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11 results on '"HLA A antigen"'

1. The australian and new zealand living kidney donor profile index.

Author

Kanellis J., Irish G., Chadban S., Boudville N., Clayton P.A., Campbell S., Kanellis J., Irish G., Chadban S., Boudville N., Clayton P.A., and Campbell S.

Abstract

Aim: We developed a risk prediction score for overall graft survival in adult recipients of a living kidney donor transplant in an Australian and New Zealand population. Background(s): Risk scores may aid risk quantification and decision-making in kidney transplantation. The Living Kidney Donor Profile Index (LKDPI) was developed to choose between living donors. The original LKDPI is not discriminatory (C = 0.59, 95% CI 0.55-0.62) or well calibrated in Australia/New Zealand. Method(s): Using data from the Australia and New Zealand Dialysis and Transplant Registry, we included adult recipients of living kidney donor transplants over 2004-2018. We constructed Cox models for overall graft survival. We refit the original USA variables and constructed a new model considering all available potential covariates. Model performance was examined by partial validation, bootstrapping, Harrell's C-statistic (C) and Akaike information criterion (AIC). Result(s): 4049 living donors were included; 58.2% were female, 10.4% had hypertension and 18.7% were obese. For the original USA LKDPI the variables of both male and donor: recipient weight ratio were mis-specified. The C-statistic for the re-fit model was 0.57 (95%CI 0.54-0.59). When remodelling the score, the new variables included were history of hypertension and HLA-A mismatches. Variables excluded were donor: recipient weight ratio, HLA-B, both male, and ABO incompatibility. The Aus/NZ LKDPIC-statistic was 0.56 (95%CI 0.54-0.58). Calibration was similar but the Aus/NZ LKDPI had better model fit (AIC: 10402 vs. 11 023). Conclusion(s): The Aus/NZ LKDPI had similar discrimination to the original LKDPI and the LKDPI with adjusted coefficients. The discrimination was low for both scores and so should be used with caution to decide between donors. The new score is better calibrated for our population so could be used to predict graft prognosis.

Published
2021

2. 5-Fluorouracil–Based Chemotherapy Enhances the Antitumor Activity of a Thymidylate Synthase–Directed Polyepitopic Peptide Vaccine

Author

Marzio Vestri, Enzo Bonmassar, Gianni Gori Savellini, Marco La Placa, Angelo Aquino, Guido Francini, Giorgio Giorgi, François Lemonnier, Giuseppa Di Genova, Renato Urso, Maria Teresa Del Vecchio, Pierpaolo Correale, Chiara Terrosi, and Maria Grazia Cusi

Subjects
Cytotoxic, Cytotoxicity, medicine.medical_treatment, animal cell, colon carcinoma, cancer cell culture, Thymidylate synthase, Transgenic, Epitope, fluorouracil, Epitopes, Mice, Antineoplastic Combined Chemotherapy Protocols, Cytotoxic T cell, Isogeneic, antineoplastic antimetabolite, target cell, epitope, drug effect, Settore BIO/14, Flow Cytometry, Antineoplastic, Immunohistochemistry, peptide, priority journal, Oncology, mouse strain, Antimetabolites, Antineoplastic, Transfection, in vivo study, Humans, human, protein expression, mouse, drug potentiation, human cell, Dendritic Cells, Immunotherapy, culture technique, transgenic mouse, Transplantation, Isogeneic, CTL, T-Lymphocyte, Cancer cell, Immunology, Peptide vaccine, genetic transfection, Peptides, T-Lymphocytes, Cytotoxic, Cytotoxicity, Immunologic, Cancer Research, peripheral blood mononuclear cell, Lymphoma, Antimetabolites, Settore MED/06 - Oncologia Medica, T-Lymphocytes, Cell Culture Techniques, Epitopes, T-Lymphocyte, major histocompatibility antigen class 1, cytotoxic T lymphocyte, carcinoma, immunology, thymidylate synthase directed polyepitopic peptide vaccine, Immunologic, antigen binding, animal, breast carcinoma, antineoplastic agent, HLA A antigen, breast tumor, apoptosis, article, colon tumor, unclassified drug, enzyme activity, female, Colonic Neoplasms, cancer vaccine, dendritic cell, Mice, Transgenic, Breast Neoplasms, thymidylate synthase, antineoplastic activity, cellular immunity, isograft, Biology, interleukin 2, Cancer Vaccines, Immune system, medicine, Animals, concentration response, immunohistochemistry, nonhuman, cytotoxicity, flow cytometry, lymphoma, metabolism, Carcinoma, Female, Fluorouracil, HLA-A Antigens, Thymidylate Synthase, Transplantation, Cancer research, biology.protein
Abstract

Background: Thymidylate synthase (TS), a key enzyme in DNA synthesis, is often overexpressed in cancer cells. Some chemotherapeutic agents, such as 5-fluorouracil (5-FU), act by inhibiting TS expression. We evaluated whether a novel 28-amino acid multiepitope peptide, TS/PP, that contains the sequences of three TS-derived epitopes with binding motifs for HLA-A(*)02.01 could induce a TS-directed cytotoxic T-lymphocyte (CTL) response with antitumor activity. Methods: TS/PP peptide immunologic activity in CTL lines derived from human leukocyte antigen (HLA)-A(*)02.01 + peripheral blood mononuclear cells (PBMCs) was tested in the presence of interleukin-2 and autologous TS/PP peptide-loaded dendritic cells. Immunologic and antitumor activities of TS/PP and its toxicity were also evaluated in vivo in HLA-A(*)02.01 transgenic (HHD) mice that were vaccinated with TS/PP, control, or TS-peptide cocktail and treated with or without 5-FU chemotherapy. The mice were also inoculated subcutaneously with TS-expressing EL-4/HHD lymphoma cells to assess immune response against these tumor cells. Results: TS/PP-specific CTL lines showed a TS-multiepitopic specificity and were able to kill TS + /HLA-A(*)02.01 + breast and colon carcinoma cells. The killing ability against target cells previously exposed to sublethal doses of 5-FU was statistically significantly greater than against untreated target cells (43.5% versus 26.5% at 25/1 effector to target ratio [Difference {diff} = 17.0]; 95% confidence interval [CI] = 12.6 to 20.4) for MDA-MB-231 breast carcinoma cells and 73.5 versus 48.5 (diff = 25.0; 95% CI = 16.2 to 33.8) for the SW-1463 colon carcinoma cells. HHD mice vaccinated with TS/PP manifested a TS-peptide-specific CTL response with no sign of autoimmunity or toxicity. Furthermore, treatment of these mice with 5-FU delayed or prevented the occurrence of tumors formed by inoculation with autologous (TS + )EL-4/HHD lymphoma cells. Conclusions: The multiepitopic TS/PP vaccine induces a tumor-specific immune response in mice and is especially potent when used in combination with 5-FU-based chemotherapy.

Published
2005
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3. ERAP2 functional knockout in humans does not alter surface heavy chains or HLA-B27, inflammatory cytokines or endoplasmic reticulum stress markers

Author

Robinson, Philip, Lau, Eugene, Keith, Patricia, Lau, Max, Thomas, Gethin, Bradbury, Linda, Brown, Matthew, Kenna, Tony, Robinson, Philip, Lau, Eugene, Keith, Patricia, Lau, Max, Thomas, Gethin, Bradbury, Linda, Brown, Matthew, and Kenna, Tony

Abstract

Introduction Single nucleotide polymorphisms in ERAP2 are strongly associated with ankylosing spondylitis (AS). One AS-associated single nucleotide polymorphism, rs2248374, causes a truncated ERAP2 protein that is degraded by nonsense-mediated decay. Approximately 25% of the populations of European ancestry are therefore natural ERAP2knockouts. We investigated the effect of this associated variant on HLA class I allele presentation, surface heavy chains, endoplasmic reticulum (ER) stress markers and cytokine gene transcription in AS. Methods Patients with AS and healthy controls with either AA or GG homozygous status for rs2248374 were studied. Antibodies to CD14, CD19-ECD, HLA-A-B-C, Valpha7.2, CD161, anti-HC10 and anti-HLA-B27 were used to analyse peripheral blood mononuclear cells. Expression levels of ER stress markers (GRP78 and CHOP) and proinflammatory genes (tumour necrosis factor (TNF), IL6, IL17 and IL22) were assessed by qPCR. Results There was no significant difference in HLA-class I allele presentation or major histocompatibility class I heavy chains or ER stress markers GRP78 and CHOP or proinflammatory gene expression between genotypes for rs2248374 either between cases, between cases and controls, and between controls. Discussion Large differences were not seen in HLA-B27 expression or cytokine levels between subjects with and without ERAP2 in AS cases and controls. This suggests that ERAP2 is more likely to influence AS risk through other mechanisms.

Published
2015

4. Activation of innate immune responses by Haemophilus influenzae lipooligosaccharide

Author

William McCready, Marina Ulanova, Andrew D. Cox, Joshua Choi, and Jianjun Li

Subjects
Lipopolysaccharides, interleukin 1beta, Lipopolysaccharide, pattern recognition receptor, Clinical Biochemistry, Nod2 Signaling Adaptor Protein, lipooligosaccharide, HLA DR antigen, medicine.disease_cause, Monocytes, Haemophilus influenzae, CD40 antigen, chemistry.chemical_compound, toll like receptor 4, HLA Antigens, Immunology and Allergy, immunostimulation, Receptors, Immunologic, lipid A, innate immunity, Vaccines, tumor necrosis factor alpha, HLA A antigen, Pattern recognition receptor, adaptive immunity, matrix assisted laser desorption ionization time of flight mass spectrometry, Acquired immune system, Intercellular Adhesion Molecule-1, HLA C antigen, intercellular adhesion molecule 1, monocyte, Cytokines, Tumor necrosis factor alpha, cytokine response, Microbiology (medical), Immunology, Biology, CD86 antigen, Microbiology, Proinflammatory cytokine, Cell Line, lymphocyte function associated antigen 3, Antigens, CD, caspase recruitment domain protein 4, medicine, Escherichia coli, Humans, protein expression, CD86, HLA B antigen, Innate immune system, caspase recruitment domain protein 15, Gene Expression Profiling, human cell, bacterial strain, Immunity, Innate, antigen presentation, chemistry, gene expression, interleukin 10, upregulation
Abstract

A Gram-negative pathogenHaemophilus influenzaehas a truncated endotoxin known as lipooligosaccharide (LOS). Recent studies onH. influenzaeLOS highlighted its structural and compositional implications for bacterial virulence; however, the role of LOS in the activation of innate and adaptive immunity is poorly understood. THP-1 monocytes were stimulated with either lipopolysaccharide (LPS) fromEscherichia colior LOS compounds derived fromH. influenzaeEagan, Rd, and Rdlic1 lpsAstrains. Cell surface expression of key antigen-presenting, costimulatory, and adhesion molecules, as well as gene expression of some cytokines and pattern recognition receptors, were studied. Eagan and Rd LOS had a lower capacity to induce the expression of ICAM-1, CD40, CD58, tumor necrosis factor alpha (TNF-α), and interleukin-1β (IL-1β) compared to LPS. In contrast, antigen-presenting (HLA-ABC or HLA-DR) and costimulatory (CD86) molecules and NOD2 were similarly upregulated in response to LOS and LPS. LOS from a mutant Rd strain (Rdlic1 lpsA) consistently induced higher expression of innate immune molecules than the wild-type LOS, suggesting the importance of phosphorylcholine and/or oligosaccharide extension in cellular responses to LOS. An LOS compound with a strong ability to upregulate antigen-presenting and costimulatory molecules combined with a low proinflammatory activity may be considered a vaccine candidate to immunize againstH. influenzae.

Published
2014
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5. A novel approach for HLA-A typing in formalin-fixed paraffin-embedded-derived DNA

Author

Barbara Seliger, Daniel A Leon Rodriguez, Giuseppe Masucci, Lisa Villabona, Emilia Andersson, and Tina Dalianis

Subjects
Blood sampling, Dna extraction, Primer dna, Gene sequence, Procedures, Polymerase Chain Reaction, Ovarian neoplasms, law.invention, chemistry.chemical_compound, law, Gene duplication, Hla a antigen, Molecular genetics, Polymerase chain reaction, Priority journal, Genetics, Allele, Ovarian Neoplasms, Ovarian cancer sequencing, Paraffin Embedding, Histocompatibility Testing, Genetic analysis, Exons, HLA-A, Paraffin, Female, Hla-a antigens, Dna primers, Histocompatibility testing, Histocompatibility test, Human, Ovary cancer, Clinical article, Molecular Sequence Data, Exon, Human leukocyte antigen, Biology, Dna polymorphism, Article, Pathology and Forensic Medicine, Paraffin embedding, Fixatives, Molecular sequence data, Formaldehyde, Humans, Typing, Human tissue, Formalin-fixed paraffin-embedded tissue, Gene, Dna fingerprinting, Alleles, DNA Primers, Gene amplification, Base Sequence, HLA-A Antigens, Gene Amplification, Hla typing, Dna, DNA, Molecular biology, Base sequence, chemistry, Ovary tumor, Fixative, Controlled study, Nucleotide sequence
Abstract

The aim of this study was to establish a novel approach for human leukocyte antigen (HLA)-typing from formalin-fixed paraffin-embedded-derived DNA. HLAs can be a prognostic factor in cancer and have an extensive polymorphism. This polymorphism is predominantly restricted to exons, which encode the peptide-binding domain of the protein. Formalin-fixed paraffin-embedded material is routinely collected in the clinic and therefore a great source of DNA for genetic analyses. However, its low quality due to fragmentation and nucleotide changes has often created obstacles in designing genetic assays. In this study, we amplified the most polymorphic exons of the HLA-A gene, exons 2, 3, and 4, in 16 formalin-fixed paraffin-embedded samples >10 years old. These tissue samples belonged to patients already HLA-typed by peripheral blood samples at the routine laboratory. Acquired amplification products were used for sequencing, which provided enough information to establish an HLA allele. The same method was applied to DNA extracted from peripheral blood from a healthy volunteer with known HLA type. Of the samples, 14/16 (88%) were successfully typed, in one sample only one of the alleles could be determined, and in one sample no allele could be determined. The amplification of the most polymorphic exons of HLA-A was a successful alternative when DNA quality prevented positive results with previously described methods. The method is usable when an HLA type is needed but the patients are deceased and/or no whole blood samples can be collected. It has thus potential to be used in several fields such as the clinic, research, and forensic science. © 2014 USCAP, Inc All rights reserved.

Published
2013

6. Monocyte-derived dendritic cells loaded with a mixture of apoptotic/ necrotic melanoma cells efficiently cross-present gp100 and MART-1 antigens to specific CD8+ T lymphocytes

Author

von Euw, E.M., Barrio, M.M., Furman, D., Bianchini, M., Levy, E.M., Yee, C., Li, Y., Wainstok, R., and Mordoh, J.

Subjects
chemokine receptor CCR7, cell cloning, HLA antigen class 3, Time Factors, HLA antigen class 2, cell migration, HLA antigen class 1, B7 antigen, glycoprotein gp 100, cell maturation, radiation exposure, Apoptosis, cytotoxic T lymphocyte, CD8-Positive T-Lymphocytes, Monocytes, CD40 antigen, fluorescence activated cell sorting, necrosis, immunology, Epitopes, cell motion, Cell Movement, dendritic cell vaccine, membrane protein, CD8+ T lymphocyte, CD83 antigen, Melanoma, time, epitope, Membrane Glycoproteins, HLA A antigen, drug effect, article, SILV protein, human, phagocytosis, Cell Differentiation, melan A, CCR7 protein, human, ultrastructure, Interleukin-12, unclassified drug, Interleukin-10, Neoplasm Proteins, cell death, cell surface, cytokine release, dextran, monocyte, gamma interferon, cancer vaccine, coculture, gp100 Melanoma Antigen, melanoma cell, Receptors, CCR7, in vitro study, HLA antigen, cell kinetics, dendritic cell, fluorescein isothiocyanate, CD86 antigen, Cross-Priming, MART-1 Antigen, tumor protein, Antigens, Neoplasm, Cell Line, Tumor, Humans, controlled study, human, electron microscopy, cross presentation, human cell, chemokine, gamma radiation, tumor cell line, Dendritic Cells, vaccination, gamma irradiation, Coculture Techniques, Gamma Rays, cytology, antigen specificity, Chemokine CCL19, interleukin 12, macrophage inflammatory protein 3beta, melanocyte protein Pmel 17, antigen expression, cell vacuole, pathology, interleukin 10, tumor antigen, MLANA protein, human, upregulation
Abstract

Background: In the present study, we demonstrate, in rigorous fashion, that human monocyte-derived immature dendritic cells (DCs) can efficiently cross-present tumor-associated antigens when co-cultured with a mixture of human melanoma cells rendered apoptotic/necrotic by γ irradiation (Apo-Nec cells). Methods: We evaluated the phagocytosis of Apo-Nec cells by FACS after PKH26 and PKH67 staining of DCs and Apo-Nec cells at different times of coculture. The kinetics of the process was also followed by electron microscopy. DCs maturation was also studied monitoring the expression of specific markers, migration towards specific chemokines and the ability to cross-present in vitro the native melanoma-associated Ags MelanA/MART-1 and gp100. Results: Apo-Nec cells were efficiently phagocytosed by immature DCs (iDC) (55 ± 10.5%) at 12 hs of coculture. By 12-24 hs we observed digested Apo-Nec cells inside DCs and large empty vacuoles as part of the cellular processing. Loading with Apo-Nec cells induced DCs maturation to levels achieved using LPS treatment, as measured by: i) the decrease in FITC - Dextran uptake (iDC: 81 ± 5%; DC/Apo-Nec 33 ± 12%); ii) the cell surface up-regulation of CD80, CD86, CD83, CCR7, CD40, HLA-I and HLA-II and iii) an increased in vitro migration towards MIP-3β. DC/Apo-Nec isolated from HLA-A*0201 donors were able to induce >600 pg/ml IFN-γ secretion of CTL clones specific for MelanA/MART-1 and gp100 Ags after 6 hs and up to 48 hs of coculture, demonstrating efficient cross-presentation of the native Ags. Intracellular IL-12 was detected in DC/Apo-Nec 24 hs post-coculture while IL-10 did not change. Conclusion: We conclude thatthe use of a mixture of four apoptotic/ necrotic melanoma cell lines is a suitable source of native melanoma Ags that provides maturation signals for DCs, increases migration to MIP-3β and allows Ag cross-presentation. This strategy could be exploited for vaccination of melanoma patients. © 2007 von Euw et al; licensee BioMed Central Ltd. Fil:von Euw, E.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Barrio, M.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Levy, E.M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.

Published
2007

7. A polyepitope DNA vaccine targeted to Her-2/ErbB-2 elicits a broad range of human and murine CTL effectors to protect against tumor challenge

Author

Giulia Cencioni, Salem Chouaib, Antonio Scardino, Maria Grazia Cusi, Jordan Marrocco, Pierpaolo Correale, Roberto Bei, Kostas Kosmatopoulos, Andrew Michael Jackson, Maurizio Alimandi, Hüseyin Firat, François A. Lemonnier, Olivier Faure, Stephanie Graf-Dubois, Steven G. Smith, Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dipartimento di Medicina Sperimental, Universita di Roma, Centro Ricerca Sperimentale, Istituto Tumori Regina Elena, Divisione di Oncologia Medica, Università degli Studi di Siena = University of Siena (UNISI)-Facoltà di Medicina, Academic Division of Oncology, University of Nottingham, UK (UON), Dipartimento di Medicina Sperimentale e Scienze Biochimiche, Università di tor, Immunité Cellulaire Antivirale, Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris]

Subjects
Cancer Research, Cytotoxic, Receptor, ErbB-2, medicine.medical_treatment, T-Lymphocytes, complementary DNA, plasmid vector, animal cell, vaccine production, cytotoxic T lymphocyte, immunogenicity, Epitope, Transgenic, Epitopes, Mice, 0302 clinical medicine, drug binding, oncogene neu, Models, Neoplasms, binding affinity, Vaccines, DNA, Cytotoxic T cell, donor, Vaccines, Tumor, HLA A antigen, cancer prevention, drug cytotoxicity, article, thymoma, 3. Good health, Vaccination, tumor growth, Oncology, priority journal, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Receptor, DNA vaccine, in vitro study, drug vehicle, Transgene, gene overexpression, Mice, Transgenic, antineoplastic activity, Biology, tumor cell, Cancer Vaccines, DNA vaccination, Cell Line, protein vax1 pet neu, in vivo study, 03 medical and health sciences, Genetic, ErbB, Cell Line, Tumor, medicine, Animals, Humans, controlled study, human, neoplasms, mouse, erbB-2, Settore MED/04 - Patologia Generale, nonhuman, Models, Genetic, cancer immunization, human cell, drug targeting, Immunotherapy, DNA, Virology, tumor immunity, transgenic mouse, CTL, provocation test, tumor volume, epidermal growth factor receptor 2, genetic transfection, molecular recognition, Peptides, Neoplasm Transplantation, Receptor, erbB-2, T-Lymphocytes, Cytotoxic, Thymoma, 030215 immunology
Abstract

A cDNA vaccine (pVax1/pet-neu) was designed to encode 12 different Her-2/ErbB-2–derived, HLA-A*0201–restricted dominant and high-affinity heteroclitic cryptic epitopes. Vaccination with pVax1/pet-neu triggered multiple and ErbB-2–specific CTL responses in HLA-A*0201 transgenic HHD mice and in HLA-A*0201 healthy donors in vitro. Human and murine CTL specific for each one of the 12 ErbB-2 peptides recognized in vitro both human and murine tumor cells overexpressing endogenous ErbB-2. Furthermore, vaccination of HHD mice with pVax1/pet-neu significantly delayed the in vivo growth of challenged ErbB-2–expressing tumor (EL4/HHD/neu murine thymoma) more actively when compared with vaccination with the empty vector (pVax1) or vehicle alone. These data indicate that the pVax1/pet-neu cDNA vaccine coding for a poly-ErbB-2 epitope is able to generate simultaneous ErbB-2–specific antitumor responses against dominant and cryptic multiple epitopes. [Cancer Res 2007;67(14):7028–36]

Published
2007
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8. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Author

Sawcer, Stephen, Hellenthal, Garrett, Pirinen, Matti, Spencer, Chris, Patsopoulos, Nikolaos, Moutsianas, Loukas, Dilthey, Alexander, Su, Zhan, Freeman, Colin, Brown, Matthew, other, and, Sawcer, Stephen, Hellenthal, Garrett, Pirinen, Matti, Spencer, Chris, Patsopoulos, Nikolaos, Moutsianas, Loukas, Dilthey, Alexander, Su, Zhan, Freeman, Colin, Brown, Matthew, and other, and

Abstract

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. © 2011 Macmillan Publishers Limited. All rights reserved.

Published
2011

9. Dendritic cell-cediated cross-presentation of antigens derived from colon carcinoma cells exposed to a highly cytotoxic multidrug regimen with gemcitabine, oxaliplatin, 5-fluorouracil, and leucovorin, elicits a powerful human antigen-specific CTL response with antitumor activity in vitro

Author

Pierpaolo, Correale, Maria Grazia, Cusi, Maria Teresa, Del Vecchio, Angelo, Aquino, Salvatore Pasquale, Prete, Salvatore, Prete, Kwong Y, Tsang, Lucia, Micheli, Cristina, Nencini, Marco, La Placa, Francesco, Montagnani, Chiara, Terrosi, Michele, Caraglia, Vincenzo, Formica, Giorgio, Giorgi, Enzo, Bonmassar, Guido, Francini, Correale, P, Cusi, Mg, DEL VECCHIO, Mt, Aquino, A, Prete, Sp, Tsang, Ky, Micheli, L, Nencini, C, LA PLACA, M, Montagnani, F, Terrosi, C, Caraglia, Michele, Formica, V, Giorgi, G, Bonmassar, E, and Francini, G.

Subjects
Cytotoxicity, Immunologic, haplotype, peripheral blood mononuclear cell, Organoplatinum Compounds, Cytotoxic, HLA antigen class 1, Settore MED/06 - Oncologia Medica, Colorectal cancer, Cytotoxicity, T-Lymphocytes, medicine.medical_treatment, Drug Evaluation, Preclinical, Leucovorin, colon carcinoma, cytotoxic T lymphocyte, immunogenicity, immunomodulation, etoposide, Deoxycytidine, fluorouracil, carcinoembryonic Ag, Immunologic, Antineoplastic Combined Chemotherapy Protocols, Leukocytes, Cytotoxic T cell, Immunology and Allergy, irinotecan, Tumor, HLA A antigen, gemcitabine, apoptosis, article, Settore BIO/14, carcinoma cell, Preclinical, priority journal, Colonic Neoplasms, immunoblotting, HT29 Cells, dendritic cell, folinic acid, Mononuclear, Immunology, antineoplastic activity, thymidylate synthase, carcinoembryonic antigen, oxaliplatin, cancer immunotherapy, cell lysate, controlled study, cross presentation, flow cytometry, genetic transfection, human, human cell, Antigens, Neoplasm, Cell Line, Tumor, Coculture Techniques, Cross-Priming, Dendritic Cells, Fluorouracil, HLA-A Antigens, Humans, Leukocytes, Mononuclear, T-Lymphocytes, Cytotoxic, Cell Line, Antigen, HLA-A2 Antigen, medicine, GOLF, antitumor activity, Antigens, business.industry, CTL lines, Cancer, Dendritic cell, Immunotherapy, medicine.disease, digestive system diseases, CTL, Cancer cell, Cancer research, Neoplasm, Drug Evaluation, business
Abstract

Gemcitabine, oxaliplatin, leucovorin, and 5-fluorouracil (GOLF) is a novel multidrug regimen inducing high levels of necrosis and apoptosis in colon carcinoma cells. This regimen is also able to promote a process of Ag remodeling including up-regulation of immunotherapy targets like carcinoembryonic Ag (CEA), thymidylate synthase (TS). We have conducted a preclinical study aimed to investigate whether these drug-induced modifications would also enhance colon cancer cell immunogenicity. Several CTL lines were thus generated by in vitro stimulating human HLA-A(*)02.01+ PBMCs, from normal donors and colon cancer patients, with autologous dendritic cells cross-primed with cell lysates of colon cancer cells untreated, irradiated, or previously exposed to different drug treatments including the GOLF regimen. Class I HLA-restricted cytolytic activity of these CTL lines was tested against colon cancer cells and CEA and TS gene transfected target cells. These experiments revealed that CTLs sensitized with GOLF-treated cancer cells were much more effective than those sensitized with the untreated colon carcinoma cells or those exposed to the other treatments. CTL lines sensitized against the GOLF-treated colon cancer cells, also expressed a greater percentage of T-lymphocyte precursors able to recognize TS- and CEA-derived peptides. These results suggest that GOLF regimen is a powerful antitumor and immunomodulating regimen that can make the tumor cells a suitable means to induce an Ag-specific CTL response. These results suggest that a rationale combination of GOLF chemotherapy with cytokine-based immunotherapy could generate a chemotherapy-modulated Ag-specific T-lymphocyte response in cancer patients able to destroy the residual disease survived to the cytotoxic drugs.

Published
2005

10. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Author

Nejentsev, Sergey, Howson, Joanna, Walker, Neil, Szeszko, Jeffrey, Field, Sarah, Stevens, Helen, Reynolds, Pamela, Hardy, Matthew, King, Erna, other, and, Brown, Matthew, Nejentsev, Sergey, Howson, Joanna, Walker, Neil, Szeszko, Jeffrey, Field, Sarah, Stevens, Helen, Reynolds, Pamela, Hardy, Matthew, King, Erna, other, and, and Brown, Matthew

Abstract

The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1–3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4, 5, 6, 7, 8, 9, 10, 11. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression...

Published
2007

11. Defective Infiltration of Natural Killer Cells in MICA/B-Positive Renal Cell Carcinoma Involves β2-Integrin-Mediated Interaction

Author

Soldano Ferrone, Giuseppe Sconocchia, Wachanan Wongsena, Luigi Tornillo, Elke Schultz-Thater, Domenico Del Principe, Luigi Terracciano, Holger Moch, Giulio C. Spagnoli, Valerio Cervelli, Stephen Wyler, Vincenza Carafa, and Maurizio Anselmi

Subjects
Cancer Research, peripheral blood mononuclear cell, cell infiltration, kidney carcinoma, Settore MED/19 - Chirurgia Plastica, CD34, cell maturation, Apoptosis, Interleukin 21, primary tumor, Cell Movement, Receptors, Killer Cells, CD34 antigen, cell interaction, target cell, cancer cell, CD18, Tumor, HLA A antigen, Reverse Transcriptase Polymerase Chain Reaction, disease course, article, Flow Cytometry, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunohistochemistry, Kidney Neoplasms, CD, chlordane, medicine.anatomical_structure, priority journal, stroma cell, Differentiation, cytoplasm, Natural, Interleukin 12, CD56, coculture, exocytosis, in vitro study, Stromal cell, IgG, caspase, CD56 antigen, chemical and pharmacologic phenomena, macrophage, protein localization, tumor cell, Biology, lcsh:RC254-282, Cell Line, Natural killer cell, reverse transcription polymerase chain reaction, medicine, Humans, controlled study, beta2 integrin, CD16 antigen, CD18 antigen, HLA B antigen, natural killer cell receptor NKG2D, antigen detection, antigen expression, apoptosis, cell differentiation, cell membrane, flow cytometry, gene expression, human, human cell, human tissue, immunohistochemistry, natural killer cell, tissue microarray, Antigens, CD, Antigens, CD18, Antigens, CD56, Antigens, Differentiation, Myelomonocytic, Carcinoma, Renal Cell, Cell Line, Tumor, Histocompatibility Antigens Class I, Killer Cells, Natural, Macrophages, Receptors, IgG, Tissue Array Analysis, Antigens, Lymphokine-activated killer cell, Carcinoma, Renal Cell, Myelomonocytic, NKG2D, Molecular biology, stomatognathic diseases, Cancer cell
Abstract

We have explored MICA/B expression and its relationship with innate inflammatory infiltrate in renal cell carcinoma (RCC). The expression of MICA/B, CD16, CD56, and CD68 in 140 RCC lesions contained in a tissue microarray (TMA) was investigated by immunohistochemistry. MICA/B gene and protein expressions in Caki-1 cells were analyzed by reverse transcription-polymerase chain reaction and flow cytometry, respectively. Natural killer (NK) cells were studied by flow cytometry. All the RCC lesions (n = 140) were MICA/B-positive. MICA/B was mainly expressed in the cytoplasm of tumor cells, whereas stromal cells were negative. Renal cell carcinoma lesions showed low NK cell infiltration, although they were rich in CD16(+)CD56(-) cells, strongly resembling macrophages. CD16(+) macrophage infiltration was more frequently detectable in metastatic lesions compared with primary tumors (P = .0223) and was associated with poor RCC differentiation (P = .007). To investigate mechanisms potentially underlying the lack of NK cells infiltration into MICA/B-positive RCC lesions, we used Caki-1 RCC cells. Caki-1 expressed MICA and MICB genes. However, MICA protein was not detectable in Caki-1 cells, whereas MICB protein was detectable in their cytoplasm and on the cell membrane. Coculture of peripheral blood mononuclear cells with Caki-1, K562, HCT116, respectively, resulted in CD56(+)CD16(+) NK cells deletion without affecting CD56(+)/CD16(-) NK subset and immature NK cells generated in vitro from CD34(+) cells. Natural killer cell apoptosis seemed to be preferentially triggered by cancer cells because HLA-A0201(+) NK cells were only marginally affected by allogeneic HLA-A0201(-) peripheral blood mononuclear cells. Caki-1 cell-mediated NK cell apoptosis was reduced by an anti-beta(2)-integrin (CD18) monoclonal antibody but was NKG2D-, granule exocytosis-, and caspase-independent.

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