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Pees, Barbara, Wentao Yang, Alejandra Zárate-Potes, Hinrich Schulenburg, and Katja Dierking. "High Innate Immune Specificity through Diversified C-Type Lectin-Like Domain Proteins in Invertebrates." Journal of Innate Immunity 8, no. 2 (November 19, 2015): 129–42. http://dx.doi.org/10.1159/000441475.
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A key question in current immunity research is how the innate immune system can generate high levels of specificity. Evidence is accumulating that invertebrates, which exclusively rely on innate defense mechanisms, can differentiate between pathogens on the species and even strain level. In this review, we identify and discuss the particular potential of C-type lectin-like domain (CTLD) proteins to generate high immune specificity. Whilst several CTLD proteins are known to act as pattern recognition receptors in the vertebrate innate immune system, the exact role of CTLD proteins in invertebrate immunity is much less understood. We show that CTLD genes are highly abundant in most metazoan genomes and summarize the current state of knowledge on CTLD protein function in insect, crustacean and nematode immune systems. We then demonstrate extreme CTLD gene diversification in the genomes of Caenorhabditis nematodes and provide an update of data from CTLD gene function studies in C. elegans, which indicate that the diversity of CTLD genes could contribute to immune specificity. In spite of recent achievements, the exact functions of the diversified invertebrate CTLD genes are still largely unknown. Our review therefore specifically discusses promising research approaches to rectify this knowledge gap.
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Dineva, Stela, Katya Uzunova, Velichka Pavlova, Elena Filipova, Krassimir Kalinov, and Toni Vekov. "Comparative efficacy and safety of chlorthalidone and hydrochlorothiazide—meta-analysis." Journal of Human Hypertension 33, no. 11 (October 8, 2019): 766–74. http://dx.doi.org/10.1038/s41371-019-0255-2.
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Abstract Hypertension is a complex syndrome of multiple hemodynamic, neuroendocrine, and metabolic abnormalities. The goals of treatment in hypertension are to optimally control high blood pressure and to reduce associated cardiovascular morbidity and mortality using the most suitable therapy available. Hydrochlorothiazide (HCTZ) and chlorthalidone (CTLD) are with proven hypertensive effects. The topic of our meta-analysis is to compare the efficacy of HCTZ and CTLD therapy in patient with hypertension. A search of electronic databases PubMed, MEDLINE, Scopus, PsyInfo, eLIBRARY.ru was performed. We chose the random-effects method for the analysis and depicted the results as forest plots. Sensitivity analyses were performed in order to evaluate the degree of significance of each study. Of the 1289 identified sources, only nine trials directly compared HCTZ and CTLD and were included in the meta-analysis. Changes in SBP lead to WMD (95% CI) equal to −3.26 mmHg showing a slight but statistically significant prevalence of CTLD. Results from analyzed studies referring to DBP lead to WMD (95% CI) equal to −2.41 mmHg, which is also statistically significant. During our analysis, we found that there were not enough studies presenting enough data on the effect of CTLD and HCTZ on levels of serum potassium and serum sodium. Our meta-analysis has demonstrated a slight superiority for CTLD regarding blood pressure control. At the same time, the two medications do not show significant differences in their safety profile.
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Bhalchandra, Seema, Jacob Ludington, Isabelle Coppens, and Honorine D. Ward. "Identification and Characterization of Cryptosporidium parvum Clec, a Novel C-Type Lectin Domain-Containing Mucin-Like Glycoprotein." Infection and Immunity 81, no. 9 (July 1, 2013): 3356–65. http://dx.doi.org/10.1128/iai.00436-13.
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ABSTRACTCryptosporidiumspecies are waterborne apicomplexan parasites that cause diarrheal disease worldwide. Although the mechanisms underlyingCryptosporidium-host cell interactions are not well understood, mucin-like glycoproteins of the parasite are known to mediate attachment and invasionin vitro. We identifiedC. parvumClec (CpClec), a novel mucin-like glycoprotein that contains a C-type lectin domain (CTLD) and has orthologs inC. hominisandC. muris. CTLD-containing proteins are ligand-binding proteins that function in adhesion and signaling and are present in a wide range of organisms, from humans to viruses. However, this is the first report of a CTLD-containing protein in protozoa and inApicomplexa. CpClec is predicted to be a type 1 membrane protein, with a CTLD, an O-glycosylated mucin-like domain, a transmembrane domain, and a cytoplasmic tail containing a YXXϕ sorting motif. The predicted structure ofCpClec displays several characteristics of canonical CTLD-containing proteins, including a long loop region hydrophobic core associated with calcium-dependent glycan binding as well as predicted calcium- and glycan-binding sites.CpClec expression duringC. parvuminfectionin vitrois maximal at 48 h postinfection, suggesting that it is developmentally regulated. The 120-kDa mass of nativeCpClec is greater than predicted, most likely due to O-glycosylation.CpClec is localized to the surface of the apical region and to dense granules of sporozoites and merozoites. Taken together, these findings, along with the known functions ofC. parvummucin-like glycoproteins and of CTLD-containing proteins, strongly implicate a significant role forCpClec inCryptosporidium-host cell interactions.
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Akatsu, Chizuru, Kenro Shinagawa, Nobutaka Numoto, Zhihong Liu, Ayse Konuskan Ucar, Mohammad Aslam, Shirly Phoon, et al. "CD72 negatively regulates B lymphocyte responses to the lupus-related endogenous toll-like receptor 7 ligand Sm/RNP." Journal of Experimental Medicine 213, no. 12 (October 24, 2016): 2691–706. http://dx.doi.org/10.1084/jem.20160560.
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Toll-like receptor 7 (TLR7) plays an essential role in development of systemic lupus erythematosus by co-stimulating B cells reactive to the endogenous TLR7 ligand Sm/ribonucleoprotein (RNP), a crucial lupus self-antigen. However, how the TLR7-mediated autoimmune response is regulated is not yet known. In this study, we demonstrate that CD72, an inhibitory B cell co-receptor known to prevent development of lupus, recognizes Sm/RNP at the extracellular C-type lectin-like domain (CTLD) and specifically inhibits B cell response to Sm/RNP. Moreover, the CTLD of CD72c, a lupus-susceptible allele, binds to Sm/RNP less strongly than that of lupus-resistant CD72a. Reduced binding of CD72c is supported by x-ray crystallographic analysis that reveals a considerable alteration in charge at the putative ligand-binding site. Thus, CD72 appears to specifically inhibit B cell response to the endogenous TLR7 ligand Sm/RNP through CTLD-mediated recognition of Sm/RNP, thereby preventing production of anti-Sm/RNP antibody crucial for development of lupus.
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Villamor, D. E. V., J. Susaimuthu, and K. C. Eastwell. "Genomic Analyses of Cherry Rusty Mottle Group and Cherry Twisted Leaf-Associated Viruses Reveal a Possible New Genus Within the FamilyBetaflexiviridae." Phytopathology® 105, no. 3 (March 2015): 399–408. http://dx.doi.org/10.1094/phyto-03-14-0066-r.
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It is demonstrated that closely related viruses within the family Betaflexiviridae are associated with a number of diseases that affect sweet cherry (Prunus avium) and other Prunus spp. Cherry rusty mottle-associated virus (CRMaV) is correlated with the appearance of cherry rusty mottle disease (CRMD), and Cherry twisted leaf-associated virus (CTLaV) is linked to cherry twisted leaf disease (CTLD) and apricot ringpox disease (ARPD). Comprehensive analysis of previously reported full genomic sequences plus those determined in this study representing isolates of CTLaV, CRMaV, Cherry green ring mottle virus, and Cherry necrotic rusty mottle virus revealed segregation of sequences into four clades corresponding to distinct virus species. High-throughput sequencing of RNA from representative source trees for CRMD, CTLD, and ARPD did not reveal additional unique virus sequences that might be associated with these diseases, thereby further substantiating the association of CRMaV and CTLaV with CRMD and CTLD or ARPD, respectively. Based on comparison of the nucleotide and amino acid sequence identity values, phylogenetic relationships with other triple-gene block-coding viruses within the family Betaflexiviridae, genome organization, and natural host range, a new genus (Robigovirus) is suggested.
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Sharif, Jalil-Ahmad. "Transfer and transition referrals of patients with intellectual disability from children's services to adult community learning disability teams." BJPsych Open 7, S1 (June 2021): S103. http://dx.doi.org/10.1192/bjo.2021.307.
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AimsThe audit aimed to assess if patients under the care of children's services in Wessex were transferred at the appropriate age and whether transition referrals to Community Learning Disability teams (CTLD) occurred timely. It also aimed to look at how many patients underwent transitions in a three month period, and if their transition support plan (TSP) was completed. A transition support plan should include chronological information on psychopharmacology, psychotherapy, and social support measures. Patients should be referred between the ages of 17–19 but require a justification after 18 years of age.MethodThe BI team was contacted to provide all IDs for patients referred within a three month period between the ages of 17–19. The BI team provided 42 patients with their ID. Patients discharged from services within a short time span were excluded for the following reason: inappropriate referral (9pts), discharged after 1st assessment (6pts), internal discussion (6pts), only referred to Autism team (4pts), moved out of area (1pts). From the initial 42 patients, 16 patients were analysed using the collection tool.Result4/16 had a TSP, and only two had a complete TSP and transitioned in another trust and were inter-team referrals.CAMHS services referred 1/16 patients.Psychotropic medication was prescribed to 12/16 prior to or on time of referral, but only two patients had a complete psychotropic medication history.8/16 patients' referral was commenced prior to their 18th birthday, and no information was provided for delay in transfer.Health records did mention psychotherapy, but apart from 2/16 TSP records, no additional information was available on the modality.ConclusionPatients with Intellectual Disability face challenges when transferring from children to adult services. Insufficient referral information may have a detrimental impact on patients wellbeing and long-term care.Access to a patient's chronological journey through the different children's services allows Adult CTLD health professionals to provide effective care. Historical psycho-social and pharmacological interventions provide a reference point for future interventions.Concerns included: limited information on most TSP regarding psycho-social and psychotropic treatments, lack of access to CAMHS/CHYPS paperwork and ineffective inter-trust communication for transition patients.This project highlighted the average number of transition cases in 3 months. It led to changes to the transition pathway, as awareness was raised in trust and CCG meetings to improve patient outcome. CTLD created the new role of transition facilitators to support children's services. They sit in meetings before patients transition referrals.
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Zelensky, Alex N., and Jill E. Gready. "Comparative analysis of structural properties of the C-type-lectin-like domain (CTLD)." Proteins: Structure, Function, and Bioinformatics 52, no. 3 (July 7, 2003): 466–77. http://dx.doi.org/10.1002/prot.10626.
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Pees, Barbara, Wentao Yang, Anke Kloock, Carola Petersen, Lena Peters, Li Fan, Meike Friedrichsen, et al. "Effector and regulator: Diverse functions of C. elegans C-type lectin-like domain proteins." PLOS Pathogens 17, no. 4 (April 1, 2021): e1009454. http://dx.doi.org/10.1371/journal.ppat.1009454.
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In C. elegans, 283 clec genes encode a highly diverse family of C-type lectin-like domain (CTLD) proteins. Since vertebrate CTLD proteins have characterized functions in defense responses against pathogens and since expression of C. elegans clec genes is pathogen-dependent, it is generally assumed that clec genes function in C. elegans immune defenses. However, little is known about the relative contribution and exact function of CLEC proteins in C. elegans immunity. Here, we focused on the C. elegans clec gene clec-4, whose expression is highly upregulated by pathogen infection, and its paralogs clec-41 and clec-42. We found that, while mutation of clec-4 resulted in enhanced resistance to the Gram-positive pathogen Bacillus thuringiensis MYBt18247 (Bt247), inactivation of clec-41 and clec-42 by RNAi enhanced susceptibility to Bt247. Further analyses revealed that enhanced resistance of clec-4 mutants to Bt247 was due to an increase in feeding cessation on the pathogen and consequently a decrease in pathogen load. Moreover, clec-4 mutants exhibited feeding deficits also on non-pathogenic bacteria that were in part reflected in the clec-4 gene expression profile, which overlapped with gene sets affected by starvation or mutation in nutrient sensing pathways. However, loss of CLEC-4 function only mildly affected life-history traits such as fertility, indicating that clec-4 mutants are not subjected to dietary restriction. While CLEC-4 function appears to be associated with the regulation of feeding behavior, we show that CLEC-41 and CLEC-42 proteins likely function as bona fide immune effector proteins that have bacterial binding and antimicrobial capacities. Together, our results exemplify functional diversification within clec gene paralogs.
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Kukreja, J., E. L. Bush, C. W. Hoopes, G. Dincheva, M. Brzezinski, J. Lee, M. Kleinhenz, et al. "Lung Transplant (LT) for Non-Scleroderma Connective Tissue Lung Disease (NS-CTLD): Wasting a Precious Commodity?" Journal of Heart and Lung Transplantation 34, no. 4 (April 2015): S256—S257. http://dx.doi.org/10.1016/j.healun.2015.01.713.
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KONG, H., E. PARK, B. NAM, Y. KIM, W. KIM, H. PARK, C. LEE, and S. LEE. "A C-type lectin like-domain (CTLD)-containing protein (PtLP) from the swimming crab Portunus trituberculatus." Fish & Shellfish Immunology 25, no. 3 (September 2008): 311–14. http://dx.doi.org/10.1016/j.fsi.2008.05.003.
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Shi, Xiaohua, Setsuko Ogawa, Toshio Otani, and Sachiko Machida. "Involvement of Conserved Hydrophobic Residues in the CTLD of Human Lectin-like Oxidized LDL Receptor in Ligand Binding." Molecular Cell Biology Research Communications 4, no. 5 (September 2001): 292–98. http://dx.doi.org/10.1006/mcbr.2001.0296.
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Parenrengi, Andi, Alimuddin Alimuddin, Sukenda Sukenda, Komar Sumantadinata, and Andi Tenriulo. "KARAKTERISTIK SEKUEN cDNA PENGKODE GEN ANTI VIRUS DARI UDANG WINDU, Penaeus monodon." Jurnal Riset Akuakultur 4, no. 1 (November 28, 2016): 1. http://dx.doi.org/10.15578/jra.4.1.2009.1-13.
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Transgenesis pada ikan merupakan sebuah teknik modern yang berpotensi besar dalam menghasilkan organisme yang memiliki karakter lebih baik melalui rekombinan DNA gen target termasuk gen anti virus dalam peningkatan resistensi pada udang. Gen anti virus PmAV (Penaeus monodon Anti Viral gene) merupakan salah satu gen pengkode anti virus yang berasal dari spesies krustase. Penelitian ini dilakukan untuk mengetahui karakteristik gen anti virus yang diisolasi dari udang windu, Penaeus monodon. Isolasi gen anti virus menggunakan metode Polymerase Chain Reaction (PCR) dan selanjutnya dipurifikasi untuk sekuensing. Data yang dihasilkan dianalisis dengan program Genetyx Versi 7 dan basic local alignment search tool (BLAST). Hasil penelitian menunjukkan bahwa gen anti virus PmAV yang berhasil diisolasi dari cDNA udang windu dengan panjang sekuen 520 bp yang mengkodekan 170 asam amino. BLAST-N menunjukkan tingkat similaritas yang sangat tinggi (100%) dengan gen anti virus yang ada di GeneBank. Komposisi asam amino penyusun gen anti virus yang paling besar adalah serin (10,00%), sedangkan yang terkecil adalah asam amino prolin dan lisin masing-masing 1,76%. Analisis sekuen gen dan deduksi asam amino (BLAST-P) memperlihatkan adanya C-type lectin-like domain (CTLD) yang memiliki kemiripan dengan gen C-type lectin yang diisolasi dari beberapa spesies krustase.Transgenic fish technology is a potential modern technique in producing better character organism through DNA recombinant of target genes including anti viral gene for improvement of shrimp immunity. PmAV (Penaeus monodon Anti Viral) gene is one of anti viral genes isolated from crustacean species. The research was conducted to analyze the characteristics anti viral gene isolated from tiger prawn, Penaeus monodon. Anti viral gene was isolated using Polymerase Chain Reaction (PCR) technique and then purified for sequencing. Data obtained were analyzed using Genetyx Version 7 software and basic local alignment search tool (BLAST). The results showed that the PmAV antiviral gene has been isolated from cDNA of tiger prawn at the position of approximately 520 bp consisting of 170 amino acids. BLAST-N showed high similarity (100%) compared to the other anti viral genes deposited at the GeneBank. The highest percentage of amino acid encoding anti viral gene is serine (10.00%), while the lowest is proline and lysine (1.76%). Sequence analysis and amino acid deduction (BLAST-P) revealed a C-type lectin-like domain (CTLD) that is similar with the C-type lectin gene isolated from several crustacean species.
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Hải, Nguyễn Lương. "Sự ảnh hưởng của chức năng kiểm soát đến hiệu quả hoạt động quản lý nhà nước trong đầu tư công xây dựng hạ tầng đường bộ tại Việt Nam." Tạp chí Khoa học Công nghệ Xây dựng (KHCNXD) - ĐHXD 14, no. 2V (May 22, 2020): 122–30. http://dx.doi.org/10.31814/stce.nuce2020-14(2v)-11.
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Kiểm soát đầu tư là một chức năng quan trọng của hoạt động quản lý Nhà nước trong đầu tư công xây dựng hạ tầng đường bộ trong điều kiện hạn chế về nguồn vốn cũng như giải quyết vấn đề thất thoát vốn đầu tư công tại Việt Nam. Bài báo nhằm đánh giá sự ảnh hưởng của chức năng kiểm soát tới hiệu quả quản lý nhà nước trong đầu tư công xây dựng hạ tầng đường bộ tại Việt Nam. Kết quả nghiên cứu đã chỉ ra các nhóm nhân tố thuộc về chức năng kiểm soát đầu tư liên quan đến “hành lang pháp lý trong công tác kiểm soát” (CTL1), “các tiêu chí kiểm soát” (CTL3), “tính minh bạch trong công tác kiểm soát” (CTL4) và “xử lý sai lệch kế hoạch” (CTL6) cho thấy sự ảnh hưởng có ý nghĩa thống kê (p << 0,05) đến hiệu quả hoạt động quản lý Nhà nước trong đầu tư công xây dựng hạ tầng đường bộ. Kết quả nghiên cứu đóng góp quan trọng về phương pháp luận khoa học trong quản lý nhà nước về đầu tư xây dựng, đồng thời góp phần nâng cao hiệu quả đầu tư công xây dựng hạ tầng đường bộ tại Việt Nam.
Từ khóa:
kiểm soát; quản lý đầu tư; đầu tư xây dựng; hạ tầng đường bộ.
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Reinhard, Linda, Gunther Zahner, Stephan Menzel, Friedrich Koch-Nolte, Rolf A. K. Stahl, and Elion Hoxha. "Clinical Relevance of Domain-Specific Phospholipase A2 Receptor 1 Antibody Levels in Patients with Membranous Nephropathy." Journal of the American Society of Nephrology 31, no. 1 (December 16, 2019): 197–207. http://dx.doi.org/10.1681/asn.2019030273.
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BackgroundAntibodies against phospholipase A2 receptor 1 (PLA2R1) are found in 80% of patients with membranous nephropathy, and previous studies described three autoantibody-targeted PLA2R1 epitope regions. Although anti-PLA2R1 antibody levels are closely associated with treatment response and disease prognosis, the clinical role of epitope regions targeted by autoantibodies is unclear.MethodsIn a prospective cohort of 150 patients with newly diagnosed PLA2R1-associated membranous nephropathy, we investigated the clinical role of epitope-recognition patterns and domain-specific PLA2R1 antibody levels by western blot and ELISA.ResultsWe identified a fourth epitope region in the CTLD8 domain of PLA2R1, which was recognized by anti-PLA2R1 antibodies in 24 (16.0%) patients. In all study patients, anti-PLA2R1 antibodies bound both the N-terminal (CysR-FnII-CTLD1) region and the C-terminal (CTLD7-CTLD8) region of PLA2R1 at study enrollment. The total anti-PLA2R1 antibody levels of patients determined detection of domain-specific PLA2R1 antibodies, and thereby epitope-recognition patterns. A remission of proteinuria occurred in 133 (89%) patients and was not dependent on the domain-recognition profiles. A newly developed ELISA showed that domain-specific PLA2R1 antibody levels targeting CysR, CTLD1, and CTLD7 strongly correlate with the total anti-PLA2R1 antibody level (Spearman’s rho, 0.95, 0.64, and 0.40; P<0.001, P<0.001, and P=0.002, respectively) but do not predict disease outcome independently of total anti-PLA2R1 antibody levels.ConclusionsAll patients with PLA2R1-associated membranous nephropathy recognize at least two epitope regions in the N- and C-terminals of PLA2R1 at diagnosis, contradicting the hypothesis that PLA2R1 “epitope spreading” determines the prognosis of membranous nephropathy. Total anti-PLA2R1 antibody levels, but not the epitope-recognition profiles at the time of diagnosis, are relevant for the clinical outcome of patients with this disease.
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KONTSEKOVÁ, SOŇA, ANNA OHRADANOVA REPIC, KATARÍNA POLČICOVÁ, PAULIINA TUOMAALA, JAROMÍR PASTOREK, SILVIA PASTOREKOVÁ, SEPPO PARKKILA, and MONIKA BARÁTHOVÁ. "Novel monoclonal antibodies specific for CTLD-SSC and sialomucin domains of endosialin, a mural cell marker of tumor vasculature." International Journal of Oncology 41, no. 4 (July 23, 2012): 1365–72. http://dx.doi.org/10.3892/ijo.2012.1566.
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Schulenburg, Hinrich, Marc P. Hoeppner, January Weiner, and Erich Bornberg-Bauer. "Specificity of the innate immune system and diversity of C-type lectin domain (CTLD) proteins in the nematode Caenorhabditis elegans." Immunobiology 213, no. 3-4 (May 2008): 237–50. http://dx.doi.org/10.1016/j.imbio.2007.12.004.
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Yuan, Cai, Henrik J. Jürgensen, Lars H. Engelholm, Rui Li, Min Liu, Longguang Jiang, Zhipu Luo, Niels Behrendt, and Mingdong Huang. "Crystal structures of the ligand-binding region of uPARAP: effect of calcium ion binding." Biochemical Journal 473, no. 15 (July 28, 2016): 2359–68. http://dx.doi.org/10.1042/bcj20160276.
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The proteins of the mannose receptor (MR) family share a common domain organization and have a broad range of biological functions. Urokinase plasminogen activator receptor-associated protein (uPARAP) (or Endo180) is a member of this family and plays an important role in extracellular matrix remodelling through interaction with its ligands, including collagens and urokinase plasminogen activator receptor (uPAR). We report the crystal structures of the first four domains of uPARAP (also named the ligand-binding region, LBR) at pH 7.4 in Ca2+-bound and Ca2+-free forms. The first domain (cysteine-rich or CysR domain) folds into a new and unique conformation different from the β-trefoil fold of typical CysR domains. The so-called long loop regions (LLRs) of the C-type lectin-like domain (CTLD) 1 and 2 (the third and fourth domain) mediate the direct contacts between these domains. These LLRs undergo a Ca2+-dependent conformational change, and this is likely to be the key structural determinant affecting the overall conformation of uPARAP. Our results provide a molecular mechanism to support the structural flexibility of uPARAP, and shed light on the structural flexibility of other members of the MR family.
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M. Conway, Edward. "Editorial [Hot Topic: The Type XIV Family of C-type Lectin-like Domain (CTLD) Containing Proteins (Guest Editor: Edward M. Conway)]." Current Drug Targets 13, no. 3 (March 1, 2012): 409–10. http://dx.doi.org/10.2174/138945012799424688.
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Guo, H. Z., P. F. Zou, J. P. Fu, Z. Guo, B. K. Zhu, P. Nie, and M. X. Chang. "Characterization of two C-type lectin-like domain (CTLD)-containing proteins from the cDNA library of Chinese mitten crab Eriocheir sinensis." Fish & Shellfish Immunology 30, no. 2 (February 2011): 515–24. http://dx.doi.org/10.1016/j.fsi.2010.11.027.
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Eble, Johannes. "Structurally Robust and Functionally Highly Versatile—C-Type Lectin (-Related) Proteins in Snake Venoms." Toxins 11, no. 3 (March 1, 2019): 136. http://dx.doi.org/10.3390/toxins11030136.
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Snake venoms contain an astounding variety of different proteins. Among them are numerous C-type lectin family members, which are grouped into classical Ca2+- and sugar-binding lectins and the non-sugar-binding snake venom C-type lectin-related proteins (SV-CLRPs), also called snaclecs. Both groups share the robust C-type lectin domain (CTLD) fold but differ in a long loop, which either contributes to a sugar-binding site or is expanded into a loop-swapping heterodimerization domain between two CLRP subunits. Most C-type lectin (-related) proteins assemble in ordered supramolecular complexes with a high versatility of subunit numbers and geometric arrays. Similarly versatile is their ability to inhibit or block their target molecules as well as to agonistically stimulate or antagonistically blunt a cellular reaction triggered by their target receptor. By utilizing distinct interaction sites differentially, SV-CLRPs target a plethora of molecules, such as distinct coagulation factors and receptors of platelets and endothelial cells that are involved in hemostasis, thrombus formation, inflammation and hematogenous metastasis. Because of their robust structure and their high affinity towards their clinically relevant targets, SV-CLRPs are and will potentially be valuable prototypes to develop new diagnostic and therapeutic tools in medicine, provided that the molecular mechanisms underlying their versatility are disclosed.
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Neubauer, Emilie F., Angela Z. Poole, Virginia M. Weis, and Simon K. Davy. "The scavenger receptor repertoire in six cnidarian species and its putative role in cnidarian-dinoflagellate symbiosis." PeerJ 4 (November 15, 2016): e2692. http://dx.doi.org/10.7717/peerj.2692.
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Many cnidarians engage in a mutualism with endosymbiotic photosynthetic dinoflagellates that forms the basis of the coral reef ecosystem. Interpartner interaction and regulation includes involvement of the host innate immune system. Basal metazoans, including cnidarians have diverse and complex innate immune repertoires that are just beginning to be described. Scavenger receptors (SR) are a diverse superfamily of innate immunity genes that recognize a broad array of microbial ligands and participate in phagocytosis of invading microbes. The superfamily includes subclades named SR-A through SR-I that are categorized based on the arrangement of sequence domains including the scavenger receptor cysteine rich (SRCR), the C-type lectin (CTLD) and the CD36 domains. Previous functional and gene expression studies on cnidarian-dinoflagellate symbiosis have implicated SR-like proteins in interpartner communication and regulation. In this study, we characterized the SR repertoire from a combination of genomic and transcriptomic resources from six cnidarian species in the Class Anthozoa. We combined these bioinformatic analyses with functional experiments using the SR inhibitor fucoidan to explore a role for SRs in cnidarian symbiosis and immunity. Bioinformatic searches revealed a large diversity of SR-like genes that resembled SR-As, SR-Bs, SR-Es and SR-Is. SRCRs, CTLDs and CD36 domains were identified in multiple sequences in combinations that were highly homologous to vertebrate SRs as well as in proteins with novel domain combinations. Phylogenetic analyses of CD36 domains of the SR-B-like sequences from a diversity of metazoans grouped cnidarian with bilaterian sequences separate from other basal metazoans. All cnidarian sequences grouped together with moderate support in a subclade separately from bilaterian sequences. Functional experiments were carried out on the sea anemone Aiptasia pallida that engages in a symbiosis with Symbiodinium minutum (clade B1). Experimental blocking of the SR ligand binding site with the inhibitor fucoidan reduced the ability of S. minutum to colonize A. pallida suggesting that host SRs play a role in host-symbiont recognition. In addition, incubation of symbiotic anemones with fucoidan elicited an immune response, indicating that host SRs function in immune modulation that results in host tolerance of the symbionts.
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Ragasa, Lorenz Rhuel P., Jaime Lorenzo N. Dinglasan, Imee Rose E. Felipe, Zubaida U. Basiao, and Michael C. Velarde. "Exposure to Aeromonas hydrophila induces inflammation and increases expression of the gene encoding for a putative dual CTLD-containing lectin in milkfish liver." Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 230 (April 2019): 37–47. http://dx.doi.org/10.1016/j.cbpb.2019.01.008.
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Chapuis, Aude G., Ilana M. Roberts, John A. Thompson, Kim A. Margolin, Shailender Bhatia, Sylvia M. Lee, Heather L. Sloan, et al. "T-Cell Therapy Using Interleukin-21–Primed Cytotoxic T-Cell Lymphocytes Combined With Cytotoxic T-Cell Lymphocyte Antigen-4 Blockade Results in Long-Term Cell Persistence and Durable Tumor Regression." Journal of Clinical Oncology 34, no. 31 (November 1, 2016): 3787–95. http://dx.doi.org/10.1200/jco.2015.65.5142.
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Purpose Peripheral blood–derived antigen-specific cytotoxic T cells (CTLs) provide a readily available source of effector cells that can be administered with minimal toxicity in an outpatient setting. In metastatic melanoma, this approach results in measurable albeit modest clinical responses in patients resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity of adoptively transferred CTLs. Patients and Methods Autologous MART1-specific CTLs were generated by priming with peptide-pulsed dendritic cells in the presence of interleukin-21 and enriched by peptide-major histocompatibility complex multimer-guided cell sorting. This expeditiously yielded polyclonal CTL lines uniformly expressing markers associated with an enhanced survival potential. In this first-in-human strategy, 10 patients with stage IV melanoma received the MART1-specific CTLs followed by a standard course of anti–CTLA-4 (ipilimumab). Results The toxicity profile of the combined treatment was comparable to that of ipilimumab monotherapy. Evaluation of best responses at 12 weeks yielded two continuous complete remissions, one partial response (PR) using RECIST criteria (two PRs using immune-related response criteria), and three instances of stable disease. Infused CTLs persisted with frequencies up to 2.9% of CD8+ T cells for as long as the patients were monitored (up to 40 weeks). In patients who experienced complete remissions, PRs, or stable disease, the persisting CTLs acquired phenotypic and functional characteristics of long-lived memory cells. Moreover, these patients also developed responses to nontargeted tumor antigens (epitope spreading). Conclusion We demonstrate that combining antigen-specific CTLs with CTLA-4 blockade is safe and produces durable clinical responses, likely reflecting both enhanced activity of transferred cells and improved recruitment of new responses, highlighting the promise of this strategy.
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Fujita, Yosuke, Tomoki Nagakura, Hiroyuki Uchino, Masato Inazu, and Tsuyoshi Yamanaka. "Functional Expression of Choline Transporters in Human Neural Stem Cells and Its Link to Cell Proliferation, Cell Viability, and Neurite Outgrowth." Cells 10, no. 2 (February 20, 2021): 453. http://dx.doi.org/10.3390/cells10020453.
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Choline and choline metabolites are essential for all cellular functions. They have also been reported to be crucial for neural development. In this work, we studied the functional characteristics of the choline uptake system in human neural stem cells (hNSCs). Additionally, we investigated the effect of extracellular choline uptake inhibition on the cellular activities in hNSCs. We found that the mRNAs and proteins of choline transporter-like protein 1 (CTL1) and CTL2 were expressed at high levels. Immunostaining showed that CTL1 and CTL2 were localized in the cell membrane and partly in the mitochondria, respectively. The uptake of extracellular choline was saturable and performed by a single uptake mechanism, which was Na+-independent and pH-dependent. We conclude that CTL1 is responsible for extracellular choline uptake, and CTL2 may uptake choline in the mitochondria and be involved in DNA methylation via choline oxidation. Extracellular choline uptake inhibition caused intracellular choline deficiency in hNSCs, which suppressed cell proliferation, cell viability, and neurite outgrowth. Our findings contribute to the understanding of the role of choline in neural development as well as the pathogenesis of various neurological diseases caused by choline deficiency or choline uptake impairment.
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Inazu, Masato. "Functional Expression of Choline Transporters in the Blood–Brain Barrier." Nutrients 11, no. 10 (September 20, 2019): 2265. http://dx.doi.org/10.3390/nu11102265.
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Cholinergic neurons in the central nervous system play a vital role in higher brain functions, such as learning and memory. Choline is essential for the synthesis of the neurotransmitter acetylcholine by cholinergic neurons. The synthesis and metabolism of acetylcholine are important mechanisms for regulating neuronal activity. Choline is a positively charged quaternary ammonium compound that requires transporters to pass through the plasma membrane. Currently, there are three groups of choline transporters with different characteristics, such as affinity for choline, tissue distribution, and sodium dependence. They include (I) polyspecific organic cation transporters (OCT1-3: SLC22A1-3) with a low affinity for choline, (II) high-affinity choline transporter 1 (CHT1: SLC5A7), and (III) choline transporter-like proteins (CTL1-5: SLC44A1-5). Brain microvascular endothelial cells, which comprise part of the blood–brain barrier, take up extracellular choline via intermediate-affinity choline transporter-like protein 1 (CTL1) and low-affinity CTL2 transporters. CTL2 is responsible for excreting a high concentration of choline taken up by the brain microvascular endothelial cells on the brain side of the blood–brain barrier. CTL2 is also highly expressed in mitochondria and may be involved in the oxidative pathway of choline metabolism. Therefore, CTL1- and CTL2-mediated choline transport to the brain through the blood–brain barrier plays an essential role in various functions of the central nervous system by acting as the rate-limiting step of cholinergic neuronal activity.
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Tang, Zhuoran, Fengzhen Mo, Aiqun Liu, Siliang Duan, Xiaomei Yang, Liu Liang, Xiaoqiong Hou, et al. "A Nanobody Against Cytotoxic T-Lymphocyte Associated Antigen-4 Increases the Anti-Tumor Effects of Specific CD8+ T Cells." Journal of Biomedical Nanotechnology 15, no. 11 (November 1, 2019): 2229–39. http://dx.doi.org/10.1166/jbn.2019.2859.
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Adoptive cell-based immunotherapy typically utilizes cytotoxic T lymphocytes (CTLs), expanding these cells ex vivo. Such expansion is traditionally accomplished through the use of autologous APCs that are capable of interactions with T cells. However, incidental inhibitory program such as CTLA-4 pathway can impair T cell proliferation. We therefore designed a nanobody which is specific for CTLA-4 (CTLA-4 Nb 16), and we then used this molecule to assess its ability to disrupt CTLA-4 signaling and thereby overcome negative costimulation of T cells. With CTLA-4 Nb16 stimulation, dendritic cell/hepatocellular carcinoma fusion cells (DC/HepG2-FCs) enhanced autologous CD8+ T cell proliferation and production of IFN-γ in vitro, thereby leading to enhanced killing of tumor cells. Using this approach in the context of adoptive CD8+ immunotherapy led to a marked suppression of tumor growth in murine NOD/SCID hepatocarcinoma or breast cancer xenograft models. We also observed significantly increased tumor cell apoptosis, and corresponding increases in murine survival. These findings thus demonstrate that in response to nanobody stimulation, DC/tumor cells-FC-induced specific CTLs exhibit superior anti-tumor efficacy, making this a potentially valuable means of achieving better adoptive immunotherapy outcomes in cancer patients.
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Weiler, M., B. Rogashev, T. Einbinder, M. J. Hausmann, J. Kaneti, C. Chaimovitz, and A. Douvdevani. "Interleukin-15, a leukocyte activator and growth factor, is produced by cortical tubular epithelial cells." Journal of the American Society of Nephrology 9, no. 7 (July 1998): 1194–201. http://dx.doi.org/10.1681/asn.v971194.
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Many renal diseases, including transplant rejection, are mediated by mononuclear cells. Interleukin-15 (IL-15) has been recently described as a cytokine with IL-2-like activity. IL-15 is an effective leukocyte growth factor, activator, and chemoattractant. In rejected human kidney allografts, elevated IL-15, but not IL-2, mRNA is expressed, suggesting a role for IL-15 in the rejection process. The aim of this study was to investigate whether human cortical tubular epithelial cells (HTC) are able to produce IL-15 and whether IL-15 expression is regulated by inflammatory mediators. HTC were isolated and characterized, and IL-15 expression was analyzed by reverse transcription-PCR, enzyme-linked immunosorbent assay, and bioactivity. It was found that HTC constitutively express IL-15. Upon stimulation of HTC with interferon-gamma (IFN gamma), the levels of both mRNA and protein increased up to twofold. In contrast, lipopolysaccharide, IL-1, IL-2, and tumor necrosis factor-alpha had no detectable effect. IFN gamma action on HTC was dose-dependent from concentrations of 5 U/ml, reaching a plateau at 50 U/ml. HTC supernatants induced proliferation of the T cell line CTLD, which could be partially blocked (50%) by specific IL-15 antibodies. This study shows that IL-15 is secreted by HTC and that the Th1-cytokine IFN gamma upregulates IL-15 expression. This suggests that HTC play a role in cell-mediated renal diseases by releasing IL-15.
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Sutmuller, Roger P. M., Leonie M. van Duivenvoorde, Andrea van Elsas, Ton N. M. Schumacher, Manon E. Wildenberg, James P. Allison, Rene E. M. Toes, Rienk Offringa, and Cornelis J. M. Melief. "Synergism of Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and Depletion of Cd25+ Regulatory T Cells in Antitumor Therapy Reveals Alternative Pathways for Suppression of Autoreactive Cytotoxic T Lymphocyte Responses." Journal of Experimental Medicine 194, no. 6 (September 17, 2001): 823–32. http://dx.doi.org/10.1084/jem.194.6.823.
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Therapeutic efficacy of a tumor cell–based vaccine against experimental B16 melanoma requires the disruption of either of two immunoregulatory mechanisms that control autoreactive T cell responses: the cytotoxic T lymphocyte–associated antigen (CTLA)-4 pathway or the CD25+ regulatory T (Treg) cells. Combination of CTLA-4 blockade and depletion of CD25+ Treg cells results in maximal tumor rejection. Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the frequency of tyrosinase-related protein 2180–188–specific CTLs detected in the periphery. Furthermore, tumor rejection is dependent on the CD8+ T cell subset. Our data demonstrate that the CTL response against melanoma antigens is an important component of the therapeutic antitumor response and that the reactivity of these CTLs can be augmented through interference with immunoregulatory mechanisms. The synergism in the effects of CTLA-4 blockade and depletion of CD25+ Treg cells indicates that CD25+ Treg cells and CTLA-4 signaling represent two alternative pathways for suppression of autoreactive T cell immunity. Simultaneous intervention with both regulatory mechanisms is therefore a promising concept for the induction of therapeutic antitumor immunity.
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Pålsson-McDermott, E. M., and L. A. J. O'Neill. "Building an immune system from nine domains." Biochemical Society Transactions 35, no. 6 (November 23, 2007): 1437–44. http://dx.doi.org/10.1042/bst0351437.
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Four families of PRRs (pattern-recognition receptors) have been identified as important components of innate immunity, participating in the sensory system for host defence against the invasion of infectious agents. The TLRs (Toll-like receptors) recognize a variety of conserved microbial PAMPs (pathogen-associated molecular patterns) derived from bacteria, viruses, protozoa and fungi. They work in synergy with the cytosolic NLRs [NOD (nucleotide binding and oligomerization domain)-like receptors] (which sense bacteria), RLRs [RIG-I (retinoic acid-inducible gene 1)-like receptors] (which sense viruses) and CLRs (C-type lectin receptors) (which sense fungi). All of these receptor families signal an increase in the expression of a range of immune and inflammatory genes. The structural architecture of these receptors is conserved, involving seven distinct domains: the LRR (leucine-rich repeat) domain, the TIR [Toll/IL (interleukin)-1 receptor] domain, the NBS (nucleotide-binding site), the CARD (caspase recruitment domain), the PYD (pyrin domain), the helicase domain and the CTLD (C-type lectin domain). Two other domains, the Ig domain and the ITAM (immunoreceptor tyrosine-based activation motif) domain also participate and are also found in antibodies and TCRs (T-cell receptors), key proteins in adaptive immunity. This total of nine domains can therefore be used to construct immune systems which are common to many, if not all, species, allowing us to speculate on the minimum requirement for a complex immune system in structural terms. These insights are important for our overall understanding of the regulation of immunity in health and disease.
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Hirai, Kaho, Saiichiro Watanabe, Nozomi Nishijima, Kaoru Shibata, Akane Hase, Tsuyoshi Yamanaka, and Masato Inazu. "Molecular and Functional Analysis of Choline Transporters and Antitumor Effects of Choline Transporter-Like Protein 1 Inhibitors in Human Pancreatic Cancer Cells." International Journal of Molecular Sciences 21, no. 15 (July 22, 2020): 5190. http://dx.doi.org/10.3390/ijms21155190.
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Choline, an organic cation, is one of the biofactors that play an important role in the structure and the function of biological membranes, and it is essential for the synthesis of phospholipids. Choline positron emission tomography-computed tomography (PET/CT) provides useful information for the imaging diagnosis of cancers, and increased choline accumulation has been identified in a variety of tumors. However, the molecular mechanisms of choline uptake and choline transporters in pancreatic cancer have not been elucidated. Here, we examined molecular and functional analyses of choline transporters in human pancreatic-cancer cell line MIA PaCa-2 and the elucidation of the action mechanism behind the antitumor effect of novel choline-transporter-like protein 1 (CTL1) inhibitors, Amb4269951 and its derivative Amb4269675. CTL1 and CTL2 mRNAs were highly expressed in MIA PaCa-2 cells, and CTL1 and CTL2 proteins were localized in the plasma membrane and the intracellular compartments, respectively. Choline uptake was characterized by Na+-independence, a single-uptake mechanism, and inhibition by choline-uptake inhibitor HC-3, similar to the function of CTL1. These results suggest that the uptake of extracellular choline in MIA PaCa-2 cells is mediated by CTL1. Choline deficiency and HC-3 treatment inhibited cell viability and increased caspase 3/7 activity, suggesting that the inhibition of CTL1 function, which is responsible for choline transport, leads to apoptosis-induced cell death. Both Amb4269951 and Amb4269675 inhibited choline uptake and cell viability and increased caspase-3/7 activity. Ceramide, which is increased by inhibiting choline uptake, also inhibited cell survival and increased caspase-3/7 activity. Lastly, both Amb4269951 and Amb4269675 significantly inhibited tumor growth in a mouse-xenograft model without any adverse effects such as weight loss. CTL1 is a target molecule for the treatment of pancreatic cancer, and its inhibitors Amb4269951 and Amb4269675 are novel lead compounds.
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Филатов, О. Ю., and В. А. Назаров. "Image-recognizing receptors of the innate immunity and their role in immunotherapy (review)." Nauchno-prakticheskii zhurnal «Patogenez», no. 4 (December 25, 2020): 4–15. http://dx.doi.org/10.25557/2310-0435.2020.04.4-15.
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Данная статья обобщает накопившуюся на сегодняшний день информацию о многообразии образраспознающих рецепторов, их роли в регуляции иммунной системы. Распознавание патогена врожденным иммунитетом происходит с помощью рецепторов к широкому спектру антигенов за счет выделения нескольких высоко консервативных структур микроорганизмов. Эти структуры были названы патоген-ассоциированные образы (Patogen-Associated Molecular Patterns - PAMP). Наиболее изученными являются липополисахарид грамм отрицательных бактерий (LPS), липотейхоевые кислоты, пептидогликан (PGN), CpG мотивы ДНК и РНК. Рецепторы, распознающие PAMP, называются PRR. Данная группа рецепторов также распознает молекулы, образующиеся при повреждении собственных тканей. Такие молекулярные структуры называются Damage-Associated Molecular Patterns (DAMP), или образы, ассоциированные с повреждением. В качестве DAMP могут выступать белки теплового шока, хроматин, фрагменты ДНК. В зависимости от локализации, образраспознающие рецепторы принято разделять на: расположенные на мембране Toll-подобные рецепторы (Toll-like receptors, TLR) и рецепторы лектина С-типа (C-type lectin receptors, CLR), а также расположенные в цитоплазме NOD-подобные рецепторы (NOD-like receptors, NLR) и цитоплазматические РНК- и ДНК-сенсоры. Сегодня у человека известно 10 типов TLR, часть из которых расположена на поверхности (TLR1-TLR6, TLR10) большинства клеток, в том числе макрофагов, В-лимфоцитов и дендритных клеток, а часть - в эндосомах (TLR3, TLR7-TLR9). CLR представляет из себя семейство рецепторов, расположенных на мембране и имеющих домены распознавания углеводов (CRD), или структурно сходные лектиноподобные домены типа C (CTLD). В данном семействе рецепторов принято по происхождению и структуре выделять 17 групп. CLR активно участвуют в противогрибковой иммунной защите, а также они играют роль в защите и от других типов микроорганизмов. NOD (нуклеотидсвязывающий и олигомеризационный домен)-подобные рецепторы расположены в цитоплазме. Благодаря этим рецепторам, патоген, который избежал распознавания на поверхности мембраны, сталкивается со вторым уровнем распознавания уже внутри клетки. В данной статье рассматриваются пути активации образраспознающих рецепторов, их эффекты и применение данных эффектов в медицине. This article summarizes currently available information about the variety of image-recognizing receptors and their role in regulation of the immune system. Pathogen recognition by the innate immunity is mediated by receptors to a wide range of antigens via recognition of several highly conservative structures of microorganisms. These structures were named pathogen-associated images or PAMP (pathogen-associated molecular pattern). The best studied types of such structures include lipopolysaccharide (LPS) of gram-negative bacteria, lipoteichoic acids, peptidoglycan (PGN), and CpG DNA and RNA motifs. PAMP-recognizing receptors (PRRS) are a group of receptors, which also recognize molecules released during damage of host tissues. Such molecular structures are called DAMPS (damage-associated molecular patterns) or damage-associated images. Heat shock proteins, chromatin, and DNA fragments may act as DAMPS. Depending on the localization, image-recognizing receptors are generally classified as membrane-located Toll-like receptors (TLR) and C-type lectin receptors (CLR), as well as cytoplasmic NOD-like receptors (NLR) and cytoplasmic RNA and DNA sensors. Today, 10 types of human TLR are known. Some of them are located on the surface (TLR1-TLR6, TLR10) of most cells, including macrophages, B-cells, and dendritic cells, and some are present in endosomes (TLR3, TLR7-TLR9). CLR is a family of membrane receptors that have carbohydrate recognition domains (CRD) or structurally similar lectin-like type C domains (CTLD). Seventeen groups are distinguished within this receptor family based on their origin and structure. CLRs are actively involved in antifungal immune defense and also play a role in protection against other types of microorganisms. NOD (nucleotide-binding and oligomerization domain)-like receptors are present in the cytoplasm. These receptors provide the second level of recognition inside the cell for the pathogens that have escaped recognition on the membrane surface. This article discusses activation pathways of image-recognizing receptors, their effects, and the use of such effects in medicine.
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Wen, Liang, Tingbo Liang, Xueli Bai, and Jianhui Zhao. "Sensitization of immunotherapeutic efficiency in HCC by polyinosinic-polycytidylic acid-triggered CXCL10 secretion in liver sinusoidal endothelial cells." Journal of Global Oncology 5, suppl (October 7, 2019): 126. http://dx.doi.org/10.1200/jgo.2019.5.suppl.126.
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126 Background: Nowadays, the efficiency of immune checkpoint blockades (ICBs) in the treatment of advanced hepatocellular carcinoma (HCC) was low. The previous study we published in Hepatology demonstrated that polyinosinic-polycytidylic acid (PolyIC), a TLR3 agonist, could trigger the accumulation, proliferation and activation of CTLs, which contributes to the enhanced anti-tumor efficiency of PD-L1 Ab in HCC. However, the mechanism remains unclear. Methods: The mouse HCC model was established by hydrodynamic transfection of combinational c-Myc/N-Ras oncogenes. PolyIC, CTLA-4 Ab, PD-L1 Ab, CD8 Ab and CXCR3 Ab were all intraperitoneal injected. Mice liver non-parenchymal cells (NPCs) were isolated after liver perfusion and multistep centrifugation. The proliferation, activation and cytotoxic function of CTLs were assessed by flow cytometry. Liver sinusoidal endothelial cells (LSECs) were isolated by magnetic cell sorting. Expressions of TLR3 and CXCL10 were quantitatively analyzed by qRT-PCR and ELISA. LSECs were cultured in vitro by using DMEM medium. Results: Combination of polyIC and PD-L1 Ab (or CTLA-4 Ab) had a synergistic anti-tumor effect on the treatment of mouse HCC. PolyIC induced the accumulation, proliferation, activation and cytotoxic function of CTLs in liver, which were further enhanced when combined ICBs. And CTLs depletion by CD8 Ab attenuated the synergistic anti-tumor effect of polyIC when combined with ICBs. TLR3 expression was much higher in NPCs than other cells in liver, especially in LSECs. Also, polyIC dramatically induced the expressions of CXCL10 in LSECs both in vivo and in vitro. And in vitro, after treated by polyIC, the CXCL10 expression in the medium and cells were all elevated. What’s more, CXCL10/CXCR3 signaling blockade by CXCR3 Ab attenuated the combinational effects of polyIC and ICBs. Meanwhile, after CXCL10/CXCR3 signaling blockade, the accumulation, proliferation and activation of CTLs were all inhibited. Conclusions: PolyIC specifically targets LSECs to induce CXCL10 expression and secretion, which contributes to the CTLs transformation and enhanced efficiency of ICBs in the treatment of HCC.
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Sheridan, Megan A., Ying Yang, Ashish Jain, Alex S. Lyons, Penghua Yang, Sambasiva R. Brahmasani, Aihua Dai, et al. "Early onset preeclampsia in a model for human placental trophoblast." Proceedings of the National Academy of Sciences 116, no. 10 (February 20, 2019): 4336–45. http://dx.doi.org/10.1073/pnas.1816150116.
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We describe a model for early onset preeclampsia (EOPE) that uses induced pluripotent stem cells (iPSCs) generated from umbilical cords of EOPE and control (CTL) pregnancies. These iPSCs were then converted to placental trophoblast (TB) representative of early pregnancy. Marker gene analysis indicated that both sets of cells differentiated at comparable rates. The cells were tested for parameters disturbed in EOPE, including invasive potential. Under 5% O2, CTL TB and EOPE TB lines did not differ, but, under hyperoxia (20% O2), invasiveness of EOPE TB was reduced. RNA sequencing analysis disclosed no consistent differences in expression of individual genes between EOPE TB and CTL TB under 20% O2, but, a weighted correlation network analysis revealed two gene modules (CTL4 and CTL9) that, in CTL TB, were significantly linked to extent of TB invasion. CTL9, which was positively correlated with 20% O2(P= 0.02) and negatively correlated with invasion (P= 0.03), was enriched for gene ontology terms relating to cell adhesion and migration, angiogenesis, preeclampsia, and stress. Two EOPE TB modules, EOPE1 and EOPE2, also correlated positively and negatively, respectively, with 20% O2conditions, but only weakly with invasion; they largely contained the same sets of genes present in modules CTL4 and CTL9. Our experiments suggest that, in EOPE, the initial step precipitating disease is a reduced capacity of placental TB to invade caused by a dysregulation of O2response mechanisms and that EOPE is a syndrome, in which unbalanced expression of various combinations of genes affecting TB invasion provoke disease onset.
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Quezada, Sergio A., Tyler R. Simpson, Karl S. Peggs, Taha Merghoub, Jelena Vider, Xiaozhou Fan, Ronald Blasberg, et al. "Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts." Journal of Experimental Medicine 207, no. 3 (February 15, 2010): 637–50. http://dx.doi.org/10.1084/jem.20091918.
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Adoptive transfer of large numbers of tumor-reactive CD8+ cytotoxic T lymphocytes (CTLs) expanded and differentiated in vitro has shown promising clinical activity against cancer. However, such protocols are complicated by extensive ex vivo manipulations of tumor-reactive cells and have largely focused on CD8+ CTLs, with much less emphasis on the role and contribution of CD4+ T cells. Using a mouse model of advanced melanoma, we found that transfer of small numbers of naive tumor-reactive CD4+ T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4+ T cells developed cytotoxic activity, and tumor rejection was dependent on class II–restricted recognition of tumors by tumor-reactive CD4+ T cells. Furthermore, blockade of the coinhibitory receptor CTL-associated antigen 4 (CTLA-4) on the transferred CD4+ T cells resulted in greater expansion of effector T cells, diminished accumulation of tumor-reactive regulatory T cells, and superior antitumor activity capable of inducing regression of spontaneous mouse melanoma. These findings suggest a novel potential therapeutic role for cytotoxic CD4+ T cells and CTLA-4 blockade in cancer immunotherapy, and demonstrate the potential advantages of differentiating tumor-reactive CD4+ cells in vivo over current protocols favoring in vitro expansion and differentiation.
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Doubrovina, Ekaterina, Banu Oflaz-Sozmen, Susan E. Prockop, Nancy A. Kernan, Sara Abramson, Julie Teruya-Feldstein, Cyrus Hedvat, et al. "Adoptive immunotherapy with unselected or EBV-specific T cells for biopsy-proven EBV+ lymphomas after allogeneic hematopoietic cell transplantation." Blood 119, no. 11 (March 15, 2012): 2644–56. http://dx.doi.org/10.1182/blood-2011-08-371971.
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AbstractWe evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ≥ 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patient's blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.
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Persechini, P. M., J. D. Young, and W. Almers. "Membrane channel formation by the lymphocyte pore-forming protein: comparison between susceptible and resistant target cells." Journal of Cell Biology 110, no. 6 (June 1, 1990): 2109–16. http://dx.doi.org/10.1083/jcb.110.6.2109.
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The assembly of pores by the pore-forming protein (perforin) of cytolytic T lymphocytes (CTLs) and natural killer cells on the membranes of different cell lines was studied. Using the patch clamp technique in the whole cell configuration, we measured the conductance increase induced by perforin in susceptible cell lines as well as in resistant CTL lines (CTLLs). The results showed that although the amplitudes of the first observed conductance steps produced in both cell types were comparable, CTLLs required at least 10-fold higher doses of perforin to form membrane pores. Outside-out patches excised from CTLL-R8, on the other hand, appeared to be more susceptible to channel formation by perforin than intact cells, as lower doses were able to induce conductance increases. Once channels were induced in CTL membranes, however, their conductances (greater than 1 nS) were indistinguishable from the ones obtained in susceptible cell lines. Fluorescence measurements with quin-2 showed that perforin induced rapid increases in the intracellular Ca2+ concentration in susceptible EL4 cells. In marked contrast, a perforin dose 60-120-fold higher than the minimal dose required to elicit Ca2+ changes in EL4 cells was not able to induce any measurable Ca2+ increase in CTLL-R8. The data suggest that the resistance of CTLs to lysis mediated by their own mediator perforin is at least in part due to their ability to avoid pore formation by this protein. The mechanism underlying this phenomenon is not yet understood, but the observation that outside-out patches excised from CTLL-R8 are more susceptible to channel formation by perforin than intact cells raises the possibility that an intracellular mechanism may be involved.
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Hernández, Javier, Alice Ko, and Linda A. Sherman. "CTLA-4 Blockade Enhances the CTL Responses to the p53 Self-Tumor Antigen." Journal of Immunology 166, no. 6 (March 15, 2001): 3908–14. http://dx.doi.org/10.4049/jimmunol.166.6.3908.
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Oudshoom, M., I. I. N. Doxiadis, B. M. Kemps-Mols, W. Verduyn, G. M. Th Schreuder, J. J. van Rood, and F. H. J. Claas. "Differential effect of HLA-C locus mismatches on the CTL precursor frequency (CTLp)." Immunology Letters 56 (May 1997): 365. http://dx.doi.org/10.1016/s0165-2478(97)86473-5.
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Oudshoom, M. "Differential effect of HLA-C locus mismatches on the CTL precursor frequency (CTLp)." Immunology Letters 56, no. 1-3 (May 1997): 365. http://dx.doi.org/10.1016/s0165-2478(97)88311-3.
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Gregory, S. R., C. Fife, J. Williams, H. Carrasco Hope, T. Andreou, F. James, R. Brownlie, J. Newton-Bishop, R. Salmond, and M. Lorger. "P08.02 Harnessing T cells to target brain metastasis." Neuro-Oncology 23, Supplement_2 (September 1, 2021): ii26. http://dx.doi.org/10.1093/neuonc/noab180.089.
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Abstract BACKGROUND Up to 60% of melanoma patients develop brain metastases (BrM). These patients have a poor prognosis and limited treatment options. Immune checkpoint inhibitors (ICI) targeting Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and Programmed cell death protein-1 (PD-1) have revolutionized the treatment of melanoma and their efficacy has been also demonstrated in melanoma BrM. Our group previously demonstrated that ICI (combined α-PD-1 and α-CTLA-4) enhances chemokine-dependent infiltration of cytotoxic T lymphocytes (CTLs) into melanoma BrMs in preclinical models, accompanied by upregulated expression of T cell attracting chemokines in tumours. Notably, CTLs infiltrating BrM expressed only some of the chemokine receptors (CRs) interacting with ICI-induced chemokines in BrM, providing a rationale to over-express the “missing” CRs in T cells to enhance their homing to tumours in the context of adoptive T cell therapy (ACT). MATERIALS AND METHODS OT-I cells were isolated from OT-I mice and differentiated ex vivo into effector (TEF) and memory (TCM) CD8+ T cells. Tumour infiltrating lymphocytes (TILs) from B16 tumour-bearing mice treated with ICI were isolated using magnetic beads, activated and expanded ex vivo. Expression of CRs and activation markers in ex vivo cultured T cells were quantified by qPCR and/or flow cytometry. The migration of human blood CD8+ T cells towards chemokines of interest were measured in ex vivo migration assays. RESULTS The same CRs that were missing on BrM-infiltrating CTLs in vivo models were also absent from OT-I TEF (CCR7low/CD44high/CD62Llow) and TCM (CCR7high/CD44low/CD62Lhigh) cells, as well as from TILs expanded ex vivo for use in ACT. Furthermore, we observed no increase in migration of human T cells towards chemokines interacting with the “missing” CRs in comparison to the baseline migration, suggesting that these CRs are also absent from human T cells. CONCLUSION Ex vivo expanded T cells that are used in ACT are missing several CRs that are interacting with chemokines upregulated in BrM. We hypothesise that the use of genetically engineered T cells expressing the “missing” CRs in ACT has the potential to enhance ACT efficacy in combination with ICI.
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Kaur, K., V. Suri, M. C. Sharma, A. Garg, A. Suri, and C. Sarkar. "P04.19 Analysis of tumor immune microenvironment and immune checkpoint modulators across infantile and pediatric pilocytic astrocytomas to elucidate the role of immunotherapy in these tumors." Neuro-Oncology 21, Supplement_3 (August 2019): iii33. http://dx.doi.org/10.1093/neuonc/noz126.114.
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Abstract BACKGROUND Pilocytic astrocytomas are the most common central nervous system tumors in pediatric age-group. Although grade I, some of the cases show recurrence and progression, and few might not be amenable to surgery due to location or size, and hence have a less favorable prognosis. Drugs blocking immune check-point interactions such as those including programmed cell death ligand-1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are now in clinical use for certain tumors. We performed this study to understand the potential candidature of pilocytic astrocytomas in infants and children for immunotherapy by analyzing the expression of immune checkpoint proteins and immune infiltrate, and correlating with clinical details, wherever possible. MATERIALS AND METHODS Cases with adequate tissue (2010–2017) diagnosed in pediatric age-group (<18 years) were retreived from the archives of Department of Pathology, AIIMS, New Delhi. Immunohistochemistry for PD-L1 (SP263, Ventana), CTLA-4, CD3, CD8, CD4 and CD68 was performed. Quantification of cytotoxic lymphocytes was done using digital imaging in the core of the tumor. RESULTS A total of 50 pilocytic astrocytomas were included, 14 of them were <3 years (infants), while 36 were of pediatric age-group (3–18 years). Overall, male preponderance was noted. Cerebellum was the most common location, followed by 4th venrticle, optic pathway, hypothalamus, cerebrum and thalamus. Almost all CD3 lymphocytes were cytotoxic T-lymphocyes (CD8 positive, CTLs). Helper T-lymphocyte infiltration was not seen. Median CTL density/mm3 was 13/mm3(Range:1–85/mm3). CTLA-4 was positive in 4 cases, positivity ranged from 1–4 cells/lpf. PD-L1 was found to be positive in 7 cases, and the positivity ranged from 1+ to 2+ in 1 to 5% of tumor cells. A median TAM (tumor associated macrophages) density of 44/hpf (range: 1–98/hpf) was noted. There was no correlation of CTL density with PD-L1 or CTLA-4 expression, and neither with TAM density. On correlation with clinical parameters, a higher density of CTLs and TAMs was noted in infants, and a higher proportion of cases revealed PD-L1 positivity, though not statistically significant. There was no correlation of TILs or TAMs with the tumor location. CONCLUSION Immune check point blockade using PD-(L)1 or CTLA4 inhibitors may not be a potential therapeutic option for unresectable or recurrent pilocytic astrocytomas, as low positivity rate as well as extremely low percentage of tumor/ immune cells found to be positive. However, alternate forms of immunotherapy might be helpful as most of the cases showed immune infiltrates and a high density of tumor-associated macrophages (TAMs). Large scale studies with larger numbers and longer follow-up periods including in-vitro and clinical studies are warranted for decoding the tumor immunogram.
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van Elsas, Andrea, Arthur A. Hurwitz, and James P. Allison. "Combination Immunotherapy of B16 Melanoma Using Anti–Cytotoxic T Lymphocyte–Associated Antigen 4 (Ctla-4) and Granulocyte/Macrophage Colony-Stimulating Factor (Gm-Csf)-Producing Vaccines Induces Rejection of Subcutaneous and Metastatic Tumors Accompanied by Autoimmune Depigmentation." Journal of Experimental Medicine 190, no. 3 (August 2, 1999): 355–66. http://dx.doi.org/10.1084/jem.190.3.355.
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We examined the effectiveness of cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)–expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6. Recently established tumors could be eradicated in 80% (68/85) of the cases using combination treatment, whereas each treatment by itself showed little or no effect. Tumor rejection was dependent on CD8+ and NK1.1+ cells but occurred irrespective of the presence of CD4+ T cells. Mice surviving a primary challenge rejected a secondary challenge with B16-BL6 or the parental B16-F0 line. The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival. Of all mice surviving B16-BL6 or B16-F10 tumors after combination treatment, 56% (38/68) developed depigmentation, starting at the site of vaccination or challenge and in most cases progressing to distant locations. Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs. This study shows that CTLA-4 blockade provides a powerful tool to enhance T cell activation and memory against a poorly immunogenic spontaneous murine tumor and that this may involve recruitment of autoreactive T cells.
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Iwao, Beniko, Miki Yara, Naomi Hara, Yuiko Kawai, Tsuyoshi Yamanaka, Hiroshi Nishihara, Takeshi Inoue, and Masato Inazu. "Functional expression of choline transporter like-protein 1 (CTL1) and CTL2 in human brain microvascular endothelial cells." Neurochemistry International 93 (February 2016): 40–50. http://dx.doi.org/10.1016/j.neuint.2015.12.011.
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Marzolini, Maria A. V., Ayse Akarca, Karen Teng, Teresa Marafioti, Satyen H. Gohil, Amit C. Nathwani, Evan Newell, Sergio A. Quezada, and Karl S. Peggs. "Cytotoxic CD4+ Cells in Chronic Lymphocytic Leukaemia: An Extended Immunophenotypic Analysis Examining Their Association with Cytomegalovirus Serostatus and Similarities with Cytotoxic CD8+ Cells." Blood 132, Supplement 1 (November 29, 2018): 3130. http://dx.doi.org/10.1182/blood-2018-99-116798.
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Abstract Introduction: CD4+ T lymphocytes play a fundamental role in the adaptive immune system and traditionally their principle function has been seen as one of a 'helper' cell, interacting with and activating fellow immune cells to orchestrate and regulate the degree of immune response. There is a subset of CD4+T lymphocytes, however, that have the ability to acquire a cytotoxic phenotype. These cytotoxic CD4+ cells have been shown to have anti-viral functions but also they have previously been reported to exhibit anti-tumour effects in murine models of solid organ malignancies e.g. melanoma. The aim of this research was to identify, quantify and characterise cytotoxic CD4+ cells (CD4+ CTLs) in patients with Chronic Lymphocytic Leukaemia (CLL), to examine their association with cytomegalovirus (CMV) and to investigate the phenotype differences of the CD4+ CTLs isolated from patients who were CMV seropositive and seronegative. Methods: The peripheral blood (PB) from 90 patients with stable CLL (that was not requiring therapy) was collected after ethical approval and consent had been obtained. Flow cytometry was performed to identify and quantify the level of cytotoxic CD4+ cells (as defined as CD4+ Granzyme B+ cells) and to characterise the extended immunophenotype of the cells including transcription factors (including GATA-3, FoxP3, Eomes and Tbet) and co-inhibitory and co-stimulatory molecules (including LAG-3, TIM3, CTLA-4, PD-1, ICOS, OX40 and 4-1BB). In a subset of patients, serial samples of PB were collected to assess whether the quantity of cytotoxic CD4 cells changed over time in untreated CLL patients. Mass cytometry was performed to detect a broad range of surface molecules and to compare the extended phenotype of CD4+ (including CD4+ CTLs) and CD8+ cells in patients who were CMV seropositive and CMV seronegative in 14 patients with untreated CLL. An analysis of the CLL tumour environment was performed using multi-colour immunohistochemistry to detect CD4+ CTLs in paired bone marrow trephine and lymph node biopsies from a subset of patients. The expression of co-inhibitory and co-stimulatory molecules on the CD4+ CTLs was also examined in the bone marrow and lymph node biopsies. Results: The median age of the patients was 67 years (range: 41-90 years) with 29 females and 61 males. Fourteen patients had previously required treatment for CLL but were not currently on treatment and 76 patients had never required treatment. There was a significant increase in the percentage of CD4+ CTLs in the PB of those patients who were CMV seropositive when compared to those who were CMV seronegative (P<0.0001). Forty-five patients had PB samples collected at two different time-points and the median time between the two samples was 189 days (range: 7-735 days). The median difference in CD4+CTL values between the 2 samples for this group of patients was 0.19% (range: -25 - 46%). The extended immunophenotyping of the CD4+ CTLs showed that they had a phenotype more similar to cytotoxic CD8+ cells than non-cytotoxic CD4+ cells, with respect to both their transcription factor and checkpoint molecule expression. The mass cytometry analysis showed that there were significant differences in the expression of surface markers on CD4+ CTLs present in the PB of patients who were CMV seropositive compared with those who were CMV seronegative. The CD4+ CTLs were identified in both the bone marrow and lymph node biopsies. There was a significantly higher percentage of CD4+CTLs in the bone marrow trephine biopsies than in the lymph node biopsies (P=0.0068). Conclusions: This research identifies the presence of CD4+ CTLs in the PB, bone marrow and lymph node biopsies of patients with CLL. The transcription factor profile of CD4+ CTLs was more similar to cytotoxic CD8+ cells than non-cytotoxic CD4+ cells. Although a significantly higher percentage of CD4+CTLs was identified in patients who were CMV seropositive, CMV seronegative patients still retained a measurable population of CD4+ CTLs. The CD4+ CTLs in patients who were CMV seronegative had phenotypic differences when compared with CD4+ CTLs isolated from CMV seropositive patients, which may indicate an alternative, non-anti-viral function. Further research is required to explore whether the alternative function of CD4+ CTLs in CLL is an anti-tumour effect and to investigate the potential to harness them for therapeutic benefit in anti-tumour immunotherapies. Disclosures Nathwani: Freeline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BioMarin: Consultancy, Patents & Royalties; UniQure: Patents & Royalties.
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Matsuo, Kazuhiko, Osamu Yoshie, Kosuke Kitahata, Momo Kamei, Yuta Hara, and Takashi Nakayama. "Recent Progress in Dendritic Cell-Based Cancer Immunotherapy." Cancers 13, no. 10 (May 20, 2021): 2495. http://dx.doi.org/10.3390/cancers13102495.
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Cancer immunotherapy aims to treat cancer by enhancing cancer-specific host immune responses. Recently, cancer immunotherapy has been attracting much attention because of the successful clinical application of immune checkpoint inhibitors targeting the CTLA-4 and PD-1/PD-L1 pathways. However, although highly effective in some patients, immune checkpoint inhibitors are beneficial only in a limited fraction of patients, possibly because of the lack of enough cancer-specific immune cells, especially CD8+ cytotoxic T-lymphocytes (CTLs), in the host. On the other hand, studies on cancer vaccines, especially DC-based ones, have made significant progress in recent years. In particular, the identification and characterization of cross-presenting DCs have greatly advanced the strategy for the development of effective DC-based vaccines. In this review, we first summarize the surface markers and functional properties of the five major DC subsets. We then describe new approaches to induce antigen-specific CTLs by targeted delivery of antigens to cross-presenting DCs. In this context, the chemokine receptor XCR1 and its ligand XCL1, being selectively expressed by cross-presenting DCs and mainly produced by activated CD8+ T cells, respectively, provide highly promising molecular tools for this purpose. In the near future, CTL-inducing DC-based cancer vaccines may provide a new breakthrough in cancer immunotherapy alone or in combination with immune checkpoint inhibitors.
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Prockop, Susan E., Ekaterina Doubrovina, Farid Boulad, Nancy A. Kernan, Rachel Kobos, Andromachi Scaradavou, Sara J. Abramson, Michael Laquaglia, Anita Price, and Richard J. O’Reilly. "Adoptive Treatment Of EBV-Associated Leiomyosarcoma In Immunodeficient Patients With EBV Specific Cytotoxic T Cells." Blood 122, no. 21 (November 15, 2013): 3267. http://dx.doi.org/10.1182/blood.v122.21.3267.3267.
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Abstract Epstein-Barr virus (EBV)-associated smooth muscle tumors or leiomyosarcomas (EBV LMS) are extremely rare. These tumors develop in patients with acquired or underlying immune deficiency including those after solid organ transplant (SOT) and exhibit a latency type II phenotype. EBV LMSs are typically aggressive and respond poorly to conventional therapy. As part of an on-going trial of EBV specific cytotoxic T lymphocytes for the treatment of EBV related malignancies we have treated 5 patients with EBV LMS with cytotoxic T cell lines generated from normal donors. Five patients, three after SOT (kidney N=1, small bowel N=2), one after solid organ (kidney) and hematopoetic stem cell transplant, and one with a poorly defined underlying immune deficiency syndrome developed EBV LMS. Two patients were successfully treated for EBV lymphoproliferative disease prior to developing EBV LMS. EBV LMS was diagnosed 18 – 46 months after SOT in 4 patients, at 9 years old in the fifth and were multifocal at diagnosis in all 5 patients. All four patients who had undergone SOT failed to respond to decreased immune suppression, one had failed treatment with autologous EBV CTLs and two had failed cytotoxic chemotherapy. The EBV LMS was of host origin in 4/5 patients and of mixed donor and host origin in one. Lines of EBV CTLs were generated as previously described by co-culture of donor peripheral blood T lymphocytes with autologous EBV transformed BLCLs. Lines are tested for EBV specific cytotoxicity, sterility and absence of alloreactivity. Patients with EBV LMS were treated with cell lines generated from unrelated as well as related donors. Three patients received EBV CTLs generated from related haplo-identical parent donors including one whose parental donor was also the donor of her transplanted kidney. One patient received EBV CTLs from an HLA identical related donor. All other lines were generated from 3rd parties. Lines from unrelated third party donors were matched at 2 – 4/8 HLA alleles. In all instances EBV directed cytotoxicity of infused lines was restricted by HLA alleles shared by the patient and the EBV LMS. Three patients achieved partial remissions (PR) lasting 18 – 122 months and one patient has had stable disease for >80 months. One patient had stable disease for 14 months before progression. Expansion of EBV CTLp was demonstrated in all patients after infusion of EBV CTLs lasting from 0.5 to 4 months. Based on the prediction that 3rd party partially matched EBV CTLs are unlikely to persist long term in vivo four of the patients have received multiple cycles of EBV CTLs in an effort to maintain these responses. EBV directed cytotoxic T cell therapy is a novel treatment strategy for EBV LMS, a malignancy that is typically associated with a very poor prognosis. EBV CTLs from immunologically normal, partially HLA-matched third party donors, appropriately specific and HLA restricted can induce significant and durable responses to EBV LMS. Approaches designed to selectively expand T-cells specific for EBV antigens expressed by these malignancies may further improve responses. Disclosures: No relevant conflicts of interest to declare.
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Offit, P. A., S. L. Cunningham, and K. I. Dudzik. "Memory and distribution of virus-specific cytotoxic T lymphocytes (CTLs) and CTL precursors after rotavirus infection." Journal of Virology 65, no. 3 (1991): 1318–24. http://dx.doi.org/10.1128/jvi.65.3.1318-1324.1991.
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Gregerson, Dale S., Kathleen L. Lew, Scott W. McPherson, Neal D. Heuss, and Deborah A. Ferrington. "RPE Cells Resist Bystander Killing by CTLs, but Are Highly Susceptible to Antigen-Dependent CTL Killing." Investigative Opthalmology & Visual Science 47, no. 12 (December 1, 2006): 5385. http://dx.doi.org/10.1167/iovs.06-0636.
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Pedersen, Anders E., and Franca Ronchese. "CTLA-4 blockade during dendritic cell based booster vaccination influences dendritic cell survival and CTL expansion." Journal of Immune Based Therapies and Vaccines 5, no. 1 (2007): 9. http://dx.doi.org/10.1186/1476-8518-5-9.
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Pandolfi, F., R. Cianci, D. Pagliari, F. Casciano, C. Bagalà, A. Astone, R. Landolfi, and C. Barone. "The Immune Response to Tumors as a Tool toward Immunotherapy." Clinical and Developmental Immunology 2011 (2011): 1–12. http://dx.doi.org/10.1155/2011/894704.
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Until recently cancer medical therapy was limited to chemotherapy that could not differentiate cancer cells from normal cells. More recently with the remarkable mushroom of immunology, newer tools became available, resulting in the novel possibility to attack cancer with the specificity of the immune system. Herein we will review some of the recent achievement of immunotherapy in such aggressive cancers as melanoma, prostatic cancer, colorectal carcinoma, and hematologic malignancies. Immunotherapy of tumors has developed several techniques: immune cell transfer, vaccines, immunobiological molecules such as monoclonal antibodies that improve the immune responses to tumors. This can be achieved by blocking pathways limiting the immune response, such as CTLA-4 or Tregs. Immunotherapy may also use cytokines especially proinflammatory cytokines to enhance the activity of cytotoxic T cells (CTLs) derived from tumor infiltrating lymphocytes (TILs). The role of newly discovered cytokines remains to be investigated. Alternatively, an other mechanism consists in enhancing the expression of TAAs on tumor cells. Finally, monoclonal antibodies may be used to target oncogenes.