scholarly journals Vaccinomics Approach for Designing Potential Peptide Vaccine by TargetingShigellaspp. Serine Protease Autotransporter Subfamily Protein SigA

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Arafat Rahman Oany ◽  
Tahmina Pervin ◽  
Mamun Mia ◽  
Motaher Hossain ◽  
Mohammad Shahnaij ◽  
...  
Keyword(s):  
Serine Protease ◽  
Bacillary Dysentery ◽  
Peptide Vaccine ◽  
Human Leukocyte ◽  
World Population ◽  
Potential Core ◽  
Antigenic Protein ◽  
Leukocyte Antigen

Shigellosis, a bacillary dysentery, is closely associated with diarrhoea in human and causes infection of 165 million people worldwide per year. Casein-degrading serine protease autotransporter of enterobacteriaceae (SPATE) subfamily protein SigA, an outer membrane protein, exerts both cytopathic and enterotoxic effects especially cytopathic to human epithelial cell type-2 (HEp-2) and is shown to be highly immunogenic. In the present study, we have tried to impose the vaccinomics approach for designing a common peptide vaccine candidate against the immunogenic SigA ofShigellaspp. At first, 44 SigA proteins from different variants ofS. flexneri,S. dysenteriae,S. boydii, andS. sonneiwere assessed to find the most antigenic protein. We retrieved 12 peptides based on the highest score for human leukocyte antigen (HLA) supertypes analysed by NetCTL. Initially, these peptides were assessed for the affinity with MHC class I and class II alleles, and four potential core epitopes VTARAGLGY, FHTVTVNTL, HTTWTLTGY, and IELAGTLTL were selected. From these, FHTVTVNTL and IELAGTLTL peptides were shown to have 100% conservancy. Finally, IELAGTLTL was shown to have the highest population coverage (83.86%) among the whole world population. In vivo study of the proposed epitope might contribute to the development of functional and unique widespread vaccine, which might be an operative alleyway to thwart dysentery from the world.

scholarly journals Vaccinomics Approach for Scheming Potential Epitope-Based Peptide Vaccine by Targeting L-protein of Marburg Virus

2020 ◽  
Author(s):  
Tahmina Pervin ◽  
Arafat Rahman Oany
Keyword(s):  
Peptide Vaccine ◽  
Cell Epitope ◽  
Human Leukocyte ◽  
Hemorrhagic Fever ◽  
Marburg Virus ◽  
World Population ◽  
In Vivo Analysis ◽  
L Proteins ◽  
Virus Spreading

AbstractMarburg virus is one of the world’s most threatening diseases, causing extreme hemorrhagic fever, with a death rate of up to ninety percent. The Food and Drug Administration (FDA) currently not authorized any treatments or vaccinations for the hindrance and post-exposure of the Marburg virus. In the Present study, the vaccinomics methodology was adopted to design a potential novel peptide vaccine against the Marburg virus, targeting RNA-directed RNA polymerase (L). A total of 48 L-proteins from diverse variants of the Marburg virus were collected from the NCBI GenBank server and used to classify the best antigenic protein leading to predict equally T and B-cell epitopes. Initially, the top 26 epitopes were evaluated for the attraction with major histocompatibility complex (MHC) class I and II alleles. Finally, four prospective central epitopes NLSDLTFLI, FRYEFTRHF, YRLRNSTAL, and YRVRNVQTL were carefully chosen. Among these, FRYEFTRHF and YRVRNVQTL peptides showed 100% conservancy. Though YRLRNSTAL showed 95.74% conservancy, it demonstrated the highest combined score as T cell epitope (2.5461) and population coverage of 94.42% among the whole world population. The epitope was found non-allergenic, and docking interactions with human leukocyte antigens (HLAs) also verified. Finally, in vivo analysis of the recommended peptides might contribute to the advancement of an efficient and exclusively prevalent vaccine that would be an active route to impede the virus spreading.

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 Susceptible and Protective Human Leukocyte Antigen Class II Alleles and Haplotypes in Bahraini Type 2 (Non-Insulin-Dependent) Diabetes Mellitus Patients

2005 ◽  
Vol 12 (1) ◽  
pp. 213-217 ◽  
Author(s):  
Ayesha A. Motala ◽  
Marc Busson ◽  
Einas M. Al-Harbi ◽  
Manal A. A. Khuzam ◽  
Emtiaz M. D. Al-Omari ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Type 1 Diabetes ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Class Ii ◽  
Hla Class Ii ◽  
Leukocyte Antigen ◽  
Insulin Dependent

ABSTRACT Whereas the genetic risk for type 1 diabetes is linked to human leukocyte antigen (HLA) class II genes, the HLA association in type 2 (non-insulin-dependent) diabetes is less clear. The association between HLA class II genotypes and type 2 diabetes was examined in adult Bahrainis, an Arab population with a high prevalence of type 2 diabetes. HLA-DRB1* and -DQB1* genotyping of 86 unrelated type 2 diabetes patients (age, 51.6 ± 8.2 years; mean duration of diabetes, 7.7 ± 7.1 years) who had a strong family history of diabetes (52 of 72 versus 0 of 89 for controls, P < 0.001) and 89 healthy subjects was done by PCR-sequence-specific priming. DRB1*040101 (0.1221 versus 0.0562, P = 0.019) and DRB1*070101 (0.2151 versus 0.0843, P < 0.001) were positively associated, while DRB1*110101 (0.0698 versus 0.1461, P = 0.014) and DRB1*160101 (0.0640 versus 0.1236, P = 0.038) were negatively associated with type 2 diabetes. DRB1*040101-DQB1*0302 (0.069 versus 0.0007; P = 0.004), DRB1*070101-DQB1*0201 (0.178 versus 0.0761, P = 0.007), DRB1*070101-DQB1*050101 (0.125 versus 0.0310, P = 0.002), and DRB1*150101-DQB1*060101 (0.0756 versus 0.0281, P = 0.008) were more prevalent among patients, while DRB1*160101-DQB1*050101 (0.0702 versus 0.0349, P = 0.05) was more prevalent among controls, conferring disease susceptibility or protection, respectively. In Bahrainis with type 2 diabetes, there is a significant association with select HLA class II genotypes, which were distinct from those in type 1 diabetes.

scholarly journals Lack of association between diabetic nephropathy and human leukocyte antigen type 2 (HLA II-DQ1) in patients with type 2 diabetes mellitus in west of Iran

2020 ◽  
Vol 10 (4) ◽  
pp. e34-e34
Author(s):  
Mahsa Mohammadi ◽  
Mohsen Rajabnia ◽  
Mohammad Saad Forghani ◽  
Khaled Rahmani ◽  
Mohammad Bahadoram
Keyword(s):  
Diabetes Mellitus ◽  
Diabetic Nephropathy ◽  
Human Leukocyte Antigen ◽  
Human Leukocyte ◽  
Diabetes Type 2 ◽  
Diabetes Type ◽  
Expression Levels ◽  
Leukocyte Antigen ◽  
Significant Difference

Introduction: Diabetic nephropathy (diabetic kidney disease) is one of the microvascular complications of diabetes mellitus. The human leukocyte antigen (HLA) is a group of genes that is related to autoimmune diseases, infections and inflammation. Studies regarding the association of type 2diabetes and HLA-II are negligible. Objectives: The aim of this study is to determinate association between diabetic nephropathy and HLA II-DQ1 in diabetes type 2 patients. Patients and Methods: In this study, 120 diabetes type 2 patients were divided into two groups of diabetic nephropathy (case group) and without diabetic nephropathy (control group). Blood samples were taken and DNA was isolated. Asymmetric polymerase chain reaction (PCR) was used to amplify the HLA II-DQ1 exon 2 and exon 3. PCR products were hybridized and labeled with probes on the chip. Determination of HLAII-DQ1 gene typing was conducted by scanning hybrid products and analyzed with PerkinElmer ScanArray software. Results: The results of chi-square test showed no significant difference between expression levels of HLA in the two groups (P<0.05). Conclusion: There was no significant difference between expression levels of HLA in two groups of patients. Various factors such as demographic characteristics, lifestyle, geographic region, and race are the factors influencing the relationship between diabetic nephropathy and DQ1-HLA II. Since this study is conducted in one region and one race and with limited population, it is suggested that future studies should be considered and the association between the mentioned variables with HLA should be considered.

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 Epitope-Based Peptide prediction of vaccine against European bat lyssaviruses type 2 Glycoprotein G with Immunoinformatic Approach

2021 ◽  
Author(s):  
Manal Abdalla Gumaa ◽  
Abeer Babiker Idris ◽  
Mohamed Hasan Bashair ◽  
Enas dk Dawoud ◽  
Lina Mohamedelamin Elhasan ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cell ◽  
Peptide Vaccine ◽  
European Countries ◽  
World Population ◽  
Population Coverage ◽  
Mhc Ii ◽  
Glycoprotein G ◽  
Peptide Prediction

Objective: European bat lyssaviruses (EBLV) type 2 is present in many European countries. Infection is usually seen in bats, the primary reservoirs of the viruses. Human deaths have been documented within few days following bat exposures. So, it is very useful to design an insilco peptide vaccine for European bat lyssaviruses type 2 virus using glycoprotein G as an immunogen to stimulate protective immune response. Results: B cell tests were conducted for Bepipred with 15 conserved epitopes, Emini surface accessibility prediction with 7 conserved epitopes in the surface and Kolaskar and Tongaonkar antigenicity tested with three conserved epitopes being antigenic. 357 conserved epitopes were predicted to interact with different MHC-1 alleles with (IC50) ≤500 while 282 conserved epitopes found to interact with MHC-II alleles with IC50≤ 1000. Among all tested epitopes for world population coverage the epitope VFSYMELKV binding to MHC11 alleles was 97.94% and it found to bind 10 different alleles that indicate strong potential to formulate peptide vaccine for lyssaviruses type 2 virus. To the best of our knowledge this is the first study to propose peptide vaccine for European bat lyssavirus type 2.

scholarly journals Anti-glomerular basement membrane disease: an update on subgroups, pathogenesis and therapies

2018 ◽  
Vol 34 (11) ◽  
pp. 1826-1832 ◽  
Author(s):  
Mårten Segelmark ◽  
Thomas Hellmark
Keyword(s):  
Basement Membrane ◽  
Glomerular Basement Membrane ◽  
De Novo ◽  
Correct Diagnosis ◽  
Rapidly Progressive Glomerulonephritis ◽  
Human Leukocyte ◽  
Pulmonary Haemorrhage ◽  
Leukocyte Antigen ◽  
Type Iv

Abstract Most patients with anti-glomerular basement membrane (anti-GBM) disease present with rapidly progressive glomerulonephritis with or without pulmonary haemorrhage; however, there are several variants and vigilance is necessary to make a correct diagnosis. Such variants include overlap with anti-neutrophil cytoplasm antibodies-associated vasculitis and membranous nephropathy as well as anti-GBM occurring de novo after renal transplantation. Moreover, patients can present with isolated pulmonary haemorrhage as well as with negative tests for circulating anti-GBM. Virtually all patients with anti-GBM disease have autoantibodies that react with two discrete epitopes on the α3 chain of type IV collagen. Recent evidence suggests that healthy persons have low-affinity natural antibodies reacting with the same epitopes, but most people are protected from developing disease-causing high-affinity autoantibodies by human leukocyte antigen-dependent regulatory T-cells (Tregs). The α3 chain-derived peptides presented by the HLA-DR15 antigen lack the ability to promote the development of such Tregs. The detection of anti-GBM in circulation using the rapid assay test has led to early diagnosis and improved prognosis. However, our present tools to curb the inflammation and to eliminate the assaulting antibodies are insufficient. Only about one-third of all patients survive with functioning native kidneys. More effective therapies need to be developed; agents that inhibit neutrophil recruitment, deplete B cells and cleave immunoglobulin G (IgG) in vivo may become new weapons in the arsenal to combat anti-GBM disease.

scholarly journals Interleukin-13 Induces Tissue Fibrosis by Selectively Stimulating and Activating Transforming Growth Factor β1

2001 ◽  
Vol 194 (6) ◽  
pp. 809-822 ◽  
Author(s):  
Chun Geun Lee ◽  
Robert J. Homer ◽  
Zhou Zhu ◽  
Sophie Lanone ◽  
Xiaoman Wang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Serine Protease ◽  
Transforming Growth Factor ◽  
Transgenic Animals ◽  
Transforming Growth Factor Β1 ◽  
Tissue Fibrosis ◽  
Helper Cell Type ◽  
Tgf Β1

Interleukin (IL)-13 is a key mediator of tissue fibrosis caused by T helper cell type 2 inflammation. We hypothesized that the fibrogenic effects of IL-13 are mediated by transforming growth factor (TGF)-β. To test this hypothesis we compared the regulation of TGF-β in lungs from wild-type mice and CC10-IL-13 mice in which IL-13 overexpression causes pulmonary fibrosis. IL-13 selectively stimulated TGF-β1 production in transgenic animals and macrophages were the major site of TGF-β1 production and deposition in these tissues. IL-13 also activated TGF-β1 in vivo. This activation was associated with decreased levels of mRNA encoding latent TGF-β–binding protein-1 and increased mRNA encoding urinary plasminogen activator, matrix metalloproteinase (MMP)-9, and CD44. TGF-β1 activation was abrogated by the plasmin/serine protease antagonist aprotinin. It was also decreased in progeny of crosses of CC10-IL-13 mice and MMP-9 null mice but was not altered in crosses with CD44 null animals. IL-13–induced fibrosis was also significantly ameliorated by treatment with the TGF-β antagonist soluble TGFβR-Fc (sTGFβR-Fc). These studies demonstrate that IL-13 is a potent stimulator and activator of TGF-β1 in vivo. They also demonstrate that this activation is mediated by a plasmin/serine protease- and MMP-9–dependent and CD44-independent mechanism(s) and that the fibrogenic effects of IL-13 are mediated, in great extent, by this TGF-β pathway.

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.

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