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Biomedical subjects

L Boumsell

Publications and source records attributed to L Boumsell.

At least 37 records · Page 2Linked to original sources
PubMed2000

Cutaneous T cell lymphoma reactive CD4+ cytotoxic T lymphocyte clones display a Th1 cytokine profile and use a fas-independent pathway for specific tumor cell lysis.

We have previously described two cytotoxic T lymphocyte clones isolated from lymphocytes infiltrating a human major histocompatibility complex class II-/class I+, CD4+ cutaneous T cell lymphoma. These clones displayed a CD4+CD8dim+ (TC5) and CD4+ CD8- (TC7) phenotype and mediated a specific major histocompatibility complex class I-restricted cytotoxic activity toward Cou-LB autologous tumor cell line. Our studies were performed to elucidate the mechanism involved in T-cell-clone-mediated cytotoxicity and to determine the cytokine profile of both the lymphoma cell line and specific cytotoxic T lymphocyte clones. The results indicate that, despite surface expression of Fas receptor on Cou-LB and Fas ligand induction on TC5 and TC7 cell membranes, the CD4+ cytotoxic T lymphocyte clones do not use this cytotoxic mechanism to lyse their specific target. The TC7 clone uses instead a granzyme-perforin-dependent pathway. Furthermore, quantitative analysis of Th1 and Th2 cytokine mRNA expression in the cutaneous T cell lymphoma cell line as well as in TC5 and TC7 clones indicated that, whereas the tumor cells display a Th2-type profile (interleukin-4, interleukin-6, and interleukin-10), the cytotoxic T lymphocyte clones express Th1-type cytokines (interferon-gamma, granulocyte macrophage colony stimulating factor, and interleukin-2). In addition, preincubation of the tumor-infiltrating lymphocyte clones with autologous tumor cells induced their activation and subsequent amplification of the Th1-type response. These results indicate a direct contribution of the malignant cells in the Th1/Th2 imbalance observed frequently in cutaneous T cell lymphoma patients and suggest their potential role in depressed cell-mediated immunity. Identification of CD4+ Th1-type cytotoxic T lymphocyte clones, the tumor antigen they recognize, and optimization of their cytokine expression profile should be useful for the design of new immunotherapy protocols in cutaneous T cell lymphoma.

Aged↗
PubMed1999

[Contribution of immunotherapy to the treatment of T-cell lymphoma of the skin].

DEFINITION: T-cell lymphomas localized predominantly or primarily in skin comprise a heterogeneous group of tumors. The most frequent is fungoid mycosis. T-CELL TUMORS AND GROWTH FACTORS: When growth factors of T-cell tumors, particularly IL-7 and IL-5, were identified, it became possible to grow T-cell tumoral clones in long-term in vitro cultures used to evidence anti-tumoral cellular immune reactions in T-cell skin cancers. Reactional T-cell clones with specific anti-tumoral reactions can be expaned ex vivo. This advance has made it possible to identify tumoral antigens and better understand the mechanisms leading to tumoral escape from anti-tumoral defense systems. THERAPEUTIC PERSPECTIVES: It is now possible to develop immunotherapy strategies based on reinjection of T lymphocytes with specific cytotoxic activity after ex vivo expansion. Injections of immunogenic peptides associated or not with dendritic cells or injection of DNA coding for these tumor antigens are other possibilities.

Growth Substances↗
PubMed1999

Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial. ANRS 048 study group.

BACKGROUND: Intermittent interleukin-2 therapy for HIV-1 by continuous intravenous infusion leads to sustained increase of CD4 T cells. This method of administration is, however, inconvenient and has limiting toxic effects. We did a randomised study to compare safety and efficacy of antiviral treatment alone or combined with various interleukin-2 regimens in HIV-1-infected patients. METHODS: 94 symptom-free patients, naïve to antiretroviral treatment, with CD4-T-cell counts of 250-550 cells/microL at baseline were randomly assigned zidovudine and didanosine alone (n=26) or combined with interleukin-2 administered intravenously (12 million IU/day, n=22) or subcutaneously (3 million IU/m2 twice daily, n=24) for 5 days, or were given polyethylene-glycol-modified (PEG) interleukin-2 (2 million IU/m2 intravenous bolus, n=22) administered every 2 months from week 2 to week 50 (seven cycles). Safety and immunological and virological results were monitored until week 56. FINDINGS: CD4-T-cell count increased to higher than baseline by a mean of 564 cells/microL (subcutaneous group), 676 cells/microL (intravenous group), 105 cells/microL (PEG group), and 55 cells/microL (antiretroviral-therapy group, p=0.0001). 68% and 77% of patients in the subcutaneous and intravenous groups, respectively, achieved an 80% increase of CD4 T cells (p<0.001). In these two groups, 50% of patients restored a CD4/CD8-T-cell ratio of more than 1. The groups did not differ significantly for changes in plasma HIV-1 RNA loads throughout the study. The duration of common side-effects of interleukin-2 was shorter in the subcutaneous group, which enabled outpatient treatment. Naïve and memory CD4 T cells, CD28 expression on CD4 and CD8 T cells, and restoration of in-vitro proliferative response to mitogens and recall antigens increased in the intravenous and subcutaneous groups. INTERPRETATION: Subcutaneous interleukin-2 is a convenient regimen that, as well as intravenous therapy, improves immunological function in HIV-1-infected patients receiving two nucleosides. Larger studies are needed to show whether immunological improvements translate into clinical benefit.

Adult↗
PubMed1999

Cutting edge: MHC class I triggering by a novel cell surface ligand costimulates proliferation of activated human T cells.

BY55 is a human cell surface molecule whose expression is restricted to NK cells, a subset of circulating CD8+ T lymphocytes, and all intestinal intraepithelial T lymphocytes. Here, we report that BY55 is a novel NK receptor showing broad specificity for both classical and nonclassical MHC class I molecules, and that optimal binding requires a prior aggregation of MHC class I complexes. Using BY55 transfectants, we have identified functional consequences of MHC class I/ligand interactions for the class I-bearing cell. The triggering of MHC class I molecules on human T cell clones by BY55 delivered a potent proliferative signal in the presence of soluble CD3 mAb. The costimulatory signal provided by MHC class I ligation was only seen in activated, and not resting, peripheral blood T cells. This observation represents an additional and/or alternative pathway to CD28 costimulation and may be of particular relevance in memory T cells lacking CD28, such as intestinal intraepithelial T lymphocytes, which are CD28- but BY55+.

Animals↗
PubMed1999

G10.3 monoclonal antibody identifies novel functional cell surface structures expressed by normal B lymphocytes and various malignant cell lines.

G10.3, a unique monoclonal antibody (mAb), was produced to better characterize lymphocyte subsets. In the present study, we show that this mAb identifies 118, 83 and 51 kDa cell surface sialylated glycoproteins on the immunizing cell line YTindi. The reactivity of G10.3 mAb is restricted in normal cells to B lymphocytes, whereas within tumoral cell lines various lymphoid and non-lymphoid cells were found positive. Interestingly, functional studies revealed that triggering G10.3 mAb reactive molecules with soluble antibody led to an inhibition of growth and to an induction of programmed cell death in tumor cell lines expressing high levels of reactive molecules.

Antibodies, Monoclonal↗
PubMed1999

Poor lymphocyte recovery following CD34-selected autologous peripheral blood stem cell transplantation for non-Hodgkin's lymphoma.

Positive selection of CD34+ cells in autologous grafts, designed to deplete tumour cells, also results in T-cell depletion. To assess the reconstitution of the different lymphocyte subsets and of the T-cell repertoire diversity following autologous transplantation of selected CD34+ peripheral blood stem cells (PBSC), we analysed sequential blood samples in eight patients autografted for advanced B-cell non-Hodgkin's lymphoma in a phase I-II pilot study. Although natural killer cell recovery was rapid, T- and B-cell recovery was delayed with a median of 110/microliters CD4+, 175/microliters CD8+ T cells and 45/microliters B cells at 12 months post-transplant. The naive CD45RA+ T-cell compartment was profoundly deficient up to 12 months for both CD4+ and CD8+ subsets. A transient expansion of memory CD8+CD45RO+ T cells consisting of an increased percentage of CD57+CD28- cells occurred within the first 3 months post-transplant, but the memory CD4+CD45RO+ T cells remained far below the normal value. The CD8+CD28+ T-cell subset did not recover. Using multiplex PCR analysis of the T-cell receptor gamma locus, we found that the repertoire diversity improved at 12 months after being poor and oligoclonal during the first 3 months post-transplant. As shown by monoplex PCRgamma analysis of every VJ combination, despite T-cell depletion of the graft, mature T cells were carried over with the selected CD34+ PBSC and contributed to the T-cell recovery after transplantation.

Antigens, CD34↗
PubMed1998

Cloning of BY55, a novel Ig superfamily member expressed on NK cells, CTL, and intestinal intraepithelial lymphocytes.

Expression of the BY55 protein has been shown to be tightly associated with NK and CD8+ T lymphocytes with cytolytic effector activity. To determine the function of this protein, we molecularly cloned BY55 cDNA. The cDNA sequence predicts a cysteine-rich, glycosylphosphatidylinositol-anchored protein of 181 amino acids with a single Ig-like domain weakly homologous to killer inhibitory receptors. Reduction and carboxyamidomethylation of immunoprecipitated BY55 gave a band of 27 kDa, whereas reduction alone led to an 80-kDa species, suggesting that BY55 is a tightly disulfide-linked multimer. RNA blot analysis revealed BY55 mRNAs of 1.5 and 1.6 kb whose expression was highly restricted to NK and T cells. BY55 was expressed on the CD56dim, CD16+ subset of NK cells, which have high cytolytic activity, but was not expressed and was not induced on the CD56bright, CD16-subset of NK cells, a subset with high proliferative, but low cytolytic, capacity. In human tissues, BY55 mRNA was expressed only in spleen, PBL, and small intestine (in gut lymphocytes). BY55 was expressed on all intestinal intraepithelial lymphocytes, which were predominantly CD3+TCRalpha/beta+CD4-CD8+CD11b+CD28-CD45RO+C D56-CD101+CD103+ (alphaEbeta7 integrin). In addition, BY55 was expressed on most CD8+CD28- peripheral blood T cells. These phenotypic relationships suggest that CD8+CD28+ precursor CTL may terminally differentiate into CD8+CD28-BY55+ effector CTL and that some of the peripheral blood CD8+CD28- subset may represent recirculation from mucosal epithelial immune sites.

Amino Acid Sequence↗
PubMed1998

Isolation of tumor-specific cytotoxic CD4+ and CD4+CD8dim+ T-cell clones infiltrating a cutaneous T-cell lymphoma.

We have isolated several T-cell clones from lymphocytes infiltrating a human major histocompatibility class (MHC) II negative cutaneous T-cell lymphoma (CTCL). We describe here two of these clones, TC5 and TC7, with, respectively, a CD4(+)CD8dim+ and CD4(+)CD8(-) phenotype. Both clones mediated a specific MHC class I-restricted cytotoxic activity toward the fresh autologous tumor cells, and autologous tumor cell lines previously established with interleukin-2 (IL-2) and IL-7 from the skin and from the blood. Analysis of the T-cell receptor (TCR) Vbeta gene expression showed that the tumor cells, which were shown to have a trisomy 7 by fluorescent in situ hybridization, expressed Vbeta7/Jbeta2.3, Vbeta13/Jbeta2.5, and Vbeta22/Jbeta2.5 rearrangements. Phenotypic analysis using specific anti-Vbeta monoclonal antibodies indicated that only Vbeta13 could be detected on the cell membrane of the tumor cells. Analysis of the TCR Vbeta gene expression of the clones showed that TC5 and TC7 expressed a unique TCR-Vbeta transcript, corresponding, respectively, to Vbeta5/Jbeta2.3 and Vbeta17/Jbeta2.7 gene segments. To determine whether these reactive T lymphocytes were present in vivo, we used specific primers corresponding to TC5- and TC7-Vbeta TCR transcripts. The results showed that both cytotoxic T-cell clones were present at the lesional skin site and amplified in vitro. TC7 was found in the patient peripheral blood invaded by tumoral cells, whereas TC5 was not, indicating that the repertoire of the reactional lymphocytes differs in the blood and at the tumor site. These results show for the first time the presence of reactive T lymphocytes with CD4 or double-positive phenotype infiltrating a CTCL. These findings raise the question of the role of these antitumoral effector T cells in the tumor growth.

Aged↗
PubMed1998

Monocyte-derived dendritic cells have a phenotype comparable to that of dermal dendritic cells and display ultrastructural granules distinct from Birbeck granules.

Most monocyte-derived dendritic cells (DC) display CD1a, like Langerhans cells (LC) and some dermal DC, but their relationship with these skin DC remains unclear. To address this issue, we studied the expression of different antigens characteristic of skin DC and of monocyte/macrophages in CD1a+ and CD1a- monocyte-derived DC. Their phenotype indicated that they may be related to dermal DC rather than to LC, i.e., they were all CD11b-positive, and 72% were Factor XIIIa-positive, but they did not express E-cadherin nor VLA-6. It is interesting that CD1a+ and CD1a-cells showed intracytoplasmic granules that were different from LC Birbeck granules. These phenotypical and ultrastructural features are comparable to those of CD14-derived DC obtained from cord blood precursors [C. Caux et al. J. Exp. Med. 184, 695-706]. These results show a close relationship between these two in vitro models, which are both related to dermal DC.

Antigens, CD↗
PubMed1998

CD100 is a leukocyte semaphorin.

CD100 was originally described as an activation molecule on the surface of human T lymphocytes. Its triggering through distinct epitopes leads to different signals of costimulation with phorbol myristate acetate (PMA) or with CD3 and CD2. Interestingly, CD100 was shown to associate with different partner molecules in T cells. First, CD100 can associate with CD45, a key molecule with protein tyrosine phosphatase activity involved in T-cell transduction: this association is physical and has functional consequences for both partners. Second, CD100 interacts in its cytoplasmic domain with a Ser/Thr kinase for which it represents a preferential substrate. Recently, CD100 was identified as a member of the semaphorin gene family. This family comprises approximately 20 structurally related proteins. The first semaphorins were identified in the developing nervous system. Function has been shown for only some of them and involves repulsion during growth cone guidance. Since CD100 was the first semaphorin identified in the immune system, this raises the possibility of the involvement of members of the semaphorin family in other physiological phenomena outside the nervous system.

Antibodies, Monoclonal↗
PubMed1998

Delineation of human cord blood hematopoietic progenitor cell subsets with a unique monoclonal antibody AY19.

AY19, a unique mAb was used to better characterize the umbilical cord blood hematopoietic progenitor subpopulations. This mAb identifies an 85 kDa cell surface glycoprotein. In this present study we showed that AY19 mAb is reactive with 50-60% of the CD34+ cord blood cells. Extensive phenotypical studies revealed that AY19 mAb defines a novel CD34+ subset different from the ones defined by anti-CD90, anti-CD38, anti-CD33, anti-CD71, anti-CD19, anti-CD7 or anti-HLA-DR mAbs. We show that AY19 mAb reacts with both primitive and committed progenitors including myeloid and lymphoid progenitors. In addition, sorted CD34+high/AY19+ cells contain an increased number of CFU-GM and a decreased number of BFU-E compared with sorted CD34+high/AY19- cells. We show that AY19 mAb exhibits agonistic properties by inducing a significant increase in the size of CFU-GM colonies when added to serum-free liquid cultures of hematopoietic progenitors. This suggests that AY19 mAb identifies a cell surface receptor which may be involved in the regulation of hematopoietic cell proliferation.

Antibodies, Monoclonal↗
PubMed1997

In vivo association of CD5 with tyrosine-phosphorylated ZAP-70 and p21 phospho-zeta molecules in human CD3+ thymocytes.

CD5 is a 67-kDa T cell surface Ag that can be found physically associated with the CD3-TCR molecular complex. In different experimental models it has been shown to act as a costimulatory receptor for T cell activation. Unexpectedly, studies in CD5-deficient mice suggested a negative role for the CD5 Ag in CD3-TCR signaling in the thymus. In this report we assessed the constitutive interactions of CD5 in freshly isolated human thymocytes with signaling elements of the CD3-TCR complex. We determined that the ZAP-70 protein tyrosine kinase was present in CD5 immunoprecipitates. The two molecules were constitutively tyrosine phosphorylated in a complex also associating with unphosphorylated as well as phosphorylated zeta-chains. Although both p21 and p23 tyrosine-phosphorylated forms of zeta as well as phospho-CD3 epsilon molecules were constitutively present in human thymocytes and could be immunoprecipitated with ZAP-70- or CD3 epsilon-specific Abs, the p21 species of zeta was predominant in CD5 immune complexes. The interaction between CD5 and ZAP-70 was not observed in CD3-negative thymocytes, where the constitutive tyrosine phosphorylation of ZAP-70 was very low. We conclude that CD5 may affect in vivo the signaling capacity of TCRs expressed by human thymocytes by altering the phosphorylation state of CD3 and/or by retaining ZAP-70 with the p21 species of zeta.

Biotinylation↗
PubMed1997

The human semaphorin-like leukocyte cell surface molecule CD100 associates with a serine kinase activity.

CD100 is a 150-kDa homodimeric glycoprotein broadly expressed on the surface of human hematopoietic cells. CD100 has been recently identified as the first lymphoid gene that belongs to the semaphorin gene family. Semaphorins function as chemorepellent molecules in the nervous system, but the function of CD100 remains poorly understood. In lymphoid cells, it has been suggested to play a role in homotypic cell adhesion and in T cell activation. We demonstrate that in T cells and natural killer cells a serine kinase activity is immunoprecipitated with CD100. Distinct epitopes of CD100 have been defined with specific monoclonal antibodies, mediating opposite effects at the functional level, especially in T cells. The kinase activity is retained only with an antibody against a particular epitope of CD100. Additionally, a fusion protein containing the cytoplasmic domain of the molecule retains the kinase activity in cellular lysates, and CD100 itself is presumably a favorite substrate of the kinase. These findings suggest that a serine kinase pathway may participate in the different functional effects triggered through the distinct epitopes of CD100 and is likely involved in the biological effects of this semaphorin-like leukocyte cell surface molecule.

Amino Acid Sequence↗
PubMed1997

Activation of T-cells through an antigen-independent alternative pathway induces precocious sensitivity to Fas-induced apoptosis.

Autoreactive T-cells can be activated inadvertently during immune responses through antigen-independent pathways. It has been suggested that Fas/Fas ligand interactions may play a role in eliminating these cells, but the extent that cells activated through such alternative pathways are sensitive to Fas-induced apoptosis has not been extensively evaluated. Proliferation of peripheral blood T-cells from normal individuals activated for 4 days with PHA or PMA + ionophore was not influenced by the presence of anti-Fas antibody. When the same cells were activated with soluble factors produced by previously activated T-cells (lymphostimulatory activity), anti-Fas antibodies inhibited thymidine incorporation by 74+/-4%. The presence of typical morphological changes and oligonucleosomal fragmentation of DNA indicated that the reduced proliferation resulted from apoptotic death of the lymphoblasts. Fas-sensitivity of T-cells activated by lymphostimulatory activity was first detectable 4 days after activation, and at 5 days the majority of lymphoblasts had become sensitive to Fas, whereas no evidence of sensitivity to Fas was observed for lymphoblasts generated by PHA or PMA + ionophore during the first 5 days of culture. Incubation of cells activated with PHA or PMA+ ionophore in the presence of IL-2 at concentrations 10-fold higher than that present in lymphostimulatory activity did not induce early sensitivity to Fas, indicating that exposure to IL-2 could not explain the precocious development of sensitivity to Fas seen following activation by lymphostimulatory activity. These studies demonstrate that T-cells activated through an antigen-independent 'alternative' pathway develop precocious sensitivity to Fas-induced apoptosis, which may be important in permitting the elimination of autoreactive bystander cells activated in the course of immune responses.

Adult↗
PubMed1997

CD101 is expressed by skin dendritic cells. Role in T-lymphocyte activation.

CD101 was first described in our laboratory using two different monoclonal antibodies, BA27 and BB27, recognizing a 140-kDa disulfide-bonded homodimeric polypeptide on a small subset of circulating T lymphocytes and on most activated T cells in vitro. Further, it has been reported that most intestinal mucosal T lymphocytes expressed CD101. The gene coding for the CD101 antigen has been cloned and found to be identical to the gene coding for the recently described V7 antigen, corresponding to a type I trans-membrane protein with seven immunoglobulin-like loops in its extracellular domain. To define surface proteins that are involved in skin dendritic cell (DC) localization or function, we looked for the expression of CD1O1 on skin DC migrating from human skin explants. The majority of these DC had a phenotype of Langerhans cell (LC)-like mature DC, i.e., HLA-DR+ CD1a+ CD1c+ CD11a+ CD11c+ CD40+ CD50+ CD54+ CD58+ CD80+ CD83+ CD86+. We found that CD101 was expressed by a major subset of these HLA-DR+ CD1a+ CD1c+ LC-like skin DC. Next, we studied the effect of anti-CD101 monoclonal antibodies on primary allogeneic and on soluble antigen-specific mixed skin DC-lymphocyte reactions. We showed that two different monoclonal antibodies, BB27 and V7.1, inhibited the T-lymphocyte proliferative responses and that the inhibitory effect was overcome by high doses of exogenous IL-2. As both DC and T lymphocytes expressed CD101 molecules, we determined that the inhibitory effect was achieved both at the responder T-cell level and at the DC level. Thus, CD101 which is expressed on a subset of circulating T lymphocytes, has also been found on a subpopulation of LC-like DC. This molecule plays a major role in the activation of T cells by skin DC.

Antigens, CD↗
PubMed1997

Interleukin-13 responsiveness and interleukin-13 receptor expression in non-Hodgkin's lymphoma and reactive lymph node B cells. Modulation by CD40 activation.

Interleukin-13 (IL-13) responsiveness was examined in lymph node B cells from patients with non-Hodgkin's lymphoma (NHL) and patients with benign reactive immune disorders. Proliferation assays showed that NHL B cells from 8 of 21 patients responded to IL-13 in the absence of a co-activation signal. IL-13-unresponsive NHL B cells from 9 of the 13 remaining patients were induced to respond to IL-13 upon antibody-triggered CD40 activation, as did reactive B cells. Binding experiments with radiolabeled IL-13 revealed that the constitutive expression of IL-13 receptors (IL-13R) was associated with IL-13 responsiveness in the absence of CD40 activation. In IL-13-unresponsive cells, IL-13R expression was induced after CD40 activation. This effect was enhanced by IL-10, which was able to potentiate the IL-13 response of CD40-activated cells. Furthermore, IL-13 was found to increase the viability of cultured NHL cells, but not that of non-malignant cells. These results suggest that IL-13, which behaves as a potent co-factor for normal lymph node B cell activation, might provide growth and/or survival advantages to NHL B cells.

B-Lymphocytes↗