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J C Renauld

Publications and source records attributed to J C Renauld.

At least 73 records · Page 4Linked to original sources
PubMed1996

The majority of autologous cytolytic T-lymphocyte clones derived from peripheral blood lymphocytes of a melanoma patient recognize an antigenic peptide derived from gene Pmel17/gp100.

Anti-melanoma cytolytic T-lymphocyte (CTL) clones were derived from peripheral blood lymphocytes of HLA-A2 melanoma patient LB265 after stimulation with the autologous tumor cell line LB265-MEL, which showed high expression of melanocyte-lineage specific genes. Of 55 CTL clones, 46 recognized HLA-A2-restricted antigens. These 46 CTL clones were studied for their ability to specifically release tumor necrosis factor in the presence of COS cells cotransfected with the HLA-A2 gene and the cDNA of either tyrosinase, Melan-A/MART1, Pmel17/gpl00, gp75/TRP1, or MSH receptor. Six CTL clones recognized the Melan-A/MART1 antigen, whereas the remaining 40 CTL clones recognized a Pmel17/gp100 antigen. These 40 anti-PmelI7/gpl00 CTL clones were all able to lyse T2 cells pulsed with the antigenic peptide YLEPGPVTA, as previously reported. The T-cell receptor beta chain hypervariable region was sequenced and found to be identical in the 15 CTL clones analyzed. Taken together, these data show a high frequency of Pmell7/gp100-specific T cells in autologous antitumor CTL clones derived from peripheral blood of a melanoma patient.

Amino Acid Sequence↗
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↗
PubMed1996

A deletion mutant of Pseudomonas exotoxin-A fused to recombinant human interleukin-9 (rhIL-9-ETA') shows specific cytotoxicity against IL-9-receptor-expressing cell lines.

The receptor for human interleukin-9 (hIL-9) might be a target for selective immunotherapy. It is expressed on a variety of malignant cells, including Hodgkin's lymphoma, non-Hodgkin lymphoma and acute myeloid leukemia (AML). We therefore constructed a new chimeric toxin by fusing hIL-9-cDNA to modified Pseudomonas aeruginosa exotoxin A (ETA'). The binding properties of the new recombinant protein, rhIL-9-ETA', were assessed on different cell lines expressing the hIL-9 receptor. The antitumor potency of rhIL-9-ETA' was evaluated against the Hodgkin-derived cell lines L540Cy, KM-H2 and L1236, the Burkitt lymphoma cell line Daudi, the erythroleukemia cell line K562, and the mastocytoma cell line P815-hIL9R, transfected with hIL-9 receptor cDNA. Recombinant hIL-9-ETA' exhibited potent specific cytotoxic effects against P815-hIL9R, K562 and L1236 cells, inhibiting protein synthesis by 50% (IC50) at concentrations of 0.05, 0.58 and 3 micrograms/ml respectively. The cytotoxic effect was abrogated after addition of polyclonal antibodies against the human IL-9. rhIL-9-ETA' might be of potential use against hIL-9R-expressing malignancies.

ADP Ribose Transferases↗
PubMed1995

Costimulation with B7-1, IL-6, and IL-12 is sufficient for primary generation of murine antitumor cytolytic T lymphocytes in vitro.

The requirements for generating CD8+ CTLs against the mastocytoma P815 were first defined by using an allogeneic mixed lymphocyte tumor culture (MLTC). Both the expansion of effector lymphocytes and the acquisition of lytic activity were dependent on the presence of accessory cells, but not CD4+ lymphocytes. Several factors were examined for their ability to replace accessory cell function. Expression of B7-1 by P815 was sufficient to induce IL-2 production by CD8+ cells, but substantial proliferation was achieved only if IL-6 was provided as well. Although IL-12 had little effect on the net proliferation of developing effector cells, it increased specific lytic activity 10-fold, acted synergistically with B7-1 in induction of IFN-gamma production during primary stimulation, and resulted in a shift toward a Th1 cytokine profile following secondary stimulation. These costimulatory factors were then studied in a primary syngeneic MLTC by using splenocytes from nonimmunized DBA/2 mice, an approach that had never before succeeded in generating specific CTLs. The combination of B7-1, IL-6, and IL-12 was sufficient to induce P815-specific CTL activity after a 5-day MLTC, which was expanded optimally following secondary stimulation in the presence of B7-1, IL-2, and IL-7. The irrelevant syngeneic tumor L1210, constructed to express B7-1 and the P815-derived tumor Ag gene P1A, also generated CTLs that lysed the parental P815. The combination of B7-1, IL-6, and IL-12 should be useful in the derivation of other tumor-specific CTLs in vitro, and may constitute the optimal stimuli for rapid proliferation and differentiation of helper-independent, tumor-specific CTLs in vivo.

Animals↗
PubMed1995

IL-9 induces expression of granzymes and high-affinity IgE receptor in murine T helper clones.

Interleukin 9 (IL-9) is a TH2 cytokine that has been shown to promote the antigen-independent growth of some mouse T helper clones. To characterize the specificity of IL-9-mediated T cell activation, we used a murine T cell clone that could grow with either IL-9 or IL-2. After differential hybridization of a cDNA library, we isolated three genes that were expressed preferentially in the presence of IL-9. Two of them correspond respectively to granzyme A and granzyme B, two proteases expressed by activated T cells. By Northern blot hybridization and functional assays, we found that IL-9 induced the expression of granzyme B in several T cell clones as well as in mast cell lines. In addition, other proteases such as the mouse mast cell proteases were also found to be expressed by IL-9-activated T cell clones. The third IL-9-induced cDNA corresponds to the alpha-chain of the high-affinity receptor for IgE. Several T cell clones expressed this IgE receptor mRNA and were able to bind IgE with high affinity. Taken together, our results indicate that IL-9 induces a mast cell-like phenotype in T cell clones.

Animals↗
PubMed1995

A cascade of cytokines is responsible for IL-9 expression in human T cells. Involvement of IL-2, IL-4, and IL-10.

We have previously demonstrated that IL-9 induction in human T cells stimulated with PMA and anti-CD3 Ab is mediated by IL-2, as it was blocked by anti-IL-2R Ab. The experiments reported here indicate that anti-IL-2R Ab also inhibited the expression of IL-4, IL-6, and IL-10, thereby raising the possibility that the blockade of IL-9 production by anti-IL-2R mAb could be secondary to the blockade of these cytokines. We found that the inhibition caused by anti-IL-2R Ab on IL-9 production could be reversed by the addition of a combination of IL-4 and IL-10. Moreover, IL-9 production by T cells stimulated with PMA and anti-CD3 Ab was blocked by the addition of anti-IL-4 and anti-IL-10 Abs. Similar results were obtained with T cells cultured on B7-1/Fc gamma RII-transfected fibroblasts in the presence of anti-CD3 Ab. Analysis of cytokine production by different T cell subsets revealed that IL-4, IL-9, and IL-10 were produced only by CD45 Ro+ T cells. Importantly, CD45 Ra+ T cells were capable of producing IL-9 provided that both IL-4 and IL-10 were added to the cultures. The possible relationship between IL-4 production and IL-10 production was clarified by experiments indicating that IL-10 production was inhibited by anti-IL-4 Ab. However, IL-4 was not sufficient to trigger IL-10 production, which required both IL-2 and IL-4. Taken together, our results demonstrate the existence of a cascade of cytokines responsible for IL-9 expression, with IL-2 being required for IL-4 production, a combination of IL-2 and IL-4 for IL-10 production, and a combination of IL-4 and IL-10 for IL-9 production. Kinetics studies of cytokine gene expression in T cells further validated this model.

Antibodies, Monoclonal↗
PubMed1995

Interleukin-9 is a major anti-apoptotic factor for thymic lymphomas.

We have recently shown that interleukin-9 (IL-9) strongly stimulates the proliferation of mouse thymic lymphomas in vitro. Here we report that this factor is also one of the most potent inhibitors of apoptosis induced by dexamethasone (DEX) in such cell lines, even if they do not depend on exogenous factors for growth. For the murine thymic lymphoma BW5147, protection against apoptosis was also obtained with IL-4 and less strongly with IL-6, whereas IL-2, IL-7, and IL-10 were inactive. Moreover, IL-4 and IL-9 maintained proliferation of these cells in the presence of DEX. Analysis of eight other factor-independent thymic lymphoma lines showed significant protection in seven and six cell lines with IL-9 and IL-4, respectively, whereas only three were protected by IL-7 and only two by IL-2. Comparison of the responses to IL-2 and IL-9 in a factor-dependent cell line that responds to both cytokines showed that IL-2 is a stronger inducer of proliferation, while IL-9 is more efficient in protecting the cells against apoptosis. Taken together, our observations suggest that, for thymic lymphomas, proliferation and apoptosis involve distinct regulatory mechanisms and can be differentially regulated by cytokines.

Alkaloids↗
PubMed1995

Interleukin-9 and its receptor: involvement in mast cell differentiation and T cell oncogenesis.

Interleukin-9 (IL-9) is a multifunctional cytokine produced by activated TH2 clones in vitro and during TH2-like T cell responses in vivo. The IL-9 receptor is a member of the hemopoietin receptor superfamily and interacts with the gamma chain of the IL-2 receptor for signal transduction. Various observations indicate that IL-9 is actively involved in mast cell responses by inducing the proliferation and differentiation of these cells. The role of IL-9 in T cell responses is less clear. Although freshly isolated normal T cells do not respond to IL-9, this cytokine induces the proliferation of murine T cell lymphomas in vitro and in vivo overexpression of IL-9 results in the development of thymic lymphomas. In the human, the existence of an IL-9-mediated autocrine loop has been suggested for some malignancies such as Hodgkin's disease. Other potential biological targets for IL-9 include B lymphocytes, hematopoietic progenitors, and immature neuronal cell lines.

Amino Acid Sequence↗
PubMed1995

BAGE: a new gene encoding an antigen recognized on human melanomas by cytolytic T lymphocytes.

Several tumor antigens are recognized by autologous cytolytic T lymphocytes (CTL) on human melanoma MZ2-MEL. Some of them are encoded by genes MAGE-1 and MAGE-3, which are not expressed in normal tissues except in testis. Here, we report the identification of a new gene that codes for another of these antigens. This gene, named BAGE, codes for a putative protein of 43 aa and seems to belong to a family of several genes. The antigen recognized by the autologous CTL consists of BAGE-encoded peptide AARAVFLAL bound to an HLA-Cw 1601 molecule. Gene BAGE is expressed in 22% of melanomas, 30% of infiltrating bladder carcinomas, 10% of mammary carcinomas, 8% of head and neck squamous cell carcinomas, and 6% of non-small cell lung carcinomas. Like the MAGE genes, it is silent in normal tissues with the exception of testis. Because of its tumor-specific expression, the BAGE-encoded antigen may prove useful for cancer immunotherapy.

Amino Acid Sequence↗
PubMed1995

Serum interleukin 10 titers in systemic lupus erythematosus reflect disease activity.

We investigated whether serum titers of interleukin 10 (IL-10), a cytokine known to shift lymphocyte responses towards humoral immunity, reflect disease activity in systemic lupus erythematosus (SLE). Sera from 72 SLE patients, 25 RA patients and 30 healthy controls were tested for IL-10 by ELISA. Low titers of IL-10 were detected in the serum of 37.5% of SLE patients and in 24% of RA patients but in only 3% of healthy controls. Interestingly, serum IL-10 titers in SLE patients were positively correlated with the SLE Disease Activity Index (SLEDAI) and with anti-DNA antibody titers, but negatively with complement fraction C3 levels. These results indicate that serum IL-10 values reflect SLE disease activity and suggest that overexpression of IL-10 might play a pathogenic role in severe lupus disease.

Adolescent↗
PubMed1995

Cloning and chromosomal localization of a pseudogene corresponding to a mRNA for a soluble IL-6 receptor.

A polymerase chain reaction assay (Lust J.A. et al. (1992). Cytokine 4:96-100) was used to detect a mRNA coding for a soluble IL-6 receptor in human hepatoma cells. In addition to the expected amplification product, we found a sequence (SR4) which could be aligned to it with 78% identity. After cloning and sequencing a genomic 2.5-2.7 kB EcoRI fragment containing SR4, this sequence turned out to be part of a pseudogene corresponding to the transmembrane domain deleted soluble IL-6 receptor. Screening of a panel of interspecies hybrids revealed that it maps to chromosome 9.

Antigens, CD↗
PubMed1994

A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas.

It has been reported previously that antitumor cytolytic T lymphocyte (CTL) clones can be isolated from blood lymphocytes of HLA-A2 melanoma patients, after stimulation in vitro with autologous tumor cells, and that some of these CTL clones lyse most HLA-A2 melanomas. A first antigen recognized by such CTL clones was previously shown to be encoded by the tyrosinase gene. We report here the identification of another gene that also directs the expression of an antigen recognized on most melanomas by CTL clones that are restricted by HLA-A2. The gene, designated Melan-A, is unrelated to any known gene. It is 18 kb long and comprises five exons. Like the tyrosinase gene, it is expressed in most melanoma tumor samples and, among normal cells, only in melanocytes.

Amino Acid Sequence↗
PubMed1994

Thymic lymphomas in interleukin 9 transgenic mice.

Transgenic mice overexpressing the interleukin 9 gene were generated to study the biological activity of this cytokine in vivo. Although no major histological or morphological modifications of the lymphoid system were observed in most animals, approximately 7% of transgenic mice developed thymic lymphomas at the age of 3-9 months. The tumor cells, which were clonal, with unique T cell rearrangements, were double positive for the expression of CD4 and CD8. The need for additional transforming events, suggested by the low incidence of spontaneous tumors, was further indicated by the high susceptibility of the transgenic animals to injections of low doses of N-methyl-N-nitrosourea, a chemical carcinogen with a thymic tropism. Expression of interleukin 9 was required for optimal tumor growth in vivo, as one of the tumors studied, which had lost the transgene, was much more efficiently transplanted into transgenic than in normal mice. Moreover, the in vitro proliferative activity of interleukin 9 on cell lines derived from such transgene-negative tumors suggests that an autocrine loop mediates the proliferation of these cells in vivo. Taken together, these results indicate that dysregulated IL-9 expression could be involved in the development of some T cell malignancies.

Animals↗
PubMed1993

Human T cell lines and clones respond to IL-9.

The activity of IL-9 on human T cells was investigated. Human T cell lines and clones, derived from PBMC by stimulation with PHA, IL-2, and irradiated allogeneic PBMC, were found to express a strong IL-9R message at the RNA level and to proliferate in the presence of IL-9, irrespectively of their CD4+ or CD8+ phenotype. Moreover, tumor-specific CTL clones also responded to IL-9. Contrasting with other T cell growth factors, such as IL-2, IL-4, or IL-7, IL-9 did not induce the proliferation of freshly isolated T cells. However, a significant proliferative response to IL-9 could be observed after a 10-day activation of PBMC with PHA, IL-2, and feeders. Taken together, our results indicate 1) that the activity of IL-9 on human T cells is wider than initially anticipated on the basis of the data obtained so far with murine cells; and 2) that proliferative responses to IL-9 require previous activation.

Cell Line↗
PubMed1993

Interleukin-9 stimulates in vitro growth of mouse thymic lymphomas.

The ability of interleukin (IL)-9 to stimulate the in vitro proliferation of freshly collected mouse thymic lymphoma cells was tested on a panel of 45 tumors, induced by N-methyl-N-nitrosourea (MNU) or by X-ray irradiation. IL-9 significantly stimulated the proliferation of 26 of these tumors. Out of 11 other factors tested, only IL-2, IL-4 and IL-7 showed similar activities. In addition to the responses to IL-9 alone, a potent synergy was often observed between IL-9 and IL-2 for MNU-induced tumors. Synergies between IL-9 and IL-7 or IL-9 and IL-4 were also observed but less frequently. The growth-promoting activity of IL-9 and the synergistic activities of IL-2 and IL-9 for thymic lymphoma cells were confirmed with cell lines established from the fresh tumors.

Animals↗
PubMed1993

Interleukin-9 potentiates the interleukin-4-induced immunoglobulin (IgG, IgM and IgE) production by normal human B lymphocytes.

IgE production by normal peripheral blood lymphocytes (PBL) is known to be triggered upon stimulation by interleukin (IL)-4. In the present study we showed that IL-9, another T cell-derived cytokine, markedly potentiated IgE production induced by suboptimal doses of IL-4, whereas no effect of IL-9 was observed in the absence of IL-4. The potentiating effect of IL-9 appeared to be associated with the increased frequency of IgE-producing cells, as revealed by a specific ELISA-spot assay. Under the same experimental conditions, IL-9 also enhanced the IL-4-induced IgG production but did not elicit IgM production. However, IL-9 did not amplify the IL-4-dependent expression of membrane-bound and soluble low affinity receptor for IgE (CD23). IL-4-induced IgE production was also potentiated by IL-6 but not by tumor necrosis factor-alpha and IL-1 beta. The possibility that the activity of IL-9 was mediated by IL-6 released from accessory cells was excluded by the observations that monocyte depletion did not abolish the effect of IL-9 and that IL-9 was still active on fluorescence-assisted cell sorted CD20+ B lymphocytes co-cultured with irradiated murine EL4 cells. In addition, IL-9 was shown to potentiate the IL-4-induced IgG and IgM production by normal human B lymphocytes preactivated with Staphylococcus aureus Cowan strain. Taken together, these data suggest that IL-9 plays a regulatory role in the IL-4-dependent immunoglobulin production.

Antibody Formation↗