast, cytotoxic T cell activity towards allogeneic cells was deficient. These findings shed light on the function of the TcR/CD3 complex and indicate that the expression of a limited number of TcR/CD3 receptors may be sufficient to trigger antigen-specific T cell activation (and, possibly, differentiation) and that anti-CD3 antibody-induced T cell activation differs somewhat from antigen/major histocompatibility complex molecule-induced activation. These results also confirm that the CD2 pathway of T cell activation is CD3 dependent.

Antigens, CD↗
PubMed1991

Opposing effects of protein tyrosine kinase inhibitors on the monoclonal antibody induced internalization of CD3 and CD4 antigens.

We have previously demonstrated that the monoclonal antibody (mAb)-induced modulation of CD3 and CD4 antigens from the surface of human peripheral blood lymphocytes is not dependent from protein kinase C activity (Thuillier et al., Eur. J. Immunol. 1990. 20:1197). In the present report we study the effect of genistein and of herbimycin A, two potent inhibitors of protein tyrosine kinases (PTK), on the mAb-induced modulation of CD3 and CD4 surface antigens. Both genistein and herbimycin inhibited the mAb-induced internalization of CD3 and, in contrast, facilitated that of CD4 antigen. These results indicate that the mAb-induced modulation of CD3 is essentially dependent on the PTK pathway, whereas PTK appear to negatively regulate the mAb-induced modulation of CD4.

Antibodies, Monoclonal↗
PubMed1991

X-linked thrombocytopenia and Wiskott-Aldrich syndrome: similar regional assignment but distinct X-inactivation pattern in carriers.

While inherited X-linked (XL) isolated thrombocytopenia is a mild condition, the Wiskott-Aldrich syndrome (WAS) associates severe thrombocytopenia with an immunodeficiency component and has a poor prognosis. Whether these conditions correspond to separate genetic entities or to different mutations of the same gene(s) remains unresolved. The Wiskott-Aldrich syndrome locus has been assigned to Xp 11.2 by means of RFLP studies. The X-inactivation pattern in female carriers has been found to follow a skewed pattern in the hematopoietic cells, thus allowing carrier detection. We studied a family with four members affected by XL thrombocytopenia and report the results of genetic segregation analysis, together with the X-inactivation pattern of hematopoietic cells from an obligate female carrier. Although the affected locus mapped to the same region as that of WAS, lymphocytes presented a skewed pattern of X-inactivation, whereas polymorphonuclear lymphocytes (PMN) did not. These results provide further evidence that the Wiskott-Aldrich syndrome and XL thrombocytopenia are different expressions of mutations within a single locus and that the severity of the disease corresponds to distinct hematopoietic cell selections in obligate carriers.

Adult↗
PubMed1991

Transport conditions and number of biopsies necessary for culture of Helicobacter pylori.

Stuart's transport medium with a charcoal impregnated swab was tested for transport of biopsies from the gastric antrum for culture of Helicobacter pylori. Biopsies were cultured under microaerophilic conditions either within 2 h or after a delay of 24 h at 4 degrees C. In 65 patients referred for gastroscopy two biopsies were taken. Helicobacter pylori was found in 39 patients. The rate of survival of Helicobacter pylori was found to be as high in Stuart's transport medium after 24 h at 4 degrees C as in the paired biopsy which was cultured immediately after transportation in normal saline. In five (13%) of 39 patients positive for Helicobacter pylori, the organism was cultured from only one of the biopsies. It is therefore recommended that two biopsies be taken for culture.

Bacteriological Techniques↗
PubMed1991

Tissue distribution of neutral endopeptidase 24.11 ('enkephalinase') activity in guinea pig trachea.

The distribution of neutral endopeptidase 24.11 (NEP; 'enkephalinase') activity was studied on tissue sections of the guinea pig trachea using a histochemical method based on the catalytic activity of the enzyme. The specificity for NEP of the histochemical reaction was verified by application of an array of peptidase inhibitors. NEP activity was most prominent on the respiratory epithelium, but occurred also in submucous glands, connective tissue of the lamina propria, perichondrium and chondrocytes. The findings suggest that NEP in the trachea is involved in various functions, cleavage of neurally released peptides being only one of them.

Animals↗
PubMed1991

X-linked immunodeficiencies: clues to genes involved in T- and B-cell differentiation.

There are five major human X-linked immunodeficiencies, each with a characteristic impairment of T-and/or B-cell differentiation. The molecular bases of these diseases remain unknown but, as Geneviève de Saint Basile and Alain Fischer report, major steps towards that goal have been taken: the location of the defective genes has been precisely defined and the cell lineages and stages of differentiation in which the genes are expressed have been partly identified.

Animals↗
PubMed1991

Primary membrane T cell immunodeficiencies.

Primary membrane T cell immunodeficiencies (ID) have recently been characterized. In this paper we describe the main findings about the leukocyte adhesion deficiencies (LAD), the ID with low expression of the T cell receptor/CD3 complex, and the Omenn's syndrome. LAD is a consequence of mutations in the beta-chain-encoding gene of the leukocyte adhesion proteins. Functional consequences mainly affect phagocytic cells which are incapable of transendothelial migration. Effector T lymphocyte functions are, however, also impaired, i.e., helper T cell activity and cytotoxicity. The latter defect may account for the inability of LAD patients to reject HLA nonidentical bone marrow. Low expression of the T cell receptor CD3 complex is a rare entity characterized by a profoundly diminished expression of the whole complex on all T cells. The basic defect has not yet been unravelled. Interestingly, such T cells differentiate normally and can be activated by some antigens while anti-CD3 and anti-CD2 antibodies are not efficient. In five patients with Omenn's syndrome (combined immunodeficiency with eosinophilia), oligoclonal T cells were detected in blood, skin, and gut. These T cells are also in vivo activated. Since in one family, one sibling presented with typical SCID, i.e., alymphocytosis, and another with the Omenn's syndrome, it is proposed that the latter syndrome may correspond to a form of leakiness of SCID as found in the mice SCID model.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1991

Experience with a new implantable pacer-, cardioverter-defibrillator for the therapy of recurrent sustained ventricular tachyarrhythmias: a step toward a universal ventricular tachyarrhythmia control device.

Ten consecutive patients (mean age 57.9 +/- 7.6 years) were treated with an investigational tachyarrhythmia control device, the implantable Medtronic Pacer-, Cardioverter-, Defibrillator model 7216A or 7217B. All patients had coronary artery disease with old myocardial infarctions and presented hemodynamically significant sustained ventricular tachyarrhythmias not suppressed by antiarrhythmic drug therapy and unrelated to acute myocardial infarction. In two patients a nonthoracotomy lead system was implanted. Lowest effective defibrillation energy ranged from 5 to 18 joules (mean 12.2 +/- 4 joules) for the epicardial bielectrode systems and were 15 and 18 joules for the nonthoracotomy lead system implants. The postoperative periods were unremarkable. Follow-up ranged from 7 to 19 months (mean 13.8 +/- 4.5 months). Spontaneous tachyarrhythmia episodes were detected and treated by the device in six patients, five of them received staged therapies. No deaths occurred and no hospital admissions were necessary for device related or ventricular tachyarrhythmia related complications. In conclusion, this integrated device represents a major step toward the development of a universal ventricular arrhythmia control device.

Aged↗
PubMed1991

Restricted heterogeneity of T lymphocytes in combined immunodeficiency with hypereosinophilia (Omenn's syndrome).

We report the immunological characteristics of five patients with Omenn's syndrome, a rare inherited immunodeficiency also known as combined immunodeficiency with hypereosinophilia. The syndrome is characterized by T cell infiltration of skin, gut, liver, and spleen leading to diffuse erythroderma, protracted diarrhea, failure to thrive, and hepatosplenomegaly. Blood T cells as well as those infiltrating the skin and gut were found to express activation markers and were partially activated by mitogens but not by antigens. Although the lesions resembled those in graft-versus-host disease, the blood T cells were shown by DNA haplotype analysis using probes revealing variable number of tandem repeats to belong to the patients as well as the T cells infiltrating the gut and skin in one patient. A given T cell subset (TCR alpha beta+, CD4+/CD8+, or TCR gamma delta+) was predominant in each patient, with a specific distribution in the skin lesions. Moreover, the study of T cell receptor beta, gamma, and delta gene rearrangements in four patients revealed oligoclonality involving C beta 1, C beta 2, or different V gamma J gamma or V delta J delta genes. This indicates that restricted heterogeneity of the T cell repertoire, previously reported in one case, is a major feature of this syndrome. The occurrence of alymphocytosis-type severe combined immunodeficiency in the brother of one of the patients suggests that the restricted heterogeneity of T cell receptor gene usage in Omenn's syndrome may arise from leakiness, within the context of a genetically determined faulty T cell differentiation.

Antigens, CD↗
PubMed1991

Influence of cytokines and cellular interactions on the glucocorticoid-induced Ig (E, G, A, M) synthesis of peripheral blood mononuclear cells.

We studied the mechanisms of action leading to the glucocorticoid (GC)-induced synthesis of the immunoglobulins (IgE, G, A, M) by human peripheral blood mononuclear cells (PBMC). It is shown that the enhanced Ig synthesis of GC-stimulated PBMC is dependent on the presence of T cells and monocytes. After stimulation of purified B cells with GC only a slight enhancement of IgM could be detected. Inhibition studies with neutralizing anti-interleukin-4 (IL-4) and anti-IL-6 antibodies revealed that the GC-induced IgE synthesis of PBMC is not dependent on the presence of IL-4 or IL-6. Stimulation of membrane-separated and co-cultured cell fractions revealed that the GC-induced enhancement of IgA and IgM synthesis is mediated by T-cell derived soluble mediators. The GC-induced IgG and IgE synthesis is dependent upon contact of B cells with monocytes. Antibodies against LFA-1 and ICAM-1 are capable to suppress the GC-induced IgE and IgG synthesis of PBMC. Furthermore, the monocyte expression of lymphocyte function antigen-1 (LFA-1), intercellular adhesion molecule-1 (ICAM-1) and HLA-DR is modulated by GC stimulation.

B-Lymphocytes↗
PubMed1991

[Morphometric findings of stab wounds].

Stabbing experiments with a single-edged blade on skin preparations taken from three regions of the body (anterior chest wall, abdominal walls, lumbar region) showed the following results: The most gaping stab wounds were found, as anticipated, if the blade was stabbed perpendicular to Langer's lines. If the blade entered parallel to these lines, which depend on the pattern of cutaneous fibres, narrow slit-like wounds were produced; the dimensions of wounds from stabs at an angle of 45 degrees were between the two extreme patterns. The length of the skin wounds in orthograde stabbing (without cutting movement) was greater in the abdominal region than in the chest and lumbar regions, but never reached the full width of the penetrated blade, not even after restoration (by approximating the edges of a gaping wound).

Humans↗