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Biomedical subjects

S Chouaib

Publications and source records attributed to S Chouaib.

At least 19 recordsLinked to original sources
PubMed2003

Detection of a functional hybrid receptor gammac/GM-CSFRbeta in human hematopoietic CD34+ cells.

A functional hybrid receptor associating the common gamma chain (gammac) with the granulocyte/macrophage colony-stimulating factor receptor beta (GM-CSFRbeta) chain is found in mobilized human peripheral blood (MPB) CD34+ hematopoietic progenitors, SCF/Flt3-L primed cord blood (CB) precursors (CBPr CD34+/CD56-), and CD34+ myeloid cell lines, but not in normal natural killer (NK) cells, the cytolytic NK-L cell line or nonhematopoietic cells. We demonstrated, using CD34+ TF1beta cells, which express an interleukin (IL)-15Ralpha/beta/gammac receptor, that within the hybrid receptor, the GM-CSFRbeta chain inhibits the IL-15-triggered gammac/JAK3-specific signaling controlling TF1beta cell proliferation. However, the gammac chain is part of a functional GM-CSFR, activating GM-CSF-dependent STAT5 nuclear translocation and the proliferation of TF1beta cells. The hybrid receptor is functional in normal hematopoietic progenitors in which both subunits control STAT5 activation. Finally, the parental TF1 cell line, which lacks the IL-15Rbeta chain, nevertheless expresses both a functional hybrid receptor that controls JAK3 phosphorylation and a novel IL-15alpha/gammac/TRAF2 complex that triggers nuclear factor kappaB activation. The lineage-dependent distribution and function of these receptors suggest that they are involved in hematopoiesis because they modify transduction pathways that play a major role in the differentiation of hematopoietic progenitors.

Antibodies, Monoclonal↗
PubMed2002

Tumor escape from killing: role of killer inhibitory receptors and acquisition of tumor resistance to cell death.

Immunotherapy of cancer has always been a very attractive fourth-modality therapeutic approach. Over the past few years, advances in the identification of tumor antigens have offered new perspectives and provided new opportunities for more accurate immunotherapy for cancer. However, when applied to patients with established tumors, it rarely leads to an objective response. This is partly due to the fact that tumors evade host immunity at both the induction and effector phases. Thus, understanding tumor escape mechanisms may be the key to successful immunotherapy for cancer. In the present review, we will focus on how the expression of killer Ig receptors (KIR) on tumor infiltrating lymphocytes can compromise their function and how tumors evade apoptotic death - two additional mechanisms of tumor escape.

Apoptosis↗
PubMed2001

Tumor-specific up-regulation of the nonclassical class I HLA-G antigen expression in renal carcinoma.

HLA-G is a nonclassical class I antigen mainly expressed at the maternofetal interface during pregnancy where it is thought to down-modulate maternal immune response against the semiallogeneic fetus. Recent studies indicate that ectopic up-regulation of HLA-G expression on melanoma cells may also favor their escape from antitumor immune response. HLA-G expression was here investigated on paraffin-embedded tumor and adjacent normal renal tissues of 18 renal cell carcinoma (RCC) patients. We provide evidence that HLA-G antigen is differentially expressed in carcinoma and normal renal cells and that up-regulation of this antigen in the tumor cells is more frequent than alterations of other MHC class I or class II antigens. We also demonstrated that HLA-G cell surface expression and secretion is maintained in a tumor cell line (DM) established from an HLA-G-positive RCC lesion. Furthermore, we show that type I (alpha and beta) and, in particular, type II (gamma) IFN treatment enhances steady-state mRNA levels and cell surface expression of HLA-G in the DM cell line. As several studies suggest that HLA-G displays various functional features that allow down-modulation of immune response in vitro, we propose that selective in vivo expression of HLA-G may participate in the impairment of antitumor immunity in RCC.

Adult↗
PubMed2001

A point mutation in the alpha-actinin-4 gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human lung carcinoma.

We have identified an antigen recognized on a human large cell carcinoma by an autologous tumor-specific CTL clone that was derived from mononuclear cells infiltrating the primary tumor. The antigenic peptide is presented by HLA-A2 molecules and is encoded by the alpha-actinin-4 gene, which is expressed ubiquitously. In the tumor cells, a point mutation generates an amino-acid change that is essential for recognition by the CTLS: The mutation was not found in alpha-actinin-4 cDNA sequences from about 50 lung carcinoma cell lines, suggesting that it is unique to this patient. Although he did not receive chemotherapy or radiotherapy, the patient has been without evidence of tumor since the resection of the primary lesion in 1996. Using tetramers of soluble HLA-A2 molecules loaded with the mutated antigenic peptide, anti-alpha-actinin-4 CTLs could be derived from blood samples collected from the patient in 1998 and 2000. It is possible that these CTLs, recognizing a truly tumor-specific antigen, play a role in the clinical evolution of this lung cancer patient.

Actinin↗
PubMed2001

Tumor cells regulate the lytic activity of tumor-specific cytotoxic t lymphocytes by modulating the inhibitory natural killer receptor function.

Tumor-infiltrating p58+ T cells from a renal tumor were specifically expanded in response to tumor cell stimulation and cloned. These p58+ T cells were found to express a memory phenotype and corresponded to clonal TCRBV3 T-cell expansion. Functionally, p58(+) CTLs displayed a low lytic activity for HLA-A2 tumor and normal cells. However, this lytic activity was significantly increased after blockade of p58 with specific monoclonal antibodies. Interestingly, we demonstrated that stimulation by tumor cells was required to trigger the inhibitory effect of p58 on the lytic activity of antigen-specific CTLs and that stimulation of the inhibitory function of p58 by tumor cells correlated with an inhibition of nuclear factor-kappaB activation in p58+ tumor-specific CTLS.

Antibodies, Monoclonal↗
PubMed2001

Role of Fas and granule exocytosis pathways in tumor-infiltrating T lymphocyte-induced apoptosis of autologous human lung-carcinoma cells.

We have isolated a cytotoxic T lymphocyte (CTL) clone, Heu161, that reacts specifically with the human autologous lung carcinoma cell line IGR-Heu. We first demonstrated that IGR-Heu lacked Fas-receptor expression and was resistant to CD95-induced apoptosis. To further elucidate the role of Fas in tumor immune surveillance, we have stably transfected IGR-Heu with a Fas-expression vector and isolated CD95-sensitive and -resistant clones. Our data indicated that the resistance of 2 selected Fas-transfected clones to CD95-mediated lysis correlated with down-regulation of caspase-8 or its lack of cleavage and subsequent activation. All Fas transfectants, either sensitive or resistant to anti-Fas agonistic antibody, were as efficiently lysed by the CTL clone as the parental cell line. In addition, neither anti-Fas-blocking antibody nor Fas-Fc molecule inhibited T-cell lysis of Fas-sensitive tumor clone. This cytotoxicity was extracellular Ca(2+)-dependent and abolished in the presence of EGTA, indicating that it was mainly granzyme-mediated. Interestingly, although the caspase inhibitor z-VAD-fmk had no effect on tumor-cell lysis, it efficiently blocked target DNA damage triggered by autologous CTLs via the granule exocytosis pathway, indicating that the latter event was caspase-dependent. The present results suggest that lung carcinoma-specific CTLs use mainly a granule exocytosis-dependent pathway to lyse autologous target cells and that these effectors are able to circumvent alteration of the Fas-triggered intracellular signalling pathway via activation of a caspase-independent cytoplasmic death mechanism.

Apoptosis↗
PubMed2001

Differential effect of high doses versus low doses of interleukin-12 on the adoptive transfer of human specific cytotoxic T lymphocyte in autologous lung tumors engrafted into severe combined immunodeficiency disease-nonobese diabetic mice: relation with interleukin-10 induction.

BACKGROUND: Interleukin (IL)-12 can enhance the development of effective immune responses against tumors as well as against certain infectious agents. It is therefore a potential candidate for therapeutic use in cancer therapy and in design of vaccines against several infectious diseases. METHODS: The authors have established a specific cytotoxic T-cell line (TIL-Heu) from lymphocytes infiltrating a human large cell carcinoma of the lung (LCC). In the current report, the authors have investigated the in vivo effect of recombinant human IL-12 (rhIL-12) on the adoptive transfer of TIL-Heu cells in autologous tumor (Heu-n) engrafted into severe combined immunodeficiency disease-nonobese diabetic (SCID-NOD) mice. RESULTS: Initial in vitro experiments indicated that rhIL-12 increased the cytotoxic potential of TIL-Heu cells in a dose-dependent manner. Heu-n tumors transplanted into SCID-NOD mice were injected with TIL-Heu cells, resulting in a significant tumor growth inhibition. When low doses of rhIL-12 were injected intratumorally after TIL-Heu transfer, a clear increase in tumor growth suppression was observed. Surprisingly, higher doses of rhIL-12 had no effect on cytotoxic T lymphocyte (CTL)-induced prevention of tumor growth. Further in vitro experiments revealed an inhibition of tumor cell lysis after incubation with supernatant of TIL-Heu cells stimulated with high doses of rhIL-12, strongly suggesting that an immunosuppressive factor secreted by the high dose IL-12-stimulated CTL may be responsible for the tumor escape observed in vivo. CONCLUSIONS: The authors' data indicate that IL-10 may play a critical role in the lack of effect of high dose IL-12, by mediating tumor cell resistance to CTL killing. Therefore, understanding the cross-talk between immunoregulatory and immunosuppressive cytokines ultimately may provide new approaches to improve cytokine-mediated cancer immunotherapy.

Adjuvants, Immunologic↗
PubMed2001

Effect of nuclear factor kappaB inhibition on tumor cell sensitivity to natural killer-mediated cytolytic function.

Inhibition of the transcription factor NF-kappaB has been reported to increase cell sensitivity to TNF and some cytotoxic drugs. We investigated the effect of NK-kappaB inhibition on the susceptibility of tumor cells to freshly isolated, nonactivated, human NK cells and to a TCRgamma/delta T cell clone displaying an MHC-unrestricted "NK-like" lysis. Using electrophoretic mobility shift assay, we first demonstrated that NF-kappaB/DNA binding activity was induced in target cells following coculture with NK cells or TCRgamma/delta T cell clone. To investigate the effect of target cell NF-kappaB inhibition on NK-mediated lysis, we blocked NF-kappaB translocation by introducing a human cDNA coding for a mutated IkappaB-alpha. Interestingly, our results indicated that inhibition of NF-kappaB did not induce any increase in either granzyme-dependent non-MHC-restricted cytotoxicity mediated by fresh non-stimulated NK cells and by TCR gamma/delta T cell clone or in CD95-mediated lysis. These results emphasize that NF-kappaB expressed in target cells does not play a role in the molecular process related to the control of target cell susceptibility to NK-mediated lysis and suggest that the NF-kappaB pathway is not a general mechanism for controlling the cytotoxic response.

Cytotoxicity, Immunologic↗
PubMed2001

Identification of HER-2/neu immunogenic epitopes presented by renal cell carcinoma and other human epithelial tumors.

HER-2/neu is a tumor-associated antigen overexpressed in a large variety of human tumors. Eight HER-2/neu peptides displaying HLA-A*0201 anchoring motifs were selected and tested for their binding affinity to HLA-A*0201 and their capacity to elicit cytotoxic T lymphocyte (CTL) responses in both HLA-A*0201 transgenic mice and in HLA-A*0201(+) healthy donors. Two high-affinity (p5 and p48) and one intermediate-affinity (p1023) peptides triggered CTL responses in both transgenic mice and humans, comparable to those observed for the well-known HER2/neu dominant peptide p369. CTL induced in transgenic mice lysed HLA-A*0201(+) RMA cells infected with recombinant HER-2/neu but not cells infected with wild-type vaccinia virus. Human CTL lysed HLA-A*0201(+) HER-2/neu(+) tumor cells of different origins (breast, colon, lung and renal cancer) irrespective of the expression levels of HER-2/neu. Importantly, primed CTL specific for these epitopes were detected in freshly isolated tumor-infiltrating lymphocytes from three renal cell carcinoma patients. Therefore, the HER-2/neu peptides p5, p48 and p1023 may be good candidates for immunotherapy of a broad spectrum of tumors, including renal cell carcinoma.

Animals↗
PubMed2001

[Technological advances in immuno-oncology: from fundamental concepts to patient immunological monitoring].

Over the past decade, cancer immunology has known several advances due to both basic research and new technologies recently developed in this field. This review will illustrate the impact of some new immunological technologies and how the latter resulted in the exploration of new territories in cancer immunology and the emergence of new concepts that allowed to revisit the immunosurveillance concept and permitted to improve the patient monitoring.

Antigens, Neoplasm↗
PubMed2001

[Fatty liver disease and other complications of obesity].

Obesity induces many organic complications (somatic, metabolic and mechanical). The aims of this prospective study were to evaluate its complications in a group of thirty fat patients. Fatty liver disease, detected by echography is noted at 70% of patients. Clinically, it makes pains at the right side and seems favorized by an elevated BMI > 40 kg/m2, and diabetes, hypertriglyceridemiae, hypercaloric and hyperglucidic ration. 10% of our patients present stone bile duct associated to fatty liver disease.

Adolescent↗
PubMed2001

[Behçet's disease associated with Crohn's disease].

INTRODUCTION: The association of Behçet's disease and of Crohn's disease is exceptional, and raises a nosological problem. CASE REPORT: A 24 year-old female developed since 1996 chronic diarrhea, abdominal pain, recurrent oral and genital ulcer and polyarthralgia. Endoscopic colonoscopy examination showed a diffuse colitis. Histological examination revealed epitheloid granuloma without vasculitis compatible with a Crohn's disease. The patient was treated with oral prednisone (1mg/kg/day). In November 1998, she was admitted for diarrhea. Many pseudofolliculitis lesions, uveitis and positive pathergy test were noted. The HLA was B 51. The diagnosis of Crohn's disease associated with Behçet's disease was made. She was treated with high doses of prednisone (1mg/kg/day and 6 monthly intravenous pulses of cyclophosphamide). Skin lesions and diarrhea improved within few days, and cleared completely within five months. Presently, the patient remains clinically free of disease. CONCLUSION: While being of different pathogenic origin, Behçet's disease and Crohn's disease may coexist within one and the same patient and cause diagnostic and therapeutic problems.

Adult↗
PubMed2000

Resistance to TNF-induced cytotoxicity correlates with an abnormal cleavage of cytosolic phospholipase A2.

To investigate the mechanism underlying the absence of arachidonic acid (AA) release by TNF in TNF-resistant cells, we first performed comparative analysis of phospholipid pools in both TNF-sensitive (MCF7) and their equivalent resistant cells (C1001). Quantification and incorporation studies of [(3)H]AA indicated that TNF-resistant cells were not depleted in AA. Furthermore, distribution of this fatty acid in different phospholipid pools was similar in both sensitive cells and their resistant counterparts, ruling out a defect in phospholipid pools. Since phospholipase A(2) (PLA(2)) are the main enzymes releasing free AA, we investigated their relative contribution in the acquisition of cell resistance to TNF-induced cell death and AA release. For this purpose, we used two PLA(2) inhibitors, methylarachidonyl fluorophosphate (MAFP) and bromoenol lactone (BEL), which selectively and irreversibly inhibit the cytosolic PLA(2) (cPLA(2)) and the Ca(2+)-independent PLA(2), respectively. Although a significant inhibitory effect of MAFP on both TNF-induced AA release and PLA(2) activity in MCF7 was observed, BEL had no effect. The inhibitory effect of MAFP on cPLA(2) activity correlated with an inhibition of TNF-induced cell death. Western blot analysis revealed that TNF induced a differential cleavage of cPLA(2) in TNF-sensitive vs TNF-resistant cells. Although the p70 (70-kDa) form of cPLA(2) was specifically increased in TNF-sensitive cells, a cleaved form, p50 (50 kDa), was selectively observed in TNF-resistant C1001 cells in the presence or absence of TNF. These findings suggest that the acquisition of cell resistance to this cytokine may involve an abnormal cPLA(2) cleavage.

Arachidonic Acid↗
PubMed2000

Altered natural killer cell differentiation in CD34+ progenitors from chronic myeloid leukemia patients.

IL-15 and SCF fail to induce NK differentiation and proliferation of CD34+ hematopoietic progenitors from chronic myeloid leukemia patients in contrast to normal stem cells although, both normal and leukemic CD34+ cells display comparable expression of c-kit or IL-15 receptor subunits. Interestingly, confocal microscopy analysis revealed that leukemic and most normal CD34+ cells produce and secrete IL-15, as shown by its trafficking through the Golgi apparatus and early endosomes. However, only leukemic progenitors express the membrane bound IL-15. Colocalization and internalization of IL-15Rbeta/gammac and IL-15Ralpha/gammac complexes indicated that IL-15 was specifically uptaken by leukemic progenitors. We also demonstrated that in both normal and leukemic progenitors, the signaling kinase Jak3 is constitutively pre-associated with the gammac chain. Anti-IL-15 neutralizing mAb treatment resulted in down-regulation of gammac chain and disruption of gammac/Jak3 interaction in normal but had no effect in leukemic progenitors. Our results suggest the existence in both normal and leukemic CD34+ cells of a constitutive production of a bioactive IL-15 that does not lead to NK differentiation and further indicate that membrane bound IL-15 and constitutive activation of gammac are hallmarks of leukemic progenitors. Oncogene (2000).

Antigens, CD34↗
PubMed2000

Killer inhibitory receptor (CD158b) modulates the lytic activity of tumor-specific T lymphocytes infiltrating renal cell carcinomas.

In this study, we showed that renal tumors contain substantial subsets of CD8(+) p58(+) T cells. From 1 of these tumors, T cells were amplified in mixed lymphocytes-tumor cell cultures and p58(+) T cells were selected immunologically. After expansion, phenotypic and functional features of p58(+) and p58(-) T cells were examined. The p58(+) T cells expressed p58.2 receptor and corresponded to CD3(+), CD8(+), T-cell receptor (TCR) alpha/beta(+) T cells that were CD56(+) and CD28(-). Functionally, p58(+) T cells showed a low level of lytic activity against autologous tumor cells that was dramatically and specifically increased by anti-p58.2 monoclonal antibody. On the other hand, p58(-) CD8(+) T cells did not lyse autologous tumor cells and had non-major histocompatibility complex-restricted cytotoxicity against K562 and Daudi cells. A p58(+) cytotoxic T lymphocyte (CTL) clone (4C7) with the same characteristics as the p58(+) T-cell line was derived. This CTL clone did not lyse autologous normal B cells but lysed several HLA-A1(+) renal tumor cell lines. Analysis of TCR repertoire diversity showed that the p58(+) T-cell line contained 3 TCR rearrangements, whereas the TCR repertoire of p58(-) T cells was polyclonal. Interestingly, TCR transcripts of p58(+) T cells and of CTL clone 4C7 were detected as prominent ex vivo in tumor cells but not in peripheral blood mononuclear cells, suggesting that these cells are antigen specific and amplified at the tumor site. (Blood. 2000;95:2883-2889)

Antigens, CD↗
PubMed2000

Adenovirus-mediated wild-type-p53-gene expression sensitizes TNF-resistant tumor cells to TNF-induced cytotoxicity by altering the cellular redox state.

We have shown that the loss of p53 function contributed to resistance of tumor cells to TNF-induced cytotoxicity. In the present study, we evaluated the effect of wild-type p53 (wt-p53) expression on TNF sensitivity, by introducing wt-p53 into MCF7/Adr cells in which p53 was deleted, via a recombinant adenovirus encoding p53 (Ad-p53). Our results indicate that infection with Ad-p53 (50-100 viral particles per cell) resulted in pronounced cytotoxicity, whereas infection with 10 viral particles per cell, which was weakly toxic for the MCF7/Adr cells, sensitized these cells to TNF-induced cell death. Moreover, expression of wt-p53 in MCF7/Adr cells induced the production of reactive oxygen intermediates (ROIs) and caused glutathione (GSH) depletion, indicating disturbances in the cellular redox state. Additional treatment of cells with the anti-oxidant and glutathione (GSH) precursor N-acetylcysteine (NAC) resulted in inhibition of p53-induced ROIs production and in partial restoration of intracellular GSH levels, which was associated with the ability of NAC to inhibit p53-modulated TNF-induced cytotoxicity. Interestingly, Ad-p53 was able to inhibit TNF-induced MnSOD mRNA expression in MCF7/Adr cells, which might contribute to the sensitization of cells to the cytotoxic action of TNF. Taken together, our data strongly suggest that wt-p53 expression sensitizes TNF-resistant MCF7 cells with p53 deletion to TNF-induced cell death by a pathway that is dependent on ROIs production.

Acetylcysteine↗