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T Boon

Publications and source records attributed to T Boon.

At least 19 recordsLinked to original sources
PubMed2002

A MAGE-3 peptide presented by HLA-B44 is also recognized by cytolytic T lymphocytes on HLA-B18.

Antigens encoded by MAGE genes are of particular interest for cancer immunotherapy because of their tumoral specificity and because they are shared by many tumors. Antigenic peptide MEVDPIGHLY, which is encoded by MAGE-3 and is known to be presented by human leukocyte antigen (HLA)-B44, is currently being used in therapeutic vaccination trials. We report here that a cytolytic T lymphocyte (CTL) clone, which is restricted by HLA-B*1801, recognizes the same peptide and, importantly, lyzes HLA-B18 tumor cells expressing MAGE-3. These results imply that the use of peptide MEVDPIGHLY can now be extended to HLA-B18 patients. We also provide evidence that, under limiting amounts of protein MAGE-3, HLA B*1801 and B*4403 compete for binding to the peptide.

Antigen Presentation↗
PubMed2001

A monoclonal cytolytic T-lymphocyte response observed in a melanoma patient vaccinated with a tumor-specific antigenic peptide encoded by gene MAGE-3.

Vaccination of melanoma patients with tumor-specific antigens recognized by cytolytic T lymphocytes (CTL) produces significant tumor regressions in a minority of patients. These regressions appear to occur in the absence of massive CTL responses. To detect low-level responses, we resorted to antigenic stimulation of blood lymphocyte cultures in limiting dilution conditions, followed by tetramer analysis, cloning of the tetramer-positive cells, and T-cell receptor (TCR) sequence analysis of the CTL clones that showed strict specificity for the tumor antigen. A monoclonal CTL response against a MAGE-3 antigen was observed in a melanoma patient, who showed partial rejection of a large metastasis after treatment with a vaccine containing only the tumor-specific antigenic peptide. Tetramer analysis after in vitro restimulation indicated that about 1/40,000 postimmunization CD8(+) blood lymphocytes were directed against the antigen. The same TCR was present in all of the positive microcultures. TCR evaluation carried out directly on blood lymphocytes by PCR amplification led to a similar frequency estimate after immunization, whereas the TCR was not found among 2.5 x 10(6) CD8(+) lymphocytes collected before immunization. Our results prove unambiguously that vaccines containing only a tumor-specific antigenic peptide can elicit a CTL response. Even though they provide no information about the effector mechanisms responsible for the observed reduction in tumor mass in this patient, they would suggest that low-level CTL responses can initiate tumor rejection.

Antigens, Neoplasm↗
PubMed2001

An overview of the MAGE gene family with the identification of all human members of the family.

The first human members of the MAGE gene family that have been described are expressed in tumor cells but silent in normal adult tissues except in the male germ line. Hence, they encode strictly tumor-specific antigens that represent attractive targets for cancer immunotherapy. However, other members of the family were recently found to be expressed in normal cells, indicating that the family is larger and more disparate than initially expected. We therefore performed a database screening to identify all of the recorded members of both classes of human MAGE genes. This report provides an overview of the MAGE family and proposes a general nomenclature for all of the MAGE genes identified thus far. We found that the MAGE-D genes were particularly well conserved between man and mouse, suggesting that they exert important functions. In addition, the genomic structure of the MAGE-D genes indicates that one of them corresponds to the founder member of the family, and that all of the other MAGE genes are retrogenes derived from that common ancestral gene. Intriguingly, the COOH-terminal domain of MAGE-D3 was found to be identical to trophinin, a previously described protein believed to be involved in embryo implantation.

Amino Acid Sequence↗
PubMed2001

An alternative open reading frame of the human macrophage colony-stimulating factor gene is independently translated and codes for an antigenic peptide of 14 amino acids recognized by tumor-infiltrating CD8 T lymphocytes.

We show that cytotoxic T lymphocytes (CTLs) infiltrating a kidney tumor recognize a peptide encoded by an alternative open reading frame (ORF) of the macrophage colony-stimulating factor (M-CSF) gene. Remarkably, this alternative ORF, which is translated in many tumors concurrently with the major ORF, is also translated in some tissues that do not produce M-CSF, such as liver and kidney. Such a dissociation of the translation of two overlapping ORFs from the same gene is unexpected. The antigenic peptide encoded by the alternative ORF is presented by human histocompatibility leukocyte antigen (HLA)-B*3501 and has a length of 14 residues. Peptide elution indicated that tumor cells naturally present this 14 mer, which is the longest peptide known to be recognized by CTLs. Binding studies of peptide analogues suggest that it binds by its two extremities and bulges out of the HLA groove to compensate for its length.

Amino Acid Sequence↗
PubMed2001

High frequency of cytolytic T lymphocytes directed against a tumor-specific mutated antigen detectable with HLA tetramers in the blood of a lung carcinoma patient with long survival.

We have identified an antigen recognized by autologous CTL on the lung carcinoma cells of a patient who enjoyed a favorable clinical evolution, being alive 10 years after partial resection of the primary tumor. The antigenic peptide is presented by HLA-A2 molecules and encoded by a mutated sequence in the gene coding for malic enzyme, an essential enzyme that converts malate to pyruvate. In the tumor cell line derived from the patient, only the mutated malic enzyme allele is expressed, because of a loss of heterozygosity in the region of chromosome 6 that contains this locus. Tetramers of soluble HLA-A2 molecules loaded with the antigenic peptide stained approximately 0.4% of the patient's blood CD8 T cells. When these cells were stimulated in clonal conditions, 25% of them proliferated, and the resulting clones were lytic and specific for the mutated malic enzyme peptide. T-cell receptor analysis indicated that almost all of these antimalic CTLs shared the same receptor. Antimalic T cells were consistently found in blood samples collected from the patient between 1990 and 1999, at frequencies ranging from 0.1 to 0.4% of the CD8 cells. Their frequency appeared to double within 2 weeks after intradermal inoculation of lethally irradiated autologous tumor cells. These results indicate that nonmelanoma cancer patients may also have a high frequency of blood CTLs directed against a tumor-specific antigen.

Amino Acid Sequence↗
PubMed2001

Sequencing of the coding exons of the LRP1 and LDLR genes on individual DNA samples reveals novel mutations in both genes.

Five coding polymorphisms in de LRP1 gene, i.e. A217V, A775P, D2080N, D2632E and G4379S were discovered by sequencing its 89 exons in three test-groups of 22 healthy individuals, 29 Alzheimer patients and 18 individuals with different clinical and molecularly uncharacterized lipid metabolism problems. No genetic defect was evident in the LRP1 gene of any of the Alzheimer's disease (AD) patients, further excluding LRP1 as a major genetic problem in AD. Lipoprotein receptor related protein (LRP) A217V (exon 6) was clearly present in all groups as a polymorphism, while D2632E was observed only once in a healthy volunteer. On the other hand, LRP1 alleles A775P, D2080N, and G4379 were encountered only in patients with FH or with undefined problems of lipid metabolism. This finding forced one to also analyze the LDL receptor (LDLR) gene, for which a method was devised to sequence the entire region comprising LDLR exons 2-18. The resulting sequence contig of 33567 nucleotides yielded finally an exact physical map that corrects published and listed LDLR gene maps in many positions. In addition, next to known mutations in LDLR that cause FH, four novel LDLR defects were defined, i.e. del e7-10, exon 9 mutation N407T, a 20 bp insertion in exon 4, and a double mutation C292W/K290R in exon 6. No evidence for pathology connected to the LRP1 'mutations' was obtained by subsequent screening for the five LRP1 variants in larger groups of 110 FH patients and 118 patients with molecularly undefined, clinical problems of cholesterol and/or lipid metabolism. In three individuals with a mutant LDLR gene a variant LRP1 allele was also present, but without direct, obvious clinical compound effects, indicating that the variant LRP1 alleles must, for the present, be considered polymorphisms.

Adolescent↗
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

Induction of cytolytic T lymphocytes by immunization of mice with an adenovirus containing a mouse homolog of the human MAGE-A genes.

The genes of the MAGE-A family code for antigens that are strictly tumor-specific and are shared by many human tumors. Melanoma patients have been immunized against these antigens and some tumor regressions have been observed. However, no unequivocal evidence of cytolytic T cell responses has been obtained by analyzing the blood lymphocytes of these patients. Hence it was considered worthwhile to examine in mouse systems whether or not immunization against antigens derived from the mouse Mage homologs can produce cytolytic T cell responses. We have identified an antigenic peptide encoded by mouse gene Mage-a2, and here we show that immunization of DBA/2 mice with a recombinant adenovirus containing either just the sequence encoding this peptide or a large part of the Mage-a2 coding sequence produces strong cytolytic T cell responses. The Mage-a2 system should prove useful for the comparison of vaccination modalities that could be applied to human patients in therapeutic vaccination trials with MAGE antigens.

Adenoviridae↗
PubMed2001

A MAGE-3 peptide recognized on HLA-B35 and HLA-A1 by cytolytic T lymphocytes.

Antigens encoded by MAGE genes are of particular interest for cancer immunotherapy because of their strict tumoral specificity and because they are shared by many tumors. Antigenic peptide EVDPIGHLY encoded by MAGE-3 and known to be presented by HLA-A*0101 is currently being used in therapeutic vaccination trials. We report here that a cytolytic T-lymphocyte (CTL) clone, which is restricted by HLA-B*3501, recognizes the same peptide and, importantly, lyses HLA-B*3501 tumor cells expressing MAGE-3. These results infer that the current clinical use of peptide EVDPIGHLY can now be extended to HLA-B*3501 patients.

Amino Acid Sequence↗
PubMed2001

Expressive puppetry in hospice care.

As treatments for cancers and other illnesses continue to improve, hospices must develop their programs to serve those with chronic illnesses in order to continue to be relevant in end-of-life care. One hospice has found a modality, called Expressive Puppetry, to improve the quality of life for many dementia patients.

Aged↗
PubMed2000

Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice.

Protein tau filaments in brain of patients suffering from Alzheimer's disease, frontotemporal dementia, and other tauopathies consist of protein tau that is hyperphosphorylated. The responsible kinases operating in vivo in neurons still need to be identified. Here we demonstrate that glycogen synthase kinase-3beta (GSK-3beta) is an effective kinase for protein tau in cerebral neurons in vivo in adult GSK-3beta and GSK-3beta x human tau40 transgenic mice. Phosphorylated protein tau migrates slower during electrophoretic separation and is revealed by phosphorylation-dependent anti-tau antibodies in Western blot analysis. In addition, its capacity to bind to re-assembled paclitaxel (Taxol((R)))-stabilized microtubules is reduced, compared with protein tau isolated from mice not overexpressing GSK-3beta. Co-expression of GSK-3beta reduces the number of axonal dilations and alleviates the motoric impairment that was typical for single htau40 transgenic animals (Spittaels, K., Van den Haute, C., Van Dorpe, J., Bruynseels, K., Vandezande, K., Laenen, I., Geerts, H., Mercken, M., Sciot, R., Van Lommel, A., Loos, R., and Van Leuven, F. (1999) Am. J. Pathol. 155, 2153-2165). Although more hyperphosphorylated protein tau is available, neither an increase in insoluble protein tau aggregates nor the presence of paired helical filaments or tangles was observed. These findings could have therapeutic implications in the field of neurodegeneration, as discussed.

Alzheimer Disease↗
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

Identification of a tumor-specific shared antigen derived from an Eph receptor and presented to CD4 T cells on HLA class II molecules.

We obtained a lytic CD4 T-cell clone that recognized an antigen presented by HLA-DRB1*1101 on the tumor cells of a melanoma patient who enjoyed an unusually favorable clinical evolution. The antigen appeared to be shared between several melanoma cell lines. To identify the encoding gene, we used a new method, based on the cotransfection into human embryonal kidney cell line 293 of a cDNA library from the tumor together with a cDNA clone encoding the class II transactivator, which induces the expression of HLA class II molecules. The product of the gene coding for the antigenic peptide is EphA3, a member of the Eph family of tyrosine kinase receptors, which mediate the repulsion of neural cells by cells carrying the ligand Ephrins on their surface. EphA3 is expressed at a high level in the retina and fetal brain, at a lower level in several normal tissues, and not at all in hematopoietic cells, the only cells that constitutively express HLA class II molecules. It is overexpressed in several types of tumors, including melanoma, lung carcinoma, and sarcoma. On the basis of this pattern of expression, EphA3 may be a source of tumor-specific antigens recognized on tumor cells that express HLA class II molecules. Anti-EphA3 T cells may have participated in a tumor rejection response in the patient, because the cells of metastases collected several years later than the metastasis used to characterize the antigen had lost expression of HLA-DR or EphA3, therefore escaping recognition by these lymphocytes.

Amino Acid Sequence↗
PubMed2000

Identification on a human sarcoma of two new genes with tumor-specific expression.

Genes MAGE, BAGE, GAGE, and LAGE-1/NY-ESO-1 code for antigens that are recognized on melanoma cells by autologous CTLs. Because the pattern of expression of these genes results in the presence of antigens on many tumors of various histological types and not on normal tissues, these antigens qualify for cancer immunotherapy. To identify new genes with tumor-specific expression, we applied a cDNA subtraction approach, ie., representational difference analysis, to a human sarcoma cell line. We obtained two cDNA clones that appeared to be tumor specific. The corresponding genes were named SAGE and HAGE because they have the same pattern of expression as genes of the MAGE family. SAGE encodes a putative protein of 904 amino acids and shows no homology to any recorded gene. Like the MAGE-A genes, it is located in the q28 region of chromosome X. Expression of gene SAGE was observed mainly in bladder carcinoma, lung carcinoma, and head and neck carcinoma but not in normal tissues, with the exception of testis. Gene HAGE, which is located on chromosome 6, encodes a putative protein of 648 amino acids. This protein is a new member of the DEAD-box family of ATP-dependent RNA helicases. Gene HAGE is expressed in many tumors of various histological types at a level that is 100-fold higher than the level observed in normal tissues except testis. Because of this tumor-specific expression, genes SAGE and HAGE ought to encode antigens that could be useful for antitumoral therapeutic vaccination.

Amino Acid Sequence↗
PubMed2000

MAGE-B5, MAGE-B6, MAGE-C2, and MAGE-C3: four new members of the MAGE family with tumor-specific expression.

A number of genes of the MAGE-A, B, and C families have been shown to code for antigens that are recognized on many human tumors by autologous cytolytic T lymphocytes. These antigens ought to be strictly tumor specific because the encoding MAGE genes are not expressed in normal adult cells except for male germline cells, which lack HLA expression. To identify new genes of this type, we performed representational difference analysis on a melanoma cell line by subtraction with a normal skin sample. This led to the identification of MAGE-C2, a new member of the MAGE-C family. A search for nucleotide sequences encoding MAGE-like proteins in public databases led to the identification of three additional MAGE genes, which were named MAGE-B5, MAGE-B6, and MAGE-C3. The four new MAGE genes are not expressed in normal tissues, except for testis, and are expressed in tumors of different histological origins. Therefore, like other MAGE genes expressed specifically in tumors, MAGE-B5, MAGE-B6, MAGE-C2, and MAGE-C3 ought to encode antigens that could be targets for cancer immunotherapy.

Alleles↗
PubMed2000

Monoclonal antibody 57B stains tumor tissues that express gene MAGE-A4.

Monoclonal antibody (Mab) 57B, which was raised against a recombinant MAGE-A3 protein, was tested for its ability to stain cells expressing various members of the MAGE-A gene family. COS-7 cells transfected with cDNAs encoding MAGE-A1, A2, A3, A4, A6, or A12 were stained, whereas those transfected with MAGE-A8, A9, A10, or A11 cDNAs were not. However, in tissue sections, we observed a different pattern of staining: the antibody effectively stained the tumors that expressed MAGE-A4 and only these tumors, regardless of the expression of the other MAGE-A genes. It seems, therefore, that at the level of MAGE gene expression found in tumors, a level clearly lower than that observed in transfected COS cells, only the MAGE-A4 protein can be reliably detected. We conclude that the 57B Mab should be useful for tumor diagnosis related to therapeutic vaccination involving MAGE-A4.

Animals↗
PubMed2000

Cytolytic T lymphocytes raised against a human bladder carcinoma recognize an antigen encoded by gene MAGE-A12.

Human bladder carcinoma line LB831-BLC expresses several distinct Ags that are recognized by different autologous CTL. Here, we show that one of these Ags is presented by HLA-Cw7 and encoded by gene MAGE-A12. This is the first time that CTL directed against a MAGE-encoded Ag have been derived from the lymphocytes of a patient with cancer other than melanoma. This new Ag was found to be nonapeptide VRIGHLYIL, corresponding to position 170-178 of the MAGE-A12 protein. Gene MAGE-A12 is silent in normal tissues except in male germline cells, which do not express HLA molecules. It is expressed in 26-62% of melanomas, infiltrating bladder carcinomas, lung carcinomas, esophageal carcinomas, and head and neck carcinomas. Because HLA-Cw7 is present in 43% of Caucasians, this new Ag is shared by many tumors and should be a useful target for cancer immunotherapy.

Aged↗