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Biomedical subjects

F Birg

Publications and source records attributed to F Birg.

At least 37 records · Page 2Linked to original sources
PubMed1997

In vivo expression of the CTLA4 inhibitory receptor in malignant and reactive cells from human lymphomas.

The CTLA4 receptor is a CD28 homologue which induces inhibitory effect on activated T-cells. Peripheral T-cells proliferate spontaneously in CTLA4-deficient mice. These results led to an analysis of CTLA4 expression in human lymphomas (n = 82) including Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHLs), using immunohistochemistry. CTLA4 was present in neoplastic cells from most (10/11) T-cell malignancies, except for anaplastic and lymphoblastic subtypes (0/4). Malignant B-cells from rare (3/55) B-NHLs (all of follicular subtype) were also CTLA4-positive. Other B-NHLs (52/55) were negative in malignant B-cells and occasionally positive in T-cells. Reactive small lymphocytes, but not Reed-Sternberg cells, from all (12/12) HD cases were strongly CTLA4-positive. The CTLA4 ligands CD80 and CD86 were simultaneously expressed in most CTLA4-negative lymphoma cases. CTLA4 is thus expressed either in the reactive or in the malignant cell populations, depending on the lymphoma subtype. These results provide new insights leading towards therapeutic strategies based either on enhancement of anti-tumour immunity by CTLA4 blockade in reactive lymphocytes or on triggering of a CTLA4-mediated inhibitory pathway in lymphoma cells.

Abatacept↗
PubMed1997

Cysteine protease CPP32, but not Ich1-L, is expressed in germinal center B cells and their neoplastic counterparts.

Ich-1/Nedd2 and CPP32/YAMA are cysteine proteases related to interleukin 1-beta-converting enzyme (ICE), which act as apoptosis effectors. Both molecules are expressed in T- and B-cell lines. The authors investigated their in vivo cellular distribution in normal and neoplastic human lymphoid tissues. Sixty-eight representative non-Hodgkin's lymphomas (NHL) and Hodgkin's disease (HD) samples, normal lymphoid organs, and nonlymphoid tumors were analyzed by immunohistochemistry (IHC). CPP32 expression in benign tissues was restricted to germinal center B cells, plasma cells, and a few interfollicular immunoblasts. All follicular NHLs and most diffuse large cell NHLs were CPP32 positive. Among T-cell NHLs, CPP32 expression was mainly observed in anaplastic large cell NHLs, whereas the other subtypes were less frequently positive. In contrast, lymphoid organs displayed only weak Ich1-L expression, located in sinusal histiocytes and thymic epithelial cells. Lymphomas were Ich1-L negative, except for T-cell-rich B-cell NHLs, and about half of the HD samples, in which Reed-Sternberg cells (RSC) were usually Ich1-L positive/CPP32 negative. Extralymphoid Ich1-L reactivity was found in particular organs like the kidney and various tumors. Western blot analysis confirmed the specificity of immunostaining. Neither CPP32 nor Ich1-L expression were correlated with intratumoral DNA fragmentation, as determined by the TUNEL assay. Altogether, these results indicate that CPP32 is preferentially expressed in germinal centers and thus could be involved in B-cell maturation. The differential expression of CPP32 and Ich1-L suggests that cysteine proteases differ in substrate specificities and carry out functions unrelated to apoptosis.

Apoptosis↗
PubMed1997

Malignant and reactive cells from human lymphomas frequently express Fas ligand but display a different sensitivity to Fas-mediated apoptosis.

Fas ligand (FasL) is capable of inducing apoptosis of lymphoid cells by cross-linking with its natural receptor, Fas. We aimed to investigate the possible role of the Fas/FasL-mediated apoptosis in the development of human lymphomas. FasL mRNA was detected by reverse transcriptase-polymerase chain reaction in 38 out of 63 lymphoma biopsy specimens representative of various subtypes of non-Hodgkin's lymphoma (NHL) and Hodgkin's disease. FasL was co-expressed with Fas mRNA in most cases. Flow cytometry (FACS) analysis showed a bright FasL staining in 31% to up to 75% of the total cell population from 14 out of 16 samples; the presence of the FasL protein was confirmed by Western blotting. Dual-color FACS analysis showed that FasL was expressed by T cells in B-NHLs and T-NHLs. A significant percentage of B cells in various B-NHLs also stained positively for FasL. Freshly separated neoplastic B cells from three FasL+ and one FasL- B-NHLs displayed a relative resistance to Fas-mediated apoptosis, when compared to reactive T cells isolated from the same tissue samples. In contrast, the sensitivity to Fas-mediated killing of the T cells isolated from two FasL+ T-NHLs was not uniform. These data show that (1) FasL is expressed in both neoplastic and reactive cells from a significant proportion of lymphoma cases, and (2) that the intratumoral FasL+/Fas+ reactive T cells are more sensitive to Fas-induced apoptosis than the neoplastic FasL+/Fas+ malignant B cells. A putative defect in the Fas/FasL pathway may thus favor the development of malignant B cell populations.

Apoptosis↗
PubMed1997

Fas ligand is not only expressed in immune privileged human organs but is also coexpressed with Fas in various epithelial tissues.

AIMS: To confirm the recent data obtained in mice, showing that the Fas ligand (FasL) is involved in the phenomenon of "immune privilege" (the apparent defect of the immune system in specific anatomical sites) and to extend this finding to humans. METHODS: The expression of FasL was analysed in a panel of histologically normal human tissues by reverse transcriptase polymerase chain reaction and Western blotting. The tissues sampled were brain, breast, bone marrow, oesophagus, kidney, liver, lung, lymph node, ovary, pancreas, pituitary gland, prostate, spleen, stomach (antrum and fundus), striated muscle, testis, thyroid, and uterus. These were obtained from patients with various neoplastic and non-neoplastic disorders; placental tissue was obtained after normal obstetric delivery, and spontaneous or voluntary abortion. RESULTS: Strong FasL expression was detected in testis and placenta. FasL expression was also detectable, although it was seen to a lesser extent, in oesophagus, prostate, lung, and uterus, which also coexpressed variable amounts of Fas mRNA or protein or both. The other organs tested for FasL expression were all negative. CONCLUSIONS: FasL in humans is expressed predominantly in immune "sanctuaries" such as testis and placenta, suggesting that, similar to mice, this expression may contribute to the immune privileged status of these organs, by preventing dangerous inflammatory responses. The coexpression of FasL and Fas in particular epithelia suggests that the physiological cell turnover of some tissues may be regulated by the Fas-FasL apoptotic pathway.

Blotting, Western↗
PubMed1996

Expression and signal transduction of the FLT3 tyrosine kinase receptor.

FLT3 is a receptor tyrosine kinase of 130-55 kDa expressed on normal bone marrow stem and early progenitor cells and on leukemic blasts from patients with acute leukemias. The FLT3 ligand, FL, is a new cytokine which acts on hematopoietic progenitors in synergy with other cytokines. FLT3 transduces FL-mediated signal through interaction with a number of cytoplasmic substrates.

Acute Disease↗
PubMed1996

A transformed human tracheal gland cell line, MM-39, that retains serous secretory functions.

Infection with the wild type SV40 virus was used to transform primary cultures of human tracheal gland serous (HTGS) cells. Over 80 different cell lines were obtained, but the majority had lost some of their epithelial and secretory features. However, one of these cell lines, MM-39, was shown to have conserved the physiologic characteristics of the genuine HTGS cells-i.e., the presence of cytokeratin, expression of cystic fibrosis transmembrane conductance regulator mRNA, a level of secretory leukocyte proteinase inhibitor secretion comparable to that of the native cells (25 +/- 3 ng/10(6) cells/h), and the responsiveness to pharmacological agonists: carbachol (+260 +/- 40%), isoproterenol (+260 +/- 40%), and adenosine 5'-triphosphate (+280 +/- 30%). These characteristics describe a transformed cell line of human tracheal gland cells which has retained the features of the native serous cells. As a result, this cell line appears to be a useful tool for large-scale physiologic and pharmacologic studies of bronchial secretion at the cellular level.

Cell Line, Transformed↗
PubMed1996

Variant and masked translocations in acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is characterized by a unique hemorrhagic syndrome, disseminated intravascular coagulation, and the association with the specific (15;17 chi q22-23:q12-21) translocation, which disrupts the retinoic acid receptor alpha (RARA) and the promyelocytic leukemia (PML) genes. The t(15;17) leads to the formation of two reciprocal fusion genes, PML/RARA on chromosome 15 and RARA/PML on chromosome 17; it is responsible for the unique response of the disease to retinoic acid (ATRA) treatment. As was described for chronic myeloid leukemia and its associated t(9;22) [Philadelphia chromosome], variant translocations have been reported in APL, which are either complex translocations involving additional chromosome(s), or simple variant translocations involving only either one chromosome 15 or 17 and any of several chromosomes. Rearrangements of RARA and PML were documented in some of these variant translocations. In contrast, recent molecular analysis of APL cases with cytogenetically normal chromosomes 15 and 17 revealed the occurrence of submicroscopic translocations, leading to the formation of non reciprocal fusion genes, either PML/RARA or RARA/PML only. Detailed analysis of such cases may shed light on the mechanisms of translocation, on the selection of oncogenic products, and on the respective role(s) of the products of the translocation. Demonstration of the existence, in some APL-like leukemias, of masked translocations with involvement of PML and RARA, thus allows to (i) confirm the diagnosis of APL, (ii) adapt the treatment and (iii) monitor the residual disease. Finally APL-like leukemias were recently reported, with either a t(11;17) or t(5;17), resulting in the fusion of RARA to genes other than PML; these patients do not appear to respond to ATRA treatment. Altogether, these results emphasize the usefulness of a molecular definition of APL.

Humans↗
PubMed1995

Complementary DNA characterization and chromosomal localization of a human gene related to the poliovirus receptor-encoding gene.

The human poliovirus (PV) receptor (PVR) is a member of the immunoglobulin (Ig) superfamily with unknown cellular function. We have isolated a human PVR-related (PRR) cDNA. The deduced amino acid (aa) sequence of PRR showed, in the extracellular region, 51.7 and 54.3% similarity with human PVR and with the murine PVR homolog, respectively. The cDNA coding sequence is 1.6-kb long and encodes a deduced 57-kDa protein; this protein has a structural organization analogous to that of PVR, that is, one V- and two C-set Ig domains, with a conserved number of aa. Northern blot analysis indicated that a major 5.9-kb transcript is present in all normal human tissues tested. In situ hybridization showed that the PRR gene is located at bands q23-q24 of human chromosome 11.

Amino Acid Sequence↗
PubMed1995

Acute promyelocytic leukemia cases with nonreciprocal PML/RARa or RARa/PML fusion genes.

Tumor-associated chromosome translocations usually lead to the formation of two reciprocal fusion genes: one thought to be involved in the transformation process, the other the mechanical consequence of the translocation event. In the case of acute promyelocytic leukemia (APL) blasts, the 15;17 chromosome translocation generates the putatively transforming PML/RARa fusion gene and its reciprocal RARa/PML. We report APL cases with submicroscopic 15;17 recombinations leading to the formation of nonreciprocal PML/RARa or RARa/PML fusion genes. Therefore, each of the two reciprocal translocation products may be independently formed and selected by the leukemic phenotype, implying that both are involved in tumorigenesis.

Base Sequence↗
PubMed1995

CD28 costimulation up-regulates long-term IL-2R beta expression in human T cells through combined transcriptional and post-transcriptional regulation.

Costimulatory molecules such as CD28 are required for induction of T cell clonal expansion and for prevention of T cell unresponsiveness. In combination with either CD3 or CD2 triggering, CD28 was shown to enhance T cell proliferation, cytolytic activity, production of cytokines and especially of IL-2, and expression of the IL-2R alpha-chain (IL-2R alpha). We and others have demonstrated that the costimulatory effect of CD28 on both IL-2 and IL-2R alpha expression results from a coordinated transcriptional activation of their genes and transcript stabilization. We show here that the CD28 stimulation, together with CD2, leads to a prolonged up-regulation of the constitutive expression of the IL-2R beta-chain in human peripheral T cells. As for IL-2R alpha, the increase in IL-2R beta gene expression seems to result from both transcriptional activation and transcript stabilization. In addition, IL-2 differentially regulates its own receptors, as only expression of IL-2R alpha, but not of IL-2R beta, is largely inhibited, at both the mRNA and protein levels, by blocking IL-2R mAbs. We propose that the long lasting T cell proliferation mediated by the CD2 and CD28 costimulation is mainly the consequence of the high and prolonged expression of both the IL-2R alpha- and beta-chains.

Blotting, Northern↗
PubMed1995

Search for rearrangements and/or allelic loss of the fas/APO-1 gene in 101 human lymphomas.

The authors analyzed the possible occurrence of rearrangements and/or allelic loss of the fas/APO-1 gene in a representative series of human lymphomas, including 101 cases of Hodgkin's disease (HD) and non-Hodgkin's lymphomas (NHL). The rationale for this study was double. Chromosome 10 alterations, frequently observed in lymphoma subtypes, encompass the chromosomal localization of fas/APO-1. In addition, Ipr mouse mutants, which present with a generalized lymphoproliferative disease, were shown to exhibit alterations of fas/APO-1 structure and expression. In this retrospective study, the authors performed gene dosage of fas/APO-1 by Southern blots. No fas/APO-1 alterations were observed in the 31 HD cases. Among 70 T-cell and B-cell NHL, allelic loss of fas/APO-1 was observed in three cases. Two cases with different clinical, phenotypic, and histologic presentations showed a rearrangement of fas/APO-1. A third case showed amplification. Thus fas/APO-1 alterations do occur in human lymphomas, although at a relatively low frequency.

Alleles↗
PubMed1995

Frequent expression of FAS/APO-1 in Hodgkin's disease and anaplastic large cell lymphomas.

FAS/APO-1 (CD95) is a membrane glycoprotein belonging to the tumour necrosis factor/nerve growth factor receptor family, and which can trigger apoptosis in some lymphoid cell lines. Immunohistochemistry combined with Northern blotting allowed determination of the pattern of FAS/APO-1 expression in a series of Ki-1 [CD30] positive lymphoid malignancies, including 27 Hodgkin's disease and eight anaplastic large cell lymphomas. CD30 negative tumours used as controls included 27 B-cell non-Hodgkin's lymphomas. 14 T-cell non-Hodgkin's lymphomas, four reactive lymphadenitis, and non-lymphoid tissues. Immunohistochemistry, performed on frozen sections, revealed a strong FAS/APO-1 expression in 25 out of 27 (92%) Hodgkin's disease cases, predominantly in Reed Sternberg cells; 50 to 100% of the neoplastic cells in eight out of (100%) anaplastic large cell lymphoma cases were positive. In contrast, positive FAS/APO-1 immunostaining was observed only in 22 out of 41 (53%) CD30 negative non-Hodgkin's lymphomas. Northern blot analysis detected variable amounts of the FAS/APO-1 transcript in the immunohistochemistry-positive samples. These results suggest possible hyper-expression of FAS/APO-1 (CD95) in Hodgkin's disease and anaplastic large cell lymphomas.

Gene Expression Regulation, Neoplastic↗
PubMed1994

Heterogeneity of rearranged T-cell receptor V-alpha and V-beta transcripts in tumor-infiltrating lymphocytes from Hodgkin's disease and non-Hodgkin's lymphoma.

Hodgkin's disease is histologically characterized by the presence of Reed-Sternberg cells (RSC) and reactive cells, including numerous T lymphocytes. Some forms of B cell-non-Hodgkin's lymphoma also contain a rich T-cell population. Previous studies have suggested that the T-cell receptor repertoire of tumor-infiltrating T lymphocytes (TITL) that act specifically against tumor-related antigens, should be restricted. The authors in this study used the polymerase chain reaction to explore the possible existence of such an immunologic response of TITL against RSC or neoplastic B cells. They studied variable (v) region genes of T-cell receptor alpha and beta chains expressed by infiltrating lymphocytes in biopsy specimens from seven patients with Hodgkin's disease and three with B cell-non-Hodgkin's lymphoma. These latter samples were selected based on a rich T-cell content. Primers specific for 18 different V-alpha and 21 V-beta families were used. In every case, TITL showed an unrestricted pattern of expression similar to the repertoire observed in peripheral blood lymphocytes. Although such experiments are limited, the apparent lack of selection of a single or a limited number of T-cell subsets in the affected tissues did not support the existence of an in vivo immunologic interaction between TITL and antigens related to RSC or neoplastic B cells.

Blotting, Southern↗
PubMed1994

The expression of FMS, KIT and FLT3 in hematopoietic malignancies.

Three receptor molecules, belonging to the class III of receptor tyrosine kinases, namely the receptors for colony-stimulating factor 1, CSF1R (product of the FMS proto-oncogene) and Steel factor, SLFR (product of the KIT proto-oncogene), as well as the recently identified FLT3/FLK2 gene product, appear to play distinct roles in normal hematopoietic differentiation. Their potential role in leukemic hematopoiesis has been approached by expression studies in hematopoietic malignancies, especially in acute leukemias of the myeloid and lymphoid lineages. We present here a review of available data, and discuss the possible significance and potential applications of these results.

Acute Disease↗
PubMed1994

Localization of the human CD40 gene to chromosome 20, bands q12-q13.2.

CD40 is a surface glycoprotein, member of the nerve growth factor receptor family, which is expressed on B cells and plays an important role in their development, growth, and differentiation. Using chromosomal in situ hybridization, we localized the CD40 gene to the long arm of chromosome 20, bands q12-q13.2. This localization correlates well with the mapping of the murine CD40 gene to the distal region of chromosome 2, syntenic to the human 20q11-q13 region.

Antigens, CD↗
PubMed1993

Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells.

The human FLT3 cDNA was cloned from a pre-B cell line and characterized. The deduced amino acid sequence shows that FLT3 codes for a receptor-type tyrosine kinase of 993 residues, presenting a strong similarity with the corresponding mouse FLT3/FLK2 protein as well as with the receptors for colony-stimulating factor 1 (CSF1R/FMS) and steel locus factor (SLFR/KIT). An analysis of the expression of the gene using amplification of reverse transcribed FLT3 mRNA by polymerase chain reaction shows that FLT3 is expressed in various lymphohematopoietic cells and tissues, including a series of immature cell lines and leukemias of lymphocytic origin.

Amino Acid Sequence↗
PubMed1993

Autoimmune polyendocrine failure--type 1 (insulin-dependent) diabetes mellitus and hypothyroidism--after allogeneic bone marrow transplantation in a patient with lymphoblastic leukaemia.

In this report we describe a patient who, after allogeneic bone marrow transplantation from her HLA-identical sister, developed polyendocrine failure in the form of Type 1 (insulin-dependent) diabetes mellitus and hypothyroidism. This was the result of the transfer of donor lymphoid cells which were activated by allogeneic bone marrow transplantation. The full chimerism of the recipient was demonstrated by restriction fragment length polymorphism analysis from nucleated blood cells and fibroblast DNA. During the 9-year follow-up, the donor developed hypothyroidism and signs of pre-Type 1 diabetes. This clinical observation resembles the adoptive transfer of diabetes observed in non-obese-diabetic mice and BB rats and confirms the role of immune processes in the pathogenesis of this disease.

Adolescent↗