Biomedical subjects

J Van Snick

Publications and source records attributed to J Van Snick.

At least 19 recordsLinked to original sources

PubMed2001

Autocrine antiapoptotic stimulation of cultured adult T-cell leukemia cells by overexpression of the chemokine I-309.

Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+) T cells caused by the human T-cell leukemia virus type 1 (HTLV-1). The viral leukemogenesis is critically dependent on its oncoprotein Tax because the protein as well as the virus can immortalize primary human lymphocytes to permanent growth. As a transcriptional transactivator, Tax can stimulate the expression of distinct cellular genes. Alterations in the expression levels of unknown growth-relevant genes may contribute to the changed growth properties of Tax-immortalized and leukemic cells. To identify genes that are linked to Tax transformation and ATL leukemogenesis, this study systematically compared the gene expression of cultured cells from patients with acute ATL with that of stimulated peripheral blood T lymphocytes. Several overexpressed RNAs that encode signal transduction functions were identified. These include a dual-specific protein phosphatase (PAC1), an interferon-inducible factor (ISG15), a basic helix-loop-helix transcription factor (DEC-1), and the secreted antiapoptotic chemokine I-309. The ATL cell culture supernatants contained an antiapoptotic activity that could be specifically inhibited by antibodies directed against I-309. Inhibition of I-309 receptor (CCR8) signaling by pertussis toxin increased the apoptosis rate of ATL cell cultures in the presence and absence of external apoptotic stimuli. Both the I-309--specific antiapoptotic activity and the proapoptotic effect of inhibitors of I-309 signaling suggest the existence of an antiapoptotic autocrine loop in ATL cells. Thus, the overexpression of this chemokine may inhibit apoptosis in ATL cells and could substantially contribute to their growth. (Blood. 2001;98:1150-1159)

Apoptosis↗

PubMed2001

Interleukin 9 promotes influx and local maturation of eosinophils.

The interleukin 9 (IL-9) pathway has recently been associated with the asthmatic phenotype including an eosinophilic tissue inflammation. The mechanism by which IL-9 affects eosinophils (eos) is not known. To investigate whether this cytokine has a direct activity on the development of eos and eosinophilic inflammation, a model of thioglycolate-induced peritoneal inflammation was used in IL-9 transgenic (TG5) and background strain (FVB) mice. In this model, a transient eosinophilic infiltration in the peritoneal cavity was observed in FVB mice 12 to 24 hours after thioglycolate injection that coincided with peak IL-5 and IL-9 release. In contrast, TG5 mice developed a massive eosinophilia that persisted at high levels (81% of total cells) even 72 hours after thioglycolate injection. Release of eosinophilic major basic protein (MBP), IL-4, and IL-5 to the peritoneal cavity of these mice was significantly increased when compared with the control FVB strain. To study the mechanism by which IL-9 exerts its effect on eos, bone marrow or peritoneal cells were cultured in the presence of IL-5, IL-9, or their combination in vitro. IL-5 alone was able to generate significant numbers of eos in TG5 but not FVB mice, whereas a combination of IL-5 and IL-9 induced marked eosinophilia in both strains indicating a synergism between these 2 cytokines. These data suggest that IL-9 may promote and sustain eosinophilic inflammation via IL-5-driven eos maturation of precursors.

Adoptive Transfer↗

PubMed2001

A MAGE-1 peptide recognized on HLA-DR15 by CD4(+) T cells.

Antigens encoded by MAGE genes and recognized by T cells are of interest for cancer immunotherapy because of their strict tumoral specificity and because they are shared by many tumors. Several MAGE-1 peptide that are recognized by CD8(+) cytolytic T lymphocytes have been used in therapeutic vaccination trials. To obtain anti-tumor immune response, vaccines combining peptides recognized by CD8(+) and peptides recognized by CD4(+) T cells might be optimal. We focused therefore on the identification of MAGE peptides recognized by CD4(+) T cells. We report here the identification of MAGE-1 epitope EYVIKVSARVRF, which is presented to CD4(+) T lymphocytes by HLA-DR15. This HLA allele is present in 29 % of Asians and 17 % of Caucasians.

Antigen Presentation↗

PubMed2001

Allergen-induced Th1 and Th2 cytokine secretion in relation to specific allergen sensitization and atopic symptoms in children.

BACKGROUND: Allergic diseases are believed to be due to T helper (Th)2-like immunity to allergens in affected tissues, and immune responses to allergens are characterized by a cross-regulation between Th1 and Th2 cells. Atopic individuals may develop IgE antibodies to only one or more allergens. However, the mechanisms behind sensitization to a specific allergen, e.g. why an individual develops IgE to cat but not birch, are not known. Our aim was to study birch- and cat-induced Th1 and Th2 cytokine secretion in children who were sensitized to birch but not to cat, and vice versa. MATERIALS AND METHODS: The subjects in the study were 60 12-year-old children. Seventeen of the children were sensitized (skin prick test and circulating IgE positive) to birch but not cat, 13 were sensitized to cat but not birch, 11 were sensitized both to birch and cat, and 19 children were skin prick test and circulating IgE negative. Forty-six children had a history of atopic symptoms, and 42 of them had current symptoms. Peripheral blood mononuclear cells were separated from venous blood and stimulated with cat or birch allergen. The levels of IL-4, IL-5, IL-9, IL-10, IL-13 and IFN-gamma in the cell supernatants were analysed by ELISA. RESULTS: Sensitized children produced more of the Th2 cytokines IL-4, IL-5, IL-9 and IL-13 than non-sensitized atopic and non-atopic children in response to stimulation with the allergen they were sensitized to. High levels of the Th2 cytokines IL-4 and IL-5 and low levels of the anti-inflammatory cytokine IL-10 were associated with atopic symptoms, and high cat-induced IL-9 levels with asthma. CONCLUSIONS: The Th2 cytokines IL-4, IL-5, IL-9 and IL-13 were all commonly detected in sensitized children after stimulation with the specific, in contrast to an unrelated, allergen. Atopic symptoms were associated with increased levels of IL-4 and IL-5 and tended to be associated with low levels of IL-10, and asthma with high cat-induced IL-9 levels.

Allergens↗

PubMed2001

Distinct requirements for IL-6 in polyclonal and specific Ig production induced by microorganisms.

The role of IL-6 in Ig production induced in the mouse by lactate dehydrogenase-elevating virus (LDV), Toxoplasma gondii or lipopolysaccharide (LPS) was assessed. Following infection with LDV, a strong activator of B cells, an early and transient IL-6 production was observed, that originated predominantly from macrophages. Whereas LDV-induced B lymphocyte proliferation appeared independent of IL-6, mice deficient for this cytokine showed a marked reduction in their total T-dependent IgG2a production when compared to their normal counterparts. By contrast, specific responses directed against either LDV or non-viral antigens administered at the time of infection were not decreased in the absence of IL-6. Similarly, polyclonal, but not anti-parasite IgG2a production triggered by T. gondii infection was strongly dependent on the presence of IL-6. Finally, T-independent total IgG3 secretion triggered by LPS was also markedly reduced in IL-6-deficient mice. These results suggest that IL-6 plays a major role in T-dependent and T-independent polyclonal Ig production following B lymphocyte activation by viruses, and parasites, but not in specific antibody responses induced by the same microorganisms.

Animals↗

PubMed2001

Interleukin-9 (IL-9) induces cell growth arrest associated with sustained signal transducer and activator of transcription activation in lymphoma cells overexpressing the IL-9 receptor.

Murine interleukin (IL)-9 inhibits apoptosis in murine T lymphomas via signal transducer and activator of transcription (STAT) factors. After transfection of the human IL-9 receptor, human IL-9 had a similar antiapoptotic activity, but, unlike the mouse protein, inhibited proliferation. This effect was correlated with the level of receptor expression and the extent of STAT phosphorylation. Expression of a moderate level of suppressor of cytokine signaling 3 (SOCS3) reduced STAT activation by human IL-9 and prevented inhibition of growth but not of apoptosis. Using mutated IL-9 receptors, we showed that inhibition of proliferation was correlated with STAT1 and STAT3 activation by IL-9 and induction of the cell cycle inhibitor p19/ink4d, a STAT3 target gene. Activation of STAT1 by IFN-gamma did not result in cell growth arrest. In this model, cell growth inhibition is therefore associated with a higher number of receptors, a more robust STAT activation, and a greater sensitivity to SOCS3 expression, compared to apoptosis inhibition.

Animals↗

PubMed2000

A MAGE-A3 peptide presented by HLA-DP4 is recognized on tumor cells by CD4+ cytolytic T lymphocytes.

Antigens encoded by MAGE-A3 and recognized by T cells are interesting targets for tumor immunotherapy because they are strictly tumor specific and shared by many tumors of various histological types. A number of MAGE-A3 antigenic peptides presented by HLA class I molecules have been used in clinical trials, and regressions of melanoma metastasis have been observed. We report here the identification of a MAGE-A3 epitope, TQHFVQENYLEY, presented to CD4+ T lymphocytes by HLA-DP4 molecules, which are expressed in approximately 76% of Caucasians. This new epitope may be useful both for therapeutic vaccination and for the evaluation of the immune response in cancer patients. Interest ingly, the CD4+ T cells lysed HLA-DP4 tumor cells expressing MAGE-A3, indicating that this epitope, in contrast to other class-II MAGE-A3 epitopes, is presented at the surface of tumor cells. The study of this disparity in the presentation of two epitopes from the same protein may lead to a better understanding of the endogenous class II presentation pathway.

Animals↗

PubMed2000

IL-9 protects mice from Gram-negative bacterial shock: suppression of TNF-alpha, IL-12, and IFN-gamma, and induction of IL-10.

IL-9 is a T cell-derived cytokine that, similar to the Th2 cytokines IL-4 and IL-10, has been implicated in the response to parasitic infections, allergy, and inflammatory processes. Because both IL-4 and IL-10 can confer protection to mice from septic shock, we investigated whether IL-9 may also be capable of conferring resistance on recipients of an otherwise lethal challenge with Pseudomonas aeruginosa. Prophylactic injections of rIL-9 appeared to be most effective in preventing the onset of a lethal shock, according to a pattern that was both dose dependent and time dependent. The protective effect of IL-9 was correlated with marked decreases in the production of the inflammatory mediators TNF-alpha, IL-12, and IFN-gamma, as well as the induction of the anti-inflammatory cytokine IL-10. Sustained levels of IL-9-specific transcripts could be detected in the spleens of mice recovering from sublethal P. aeruginosa infection. Therefore, IL-9 may be protective in septic shock via a rather unique mechanism involving a complex modulation of inflammatory and anti-inflammatory mediators.

Adjuvants, Immunologic↗

PubMed2000

Signals from the IL-9 receptor are critical for the early stages of human intrathymic T cell development.

Highly purified human CD34+ hemopoietic precursor cells differentiate into mature T cells when seeded in vitro in isolated fetal thymic lobes of SCID mice followed by fetal thymus organ culture (FTOC). Here, this chimeric human-mouse FTOC was used to address the role of IL-9 and of the alpha-chain of the IL-9 receptor (IL-9Ralpha) in early human T cell development. We report that addition of the mAb AH9R7, which recognizes and blocks selectively the human high affinity alpha-chain of the IL-9R, results in a profound reduction of the number of human thymocytes. Analysis of lymphoid subpopulations indicates that a highly reduced number of cells undergo maturation from CD34+ precursor cells toward CD4+CD3-CD8-CD1+ progenitor cells and subsequently toward CD4+CD8+ double positive (DP) thymocytes. Addition of IL-9 to the FTOC resulted in an increase in cell number, without disturbing the frequencies of the different subsets. These data suggest that IL-9Ralpha signaling is critical in early T lymphoid development.

Adjuvants, Immunologic↗

PubMed2000

Anti-IL-9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris muris-infected mice.

Production of neutralizing anti-IL-9 antibodies was induced in mice by immunization with mouse IL-9 coupled to ovalbumin. In the six mouse strains tested, a strong and long-lasting anti-IL-9 response developed with seric inhibitory titers of 10(-3) to 10(-5), as measured in an in vitro IL-9-dependent cell proliferation assay. In vivo, this immunization completely abrogated the increase in mast-cell protease-1 levels as well as the eosinophilia observed in mice after implantation of an IL-9-secreting tumor. We took advantage of this method to assess the role of IL-9 in infections with nematode Trichuris muris, where IL-9 production correlates with the resistant phenotype. C57BL/6 mice, which normally expel the parasite, became susceptible after anti-IL-9 immunization, demonstrating that IL-9 plays a critical role in this model. In addition, neutralization of IL-9 also inhibited parasite-induced blood eosinophilia. Taken together, the present data demonstrate the potency of our strategy to antagonize IL-9 in vivo and shows that this cytokine plays a major role in resistance against T. muris infection.

Animals↗

PubMed2000

An animal model for anaplastic large cell lymphoma in the immunocompetent syngeneic C57Bl/6 mouse.

We report on the analysis of a murine anaplastic lymphoid cell line TS1G6, established recently by interleukin (IL)-9 transfection. TS1G6 revealed a highly characteristic pattern of large anaplastic cells with mononuclear, binuclear, or multinuclear cells resembling Hodgkin (H) or Sternberg-Reed (SR) cells. This cell line is tumorigenous after injection of as few as 10(4) lymphoma cells into nude or immunocompetent C57Bl/6 mice and leads to death from progressive disease of all treated animals within a few weeks. The histological analysis of these tumors revealed a diffuse large cell malignant lymphoma that is morphologically almost identical to human anaplastic large cell lymphoma (ALCL). The lymphoma cells did not show overexpression of the anaplastic lymphoma kinase (ALK) gene, which is found in about 50% of the cases of human ALCL. Thus, this model may be an animal model for an important subset of human ALCL. The cytokine profile, which is of the T helper 2 type, showed strong parallels to the human lymphoma counterpart. Mice suffering from such lymphomas could not be cured with a regimen using high dose cyclophosphamide similar to many ALCL patients. Such an animal model for ALCL has not yet been recognized, but may provide the basis for investigating new antitumor immunotherapies in a fully immunocompetent host.

Anaplastic Lymphoma Kinase↗

PubMed2000

Expression of interleukin-9 leads to Th2 cytokine-dominated responses and fatal enteropathy in mice with chronic Schistosoma mansoni infections.

Mice infected with Schistosoma mansoni develop Th2 cytokine-mediated granulomatous pathology that is focused on the liver and intestines. In this study, transgenic mice constitutively expressing IL-9 were infected with S. mansoni and the outcome of infection was determined. Eight weeks after infection, transgenic mice with acute infections had a moderate increase in Th2 cytokine production but were overtly normal with respect to parasite infection and pathological responses. Transgenic mice with chronic infections died 10 weeks after infection, with 86% of transgenic mice dead by week 12 of infection, compared to 7% mortality in infected wild-type mice. Stimulation of mesenteric lymph node cells from infected transgenic mice with parasite antigen elicited elevated interleukin-4 (IL-4) and IL-5 production and reduced gamma interferon and tumor necrosis factor alpha production compared to the responses in wild-type mice. Morbid transgenic mice had substantial enlargement of the ileum, which was associated with muscular hypertrophy, mastocytosis, eosinophilia, goblet cell hyperplasia, and increased mucin expression. We also observed that uninfected transgenic mice exhibited alterations in their intestines. Although there was hepatic mastocytosis and eosinophilia in infected transgenic mice, there was no hepatocyte damage. Death of transgenic mice expressing IL-9 during schistosome infection was primarily associated with enteropathy. This study highlights the pleiotropic in vivo activity of IL-9 and demonstrates that an elevated Th2 cytokine phenotype leads to death during murine schistosome infection.

Animals↗

PubMed1998

Interleukin-9 enhances resistance to the intestinal nematode Trichuris muris.

Upon infection with the cecum-dwelling nematode Trichuris muris, the majority of inbred strains of mice launch a Th2-type immune response and in doing so expel the parasite before patency. In contrast, there are a few mouse strains which develop a nonprotective Th1-type response resulting in a chronic infection and the presence of adult worms. Of the Th2 cytokines known to be associated with the resistant phenotype (interleukin-4 [IL-4], IL-5, IL-9, and IL-13), comparatively little is known about the contribution that IL-9 makes towards the protective immune response. In this study we demonstrate that IL-9 is expressed early during the Th2-type response and that its elevation in vivo results in the enhancement of intestinal mastocytosis and the production of both the immunoglobulin E (IgE) and IgG1 isotypes. In addition, elevated IL-9 levels in vivo facilitated the loss of T. muris from the intestine. That IL-9 is important in promoting worm expulsion was also seen following infection of IL-9-transgenic mice, which constitutively overexpress the cytokine. These animals displayed an extremely rapid, but immune mediated, expulsion of the parasite. Also evident in these animals was a pronounced intestinal mastocytosis, which was previously shown by us to be responsible for the expulsion of the related nematode Trichinella spiralis from these animals. Taken together with observations of IL-9 production following infection with other helminths, the results imply that IL-9 contributes to the general mast cell and IgE response characteristic of these infections and, more specifically, enhances resistance to T. muris.

Animals↗

PubMed1997

Interleukin-9 is involved in host protective immunity to intestinal nematode infection.

Murine studies have demonstrated that, as with other nematodes, infection with the intestinal nematode Trichinella spiralis is associated with a pronounced intestinal mastocytosis, eosinophilia and an elevation in serum levels of total IgE. Both interleukin (IL)-4 and IL-5 are clearly important in the generation of IgE responses and eosinophilia, respectively, but the control of mucosal mastocytosis in vivo is not as well defined. Mucosal mast cells appear to be particularly important with regard to T. spiralis infections as there is good evidence to suggest their involvement in expulsion of the parasite from the host. In this study we examined the effect of the overproduction of the Th2 cytokine IL-9 on infection with this nematode. We demonstrate that naive IL-9-transgenic mice have an intense intestinal mastocytosis and high serum levels of mouse mast cell protease-1. Moreover, upon infection high titers of parasite-specific IgG1 were observed with a heightened mast cell response, which was associated with the rapid expulsion of T. spiralis from the gut. Furthermore, as depression of this mast cell response, using anti-c-kit antibodies, resulted in the inability of these mice to expel the parasite, this study clearly demonstrates an activity of IL-9 on mucosal mastocytosis and the host protective immune response in vivo.

Animals↗

PubMed1996

I-309/T cell activation gene-3 chemokine protects murine T cell lymphomas against dexamethasone-induced apoptosis.

We have previously reported that cytokines such as IL-9, IL-4, and IL-6 protect murine thymic lymphoma cell lines against dexamethasone-induced apoptosis. A similar activity, which could not be ascribed to any of these factors, was found in a number of human T cell supernatants that enabled mouse BW5147 thymic lymphoma not only to escape apoptosis but also to maintain proliferation. The protein responsible for this activity was purified to homogeneity from the culture medium of activated leukemic T cells and was found to be identical with the I-309 chemokine. Half-maximal anti-apoptotic activity was obtained with approximately 1 ng/ml, a concentration considerably lower than that required for the monocyte chemotactic activity of this molecule, as measured on THP-1 cells. The purified I-309 also improved the survival of two other mouse thymic lymphoma cell lines. This activity was as potent as that of IL-9, which was the strongest anti-apoptotic factor found to date for these cells. Similar results were obtained for BW5147 cells with recombinant I-309 and with T cell activation gene-3, the murine homologue of I-309, but not with other members of the chemokine family, including IL-8, neutrophil-activating peptide-2, granulocyte chemotactic protein-2, macrophage inflammatory protein-1a, RANTES (regulated upon activation, normal T cell expressed and secreted), monocyte chemotactic protein-1 (MCP-1), and MCP-2. MCP-3, however, showed a minor, but significant effect in this model. Unlike that of IL-9, the activity of I-309 was completely inhibited in the presence of pertussis toxin, indicating the involvement of a G protein in this process.

Animals↗

PubMed1996

Differential activity of dexamethasone on IL-2-, IL-4-, or IL-9-induced proliferation of murine factor-dependent T cell lines.

Mouse helper T cell lines were developed that proliferate permanently without Ag and APCs in response to either IL-2, IL-4, or IL-9, three cytokines whose receptors interact with the IL-2R gamma-chain for signal transduction. Depending on the growth factor, a marked difference was observed regarding the ability of dexamethasone (DEX) to inhibit cell proliferation. In three different cell lines, proliferation induced by IL-2 was completely arrested, while that supported by IL-9 was hardly affected. With IL-4, proliferation was also maintained but less markedly than with IL-9. Although DEX was able to induce apoptosis in these cells, the inhibition of IL-2-induced proliferation was not the result of apoptosis, as this process was equally antagonized by all three factors. Moreover, addition of IL-4 or IL-9 to cultures previously incubated with IL-2 and DEX for several days restored cell proliferation. Finally, autonomous cell variants derived from the factor-dependent cell lines were still protected by IL-4 and IL-9 against growth inhibition by DEX. Together, these results indicate that growth stimulation in the presence of glucocorticoids and inhibition of apoptosis involve distinct aspects of cytokine activities.

Animals↗

PubMed1996

Dispensability of Jak1 tyrosine kinase for interleukin-2-induced cell growth signaling in a human T cell line.

The tyrosine kinases Jak1 and Jak3 are known to be associated with the beta and gamma chains of interleukin-2 receptor (IL-2R). They are activated by stimulation with IL-2, IL-4, IL-7, IL-9, or IL-15, receptors of which share the gamma chain of the IL-2R. We have obtained direct evidence of Jak1 association with the alpha chains of receptors for IL-4, IL-7 and IL-9 and with the beta chain of IL-2R, which is also common to the IL-15R. Furthermore, we have prepared mutant IL-2R beta chains with a mutation in the box 1 region, which is conserved among the IL-2R beta chain and the alpha chains of the other cytokine receptors sharing the IL-2R gamma chain. Using MOLT-4 transfectants with the mutant beta chains, we found that two conserved proline residues within the box 1 region are essentially involved in association with Jak1. The MOLT-4 transfectants with the mutant beta chains lacking Jak1 association showed IL-2 responsiveness, in terms of activation of Jak3 and Stat5 and induction of cell growth, indicating that Jak1 is dispensable for IL-2-mediated cell growth signaling and that Jak1 activation is not required for activation of Jak3 and Stat5 in the MOLT-4 transfectants.

Antigens, CD↗

PubMed1996

A single tyrosine of the interleukin-9 (IL-9) receptor is required for STAT activation, antiapoptotic activity, and growth regulation by IL-9.

Interleukin-9 (IL-9), a T-cell-derived cytokine, interacts with a specific receptor associated with the IL-2 receptor gamma chain. In this report, we analyze the functional domains of the human IL-9 receptor transfected into mouse lymphoid cell lines. Three different functions were examined: growth stimulation in factor-dependent pro-B Ba/F3 cells, protection against dexamethasone-induced apoptosis, and Ly-6A2 induction in BW5147 lymphoma cells. The results indicated that a single tyrosine, at position 116 in the cytoplasmic domain, was required for all three activities. In addition, we observed that human IL-9 reduced the proliferation rate of transfected BW5147 cells, an effect also dependent on the same tyrosine. This amino acid was necessary for IL-9-mediated tyrosine phosphorylation of the receptor and for STAT activation but not for IRS-2/4PS activation or for JAK1 phosphorylation, which depended on a domain closer to the plasma membrane. We also showed that JAK1 was constitutively associated with the IL-9 receptor. Activated STAT complexes induced by IL-9 were found to contain STAT1, STAT3, and STAT5 transcription factors. Moreover, sequence homologies between human IL-9 receptor tyrosine 116 and tyrosines (of other receptors activating STAT3 and STAT5 were observed. Taken together, these data indicate that a single tyrosine of the IL-9 receptor, required for activation of three different STAT proteins, is necessary for distinct activities of this cytokine, including proliferative responses.

Amino Acid Sequence↗