scholarly journals Identification of an HLA-A*0201-restricted cytotoxic T-lymphocyte epitope in rotavirus VP6 protein

2006 ◽  
Vol 87 (11) ◽  
pp. 3393-3396 ◽  
Author(s):  
Jing Wei ◽  
Jin-Tao Li ◽  
Xiao-Ping Zhang ◽  
Yan Tang ◽  
Jing-Xue Wang ◽  
...  
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Peripheral Blood Lymphocytes ◽  
T Cell Epitopes ◽  
Computer Algorithms ◽  
Leukocyte Antigen ◽  
Healthy Donors

The function of cytotoxic T lymphocytes (CTLs) in rotavirus (RV) infection in humans is poorly understood. To date, no RV-specific human leukocyte antigen (HLA) class I-restricted T-cell epitopes have been described. In this study, four peptides derived from human RV Wa strain VP6 protein were predicted by computer algorithms and verified by an HLA*0201-binding assay. Two peptides with high affinity for HLA-A*0201 molecules were further assessed. The CTLs induced in vitro by P340–348 (TLLANVTAV)-loaded autologous dendritic cells from peripheral blood lymphocytes of HLA-A*0201-matched healthy donors released gamma interferon specifically upon stimulation with P340–348-loaded T2 cells. The CTLs lysed both P340–348-loaded T2 cells and human RV Wa strain-infected HLA-A*0201+ Caco-2 cells in an antigen-specific and HLA-A*0201-restricted manner. At the same time, P340–348 was shown to be immunogenic in vivo in HLA-A*0201/Kb transgenic mice. It is proposed that P340–348 is an HLA-A*0201-restricted CTL epitope.

scholarly journals HLA-A2-Restricted Epitopes Identified from MTA1 Could Elicit Antigen-Specific Cytotoxic T Lymphocyte Response

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Yahong Wu ◽  
Wenjie Zhai ◽  
Xiuman Zhou ◽  
Zhiwei Wang ◽  
Yan Lin ◽  
...  
Keyword(s):  
Tumor Invasion ◽  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
Binding Ability ◽  
Therapeutic Vaccines ◽  
Recombinant Fragment ◽  
Leukocyte Antigen ◽  
Cytotoxic T Lymphocyte Response

Overexpression of metastasis-associated protein 1 (MTA1) has been observed in many human malignancies and is significantly related to tumor invasion and metastasis, therapeutic resistance to radiation and chemotherapy, making MTA1 an ideal candidate tumor antigen. We identified several human leukocyte antigen- (HLA-) A2-restricted epitopes in MTA1 and evaluated their binding ability to HLA-A∗0201 molecules. Subsequently, a recombinant fragment encompassing the dominant epitopes, MTA1(1–283), was expressed, and the abilities of the selected epitopes of MTA1 and the MTA1(1–283) fragment to induce cytotoxic T lymphocytes (CTLs) were examined. Our results indicated that the epitopes and MTA1(1–283) fragment elicited HLA-A2-restricted and antigen-specific CTL responses both in vitro and in vivo. The new epitopes identified here may help promote the development of new therapeutic vaccines for HLA-A2+ patients expressing MTA1.

scholarly journals Interferon beta-1a induces expression of brain-derived neurotrophic factor in human T lymphocytes in vitro and not in vivo

2020 ◽  
Vol 15 (1) ◽  
pp. FNL38 ◽  
Author(s):  
Zarlascht Karmand ◽  
Hans-Peter Hartung ◽  
Oliver Neuhaus
Keyword(s):  
T Cell ◽  
Neurotrophic Factor ◽  
Serum Levels ◽  
Brain Derived Neurotrophic Factor ◽  
Peripheral Blood Lymphocytes ◽  
T Cell Proliferation ◽  
Bdnf Expression ◽  
Healthy Donors

Aim: To detect IFN β-1a-induced expression of brain-derived neurotrophic factor (BDNF) to undermine the hypothesis of IFN β-1a-associated neuroprotection in multiple sclerosis (MS). Methods: The influence of IFN β-1a on in vitro activated peripheral blood lymphocytes from healthy donors was tested. Proliferation analyses were made to detect T-cell growth. BDNF expression was measured by standard ELISA. To assess the influence of IFN β-1a on BDNF expression in vivo, BDNF serum levels of MS patients treated with IFN β-1a were compared with those of untreated patients. Results: IFN β-1a inhibited T-cell proliferation dose dependently. It induced BDNF expression at middle concentrations. MS patients treated with IFN β-1a exhibited significantly lower BDNF serum levels than untreated patients. Conclusion: IFN β-1a may promote neuroprotection by inducing BDNF expression, but its importance in vivo remains open.

scholarly journals Targeting human leukocyte antigen G with chimeric antigen receptors of natural killer cells convert immunosuppression to ablate solid tumors

2021 ◽  
Vol 9 (10) ◽  
pp. e003050
Author(s):  
Chia-Ing Jan ◽  
Shi-Wei Huang ◽  
Peter Canoll ◽  
Jeffrey N Bruce ◽  
Yu-Chuan Lin ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Natural Killer ◽  
Solid Tumors ◽  
Low Dose ◽  
Human Leukocyte ◽  
Leukocyte Antigen ◽  
Low Dose Chemotherapy ◽  
Human Leukocyte Antigen G

BackgroundImmunotherapy against solid tumors has long been hampered by the development of immunosuppressive tumor microenvironment, and the lack of a specific tumor-associated antigen that could be targeted in different kinds of solid tumors. Human leukocyte antigen G (HLA-G) is an immune checkpoint protein (ICP) that is neoexpressed in most tumor cells as a way to evade immune attack and has been recently demonstrated as a useful target for chimeric antigen receptor (CAR)-T therapy of leukemia by in vitro studies. Here, we design and test for targeting HLA-G in solid tumors using a CAR strategy.MethodsWe developed a novel CAR strategy using natural killer (NK) cell as effector cells, featuring enhanced cytolytic effect via DAP12-based intracellular signal amplification. A single-chain variable fragment (scFv) against HLA-G is designed as the targeting moiety, and the construct is tested both in vitro and in vivo on four different solid tumor models. We also evaluated the synergy of this anti-HLA-G CAR-NK strategy with low-dose chemotherapy as combination therapy.ResultsHLA-G CAR-transduced NK cells present effective cytolysis of breast, brain, pancreatic, and ovarian cancer cells in vitro, as well as reduced xenograft tumor growth with extended median survival in orthotopic mouse models. In tumor coculture assays, the anti-HLA-G scFv moiety promotes Syk/Zap70 activation of NK cells, suggesting reversal of the HLA-G-mediated immunosuppression and hence restoration of native NK cytolytic functions. Tumor expression of HLA-G can be further induced using low-dose chemotherapy, which when combined with anti-HLA-G CAR-NK results in extensive tumor ablation both in vitro and in vivo. This upregulation of tumor HLA-G involves inhibition of DNMT1 and demethylation of transporter associated with antigen processing 1 promoter.ConclusionsOur novel CAR-NK strategy exploits the dual nature of HLA-G as both a tumor-associated neoantigen and an ICP to counteract tumor spread. Further ablation of tumors can be boosted when combined with administration of chemotherapeutic agents in clinical use. The readiness of this novel strategy envisions a wide applicability in treating solid tumors.

scholarly journals GENOME-WIDE PREDICTION OF HUMAN PAPILLOMA VIRUS SPECIFIC T-CELL EPITOPES USING A COMBINATION OF MATRIX BASED COMPUTATIONAL TOOLS

2017 ◽  
Vol 9 (10) ◽  
pp. 175
Author(s):  
Manikandan Mohan ◽  
Krishnan Sundar
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
T Cell Epitopes ◽  
Computational Tools ◽  
Hpv 16 ◽  
Papilloma Virus ◽  
In Vivo Assays ◽  
Genome Wide ◽  
Hpv 18

Objective: To predict the immunogenic epitopes from human papillomavirus (HPV) virus using matrix based computational tools.Methods: In the present study, three matrix based algorithms, SYFPETHI, BIMAS and RANKPEP were used to predict the cytotoxic T lymphocyte (CTL) epitopes of HPV 16 and 18. The ability of the peptides to bind HLA A_0201, a most common allele, was evaluated using these algorithms. High scoring peptides were considered as potential binders.Results: Evaluation of HPV 16 proteome resulted in the prediction of 249 peptides as potential binders. Out of these only 25 peptides were predicted as binders by all three algorithms. Analysis of HPV 18 predicted 215 peptides, as potential binders. Among the 215 peptides only 20 peptides were predicted as binders by all three algorithms.Conclusion: The efficacy of these peptides in inducing a stronger immune response needs to be tested using in vitro and in vivo assays. The identified epitopes could be used in designing a novel epitope vaccine for HPV.

scholarly journals T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes

2021 ◽  
Author(s):  
Muhammad Ali ◽  
Eirini Giannakopoulou ◽  
Yingqian Li ◽  
Madeleine Lehander ◽  
Stina Virding Culleton ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Human Leukocyte ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Antigen Receptors ◽  
Leukocyte Antigen ◽  
Intracellular Targets

AbstractUnlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.

scholarly journals ASOSIASI HUMAN LEUKOCYTE ANTIGEN (HLA) KARSINOMA NASOFARING (KNF)

2018 ◽  
Vol 15 (2) ◽  
pp. 52
Author(s):  
F.M. Judajana
Keyword(s):  
Nasopharyngeal Carcinoma ◽  
Human Leukocyte Antigen ◽  
B Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Genetic System ◽  
Class I ◽  
Leukocyte Antigen ◽  
Barr Virus

Nasopharyngeal Carcinoma (NPC) is one of the most frequent malignancy disease in Java and the incidence rate at several Hospitalsseems increasing yearly. Prevalence of NCP in Indonesian were 3.9 per 100.000 citizen each year. Eipsten-Barr Virus (EBV) is one of theetiological agents of Nasopharyngeal Carcinoma (NPC) and infected B lymphocyte that cause transformation of it to LymphoblastoidCell Line and expresses several antigens. One of them is known as Latent membrane Protein 2A (LMP2A). These antigens is the maintarget of Cytotoxic T lymphocyte (CTL) in immune system surveillance by recognizing an epitope Human Leukocyte Antigen (HLA)class I complexes which expressed on the target cell surface. Beside EBV, there are other factors that. Research of the HLA class I antigenis one of the immune genetic system that has the ability as genetic sensitivity to the disease. The research in NPC patients is not tobe done to show representative for of population in Indonesia especially in Java. The aim of the study was to know the associationbetween HLA class I profile and NPC patients in Java population and to isolate lymphocyte from peripheral blood 24 NPC patients formicrolymphocytotoxicity test with Terasaki Plate derived from UCLA-USA. The results is significantly associated to HLA – A 24 (RR 2.25),HLA A2 (RR 1.635) and HLA A11 (RR 1.065). Based on these HLA class 1 profile as an immune genetics marker on NPC is one of themost important target. In order to develop EBV vaccine in the future, this is necessary especially for Java Population in Indonesia.

scholarly journals Delivery of Multiple Epitopes by Recombinant Detoxified Adenylate Cyclase of Bordetella pertussisInduces Protective Antiviral Immunity

2001 ◽  
Vol 75 (16) ◽  
pp. 7330-7338 ◽  
Author(s):  
Catherine Fayolle ◽  
Adriana Osickova ◽  
Radim Osicka ◽  
Thomas Henry ◽  
Marie-Jésus Rojas ◽  
...  
Keyword(s):  
T Cell ◽  
Adenylate Cyclase ◽  
Catalytic Domain ◽  
Cytotoxic T Lymphocyte ◽  
Antigen Presenting Cells ◽  
T Cell Epitopes ◽  
Antigen Presenting ◽  
Ctl Responses

ABSTRACT CyaA, the adenylate cyclase toxin from Bordetella pertussis, can deliver its N-terminal catalytic domain into the cytosol of a large number of eukaryotic cells and particularly into professional antigen-presenting cells. We have previously identified within the primary structure of CyaA several permissive sites at which insertion of peptides does not alter the ability of the toxin to enter cells. This property has been exploited to design recombinant CyaA toxoids capable of delivering major histocompatibility complex (MHC) class I-restricted CD8+ T-cell epitopes into antigen-presenting cells and to induce specific CD8+cytotoxic T-lymphocyte (CTL) responses in vivo. Here we have explored the capacity of the CyaA vector carrying several different CD8+ T-cell epitopes to prime multiple CTL responses. The model vaccine consisted of a polyepitope made of three CTL epitopes from lymphocytic choriomeningitis virus (LCMV), the V3 region of human immunodeficiency virus gp120, and chicken ovalbumin, inserted at three different sites of the catalytic domain of genetically detoxified CyaA. Each of these epitopes was processed on delivery by CyaA and presented in vitro to specific T-cell hybridomas. Immunization of mice by CyaA toxoids carrying the polyepitope lead to the induction of specific CTL responses for each of the three epitopes, as well as to protection against a lethal viral challenge. Moreover, mice primed against the vector by mock CyaA or a recombinant toxoid were still able to develop strong CTL responses after subsequent immunization with a recombinant CyaA carrying a foreign CD8+ CTL epitope. These results highlight the potency of the adenylate cyclase vector for induction of protective CTL responses with multiple specificity and/or broad MHC restriction.

96 Decitabine gene modulation sensitizes human non–small cell lung cancer (NSCLC) to NY-ESO-1 TCR immunotherapy (letetresgene autoleucel; GSK3377794) in vivo

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A107-A107
Author(s):  
Dmitry Pankov ◽  
Ioanna Eleftheriadou ◽  
Anna Domogala ◽  
Sara Brett ◽  
Lea Patasic ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cell ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
List Type ◽  
Leukocyte Antigen ◽  
Engineered T Cells

BackgroundNY-ESO-1–specific T cells (letetresgene autoleucel [lete-cel] GSK3377794) are autologous CD4+ and CD8+ T cells transduced to express a high-affinity T-cell receptor (TCR) capable of recognizing NY-ESO-1 and LAGE-1a antigens in complex with human leukocyte antigen (HLA)-A*02. NY-ESO-1 (CTAG1B) and LAGE-1a (CTAG2) are tumor-associated antigens (TAA) that share the SLLMWITQC peptide bound to human leukocyte antigen HLA-A*02 and are expressed in various cancers. Emerging evidence suggests that TCR-engineered T cells targeting NY-ESO-1 hold promise for patients with solid tumors.1 Approximately 75% of synovial sarcomas can over-express NY-ESO-1 vs 12% of NSCLC,2 however, NSCLC expression of NY-ESO-1/LAGE1-a may have therapeutic potential.3 A separate study using engineered T cells targeting NY-ESO-1 has shown a partial response in a patient with advanced lung adenocarcinoma.4 Decitabine (DAC) is a hypomethylating agent and potent inducer of TAA, including NY-ESO-1.5 We have reported in vitro use of DAC to selectively modulate TAA expression in TAA low-expressing tumor cell lines in order to enhance lete-cel therapy.3 The aim of this study was to assess enhancement of combination therapy with lete-cel and DAC in an in vivo NSCLC model.MethodsNOD scid gamma (NSG) mice were injected subcutaneously with the human NSCLC tumor cell line NCI-H1703. Upon engraftment, tumor-bearing mice were treated with a 5-day course of DAC or vehicle control followed by 2 days of rest. Lete-cel was infused on Day 8. RNA was isolated from tumor formalin-fixed paraffin-embedded blocks, and levels of NY-ESO-1 and LAGE-1a transcript were measured by RT-qPCR. Expression pattern of the NY-ESO-1 protein was assessed via immunohistochemistry. Efficacy was defined by changes in tumor volume and systemic IFN-γ secretion.ResultsConsistent with our previous in vitro studies, DAC treatment in vivo resulted in induction of NY-ESO-1 and LAGE-1a in NSCLC tumors. Lete-cel in combination with DAC significantly enhanced antitumor efficacy in vivo compared with lete-cel alone. This was associated with increased interferon-γ secretion. Mice that received DAC treatment only did not show statistically significant tumor reduction compared with untreated mice.Ethics ApprovalAll animal studies were ethically reviewed and carried out in accordance with Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care, Welfare and Treatment of Animals. Human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents under an Institutional Review Board/Ethics Committee approved protocol.ConclusionsGSK is currently enrolling a Phase Ib/IIa, multi-arm, open-label pilot study (NCT03709706) of lete-cel as a monotherapy or in combination with pembrolizumab in HLA-A*02–positive patients with NSCLC whose tumors express NY-ESO-1/LAGE-1a. This work may support rationale for the use of DAC in combination with lete-cel to improve adoptive T-cell therapy by increasing levels of target antigens and antitumor effect in NSCLC.AcknowledgementsFunding: GSKReferencesD’Angelo SP, Melchiori L, Merchant MS, et al. Cancer Discov 2018;8:944–957.Kerkar SP, Wang Z-F, Lasota J, et al. J Immunother 2016;39:181–187.Eleftheriadou I, Brett S, Domogala A, et al. Ann Oncol 2019:30(Suppl 5):v475–v532.Xia Y, Tian X, Wang J, et al. Oncol Lett 2018;16:6998–7007.Schrump DS, Fischette MR, Nguyen DM, et al. Clin Cancer Res 2006;12:5777–5785.

scholarly journals Predicting the Immunogenicity of T cell epitopes: From HIV to SARS-CoV-2

2020 ◽  
Author(s):  
Ang Gao ◽  
Zhilin Chen ◽  
Florencia Pereyra Segal ◽  
Mary Carrington ◽  
Hendrik Streeck ◽  
...  
Keyword(s):  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
T Cell Epitopes ◽  
Population Coverage ◽  
Ctl Epitopes ◽  
Leukocyte Antigen ◽  
Immunodeficiency Virus ◽  
Hla Genotype ◽  
Hla Molecules ◽  
Do So

AbstractWe describe a physics-based learning model for predicting the immunogenicity of Cytotoxic T Lymphocyte (CTL) epitopes derived from diverse pathogens, given a Human Leukocyte Antigen (HLA) genotype. The model was trained and tested on experimental data on the relative immunodominance of CTL epitopes in Human Immunodeficiency Virus infection. The method is more accurate than publicly available models. Our model predicts that only a fraction of SARS-CoV-2 epitopes that have been predicted to bind to HLA molecules is immunogenic. The immunogenic CTL epitopes across all SARS-CoV-2 proteins are predicted to provide broad population coverage, but the immunogenic epitopes in the SARS-CoV-2 spike protein alone are unlikely to do so. Our model predicts that several immunogenic SARS-CoV-2 CTL epitopes are identical to those contained in low-pathogenicity coronaviruses circulating in the population. Thus, we suggest that some level of CTL immunity against COVID-19 may be present in some individuals prior to SARS-CoV-2 infection.

scholarly journals Generation of HLA Universal Megakaryocytes and Platelets by Genetic Engineering

2021 ◽  
Vol 12 ◽  
Author(s):  
Constanca Figueiredo ◽  
Rainer Blasczyk
Keyword(s):  
Genetic Engineering ◽  
New Technologies ◽  
Human Leukocyte ◽  
Hla Class I ◽  
Genetically Engineered ◽  
Leukocyte Antigens ◽  
Cell Sources ◽  
Technical Advances

Patelet transfusion refractoriness remains a relevant hurdle in the treatment of severe alloimmunized thrombocytopenic patients. Antibodies specific for the human leukocyte antigens (HLA) class I are considered the major immunological cause for PLT transfusion refractoriness. Due to the insufficient availability of HLA-matched PLTs, the development of new technologies is highly desirable to provide an adequate management of thrombocytopenia in immunized patients. Blood pharming is a promising strategy not only to generate an alternative to donor blood products, but it may offer the possibility to optimize the therapeutic effect of the produced blood cells by genetic modification. Recently, enormous technical advances in the field of in vitro production of megakaryocytes (MKs) and PLTs have been achieved by combining progresses made at different levels including identification of suitable cell sources, cell pharming technologies, bioreactors and application of genetic engineering tools. In particular, use of RNA interference, TALEN and CRISPR/Cas9 nucleases or nickases has allowed for the generation of HLA universal PLTs with the potential to survive under refractoriness conditions. Genetically engineered HLA-silenced MKs and PLTs were shown to be functional and to have the capability to survive cell- and antibody-mediated cytotoxicity using in vitro and in vivo models. This review is focused on the methods to generate in vitro genetically engineered MKs and PLTs with the capacity to evade allogeneic immune responses.

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