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https://www.readbyqxmd.com/read/28939757/pd-1-blockade-promotes-epitope-spreading-in-anticancer-cd8-t-cell-responses-by-preventing-fratricidal-death-of-subdominant-clones-to-relieve-immunodomination
#1
Arash Memarnejadian, Courtney E Meilleur, Christopher R Shaler, Khashayarsha Khazaie, Jack R Bennink, Todd D Schell, S M Mansour Haeryfar
The interactions between programmed death-1 (PD-1) and its ligands hamper tumor-specific CD8(+) T cell (TCD8) responses, and PD-1-based "checkpoint inhibitors" have shown promise in certain cancers, thus revitalizing interest in immunotherapy. PD-1-targeted therapies reverse TCD8 exhaustion/anergy. However, whether they alter the epitope breadth of TCD8 responses remains unclear. This is an important question because subdominant TCD8 are more likely than immunodominant clones to escape tolerance mechanisms and may contribute to protective anticancer immunity...
September 22, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28939412/th1-signatures-are-present-in-the-lower-airways-of-children-with-severe-asthma-regardless-of-allergic-status
#2
Julia A Wisniewski, Lyndsey M Muehling, Jacob D Eccles, Brian J Capaldo, Rachana Agrawal, Debbie-Ann Shirley, James T Patrie, Lisa J Workman, Alexander J Schuyler, Monica G Lawrence, W Gerald Teague, Judith A Woodfolk
BACKGROUND: The pathogenesis of severe asthma in childhood remains poorly understood. OBJECTIVE: To construct the immunological landscape in the airways of children with severe asthma. METHODS: Comprehensive analysis of multiple cell types and mediators was performed by flow cytometry and multiplex assay using bronchoalveolar lavage (BAL) specimens (n=68) from 52 highly characterized allergic and non-allergic children (0.5-17 years) with severe treatment-refractory asthma...
September 19, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28937972/a-risk-factor-analysis-of-cognitive-impairment-in-elderly-patients-with-chronic-diseases-in-a-chinese-population
#3
Ye Li, Xiang Fang, Wei-Gang Zhao, Yan Chen, Shi-Lian Hu
BACKGROUND This study analyzed the risk factors of cognitive impairment (CI) in elderly patients with chronic diseases. MATERIAL AND METHODS In total of 385 elderly patients with chronic diseases were selected and assigned into CI and normal groups. The activities of daily living (ADL), global deterioration scale (GDS), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment Scale (MoCA), patient-generated subjective global assessment (PG-SGA), and mini nutritional assessment (MNA) were performed to analyze the differences between the 2 groups...
September 22, 2017: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/28935575/non-pathological-infection-of-macaques-by-an-attenuated-mycobacterial-vaccine-is-not-reactivated-in-the-setting-of-hiv-coinfection
#4
Taylor Wayne Foreman, Ashley Victoria Veatch, Denae Nadine LoBato, Peter John Didier, Lara Angela Doyle-Meyers, Kasi Elizabeth Russell-Lodrigue, Andrew Alan Lackner, Konstantin Gus Kousoulas, Shabaana Abdul Khader, Deepak Kaushal, Smriti Mehra
Failure to replace BCG with efficacious anti-TB vaccines have prompted out-of-the-box thinking, including pulmonary vaccination in order to elicit local immunity. MtbΔsigH, a stress-response attenuated strain, protected against lethal TB when used to vaccinate macaques via inhalation. While live mycobacterial vaccines show promising efficacy, HIV co-infection and the resulting immunodeficiency prompts safety concerns about their use. We assessed the persistence and safety of MtbΔsigH, delivered directly to the lungs, in the setting of HIV coinfection...
September 18, 2017: American Journal of Pathology
https://www.readbyqxmd.com/read/28934479/targeted-reconstruction-of-t-cell-receptor-sequence-from-single-cell-rna-seq-links-cdr3-length-to-t-cell-differentiation-state
#5
Shaked Afik, Kathleen B Yates, Kevin Bi, Samuel Darko, Jernej Godec, Ulrike Gerdemann, Leo Swadling, Daniel C Douek, Paul Klenerman, Eleanor J Barnes, Arlene H Sharpe, W Nicholas Haining, Nir Yosef
The T cell compartment must contain diversity in both T cell receptor (TCR) repertoire and cell state to provide effective immunity against pathogens. However, it remains unclear how differences in the TCR contribute to heterogeneity in T cell state. Single cell RNA-sequencing (scRNA-seq) can allow simultaneous measurement of TCR sequence and global transcriptional profile from single cells. However, current methods for TCR inference from scRNA-seq are limited in their sensitivity and require long sequencing reads, thus increasing the cost and decreasing the number of cells that can be feasibly analyzed...
September 19, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28934428/hiv-infected-children-have-elevated-levels-of-pd-1-memory-cd4-t-cells-with-low-proliferative-capacity-and-high-inflammatory-cytokine-effector-functions
#6
Julia Foldi, Lina Kozhaya, Bret McCarty, Mussa Mwamzuka, Fatma Marshed, Tiina Ilmet, Max Kilberg, Adam Kravietz, Aabid Ahmed, William Borkowsky, Derya Unutmaz, Alka Khaitan
Background: During human immunodeficiency virus (HIV) disease, chronic immune activation leads to T-cell exhaustion. PD-1 identifies "exhausted" CD8 T cells with impaired HIV-specific effector functions, but its role on CD4 T cells and in HIV-infected children is poorly understood. Methods: In a Kenyan cohort of vertically HIV-infected children, we measured PD-1+ CD4 T-cell frequencies and phenotype by flow cytometry and their correlation with HIV disease progression and immune activation...
September 15, 2017: Journal of Infectious Diseases
https://www.readbyqxmd.com/read/28934217/elevated-humoral-response-to-cytomegalovirus-in-hiv-infected-individuals-with-poor-cd4-t-cell-immune-recovery
#7
Elisabet Gómez-Mora, Marta Massanella, Elisabet García, David Giles, Marta Bernadó, Victor Urrea, Jorge Carrillo, Dan Ouchi, Jordi Puig, Eugenia Negredo, Bonaventura Clotet, Julià Blanco, Cecilia Cabrera
Some HIV-infected c-ART-suppressed individuals show incomplete CD4+ T-cell recovery, abnormal T-cell activation and higher mortality. One potential source of immune activation could be coinfection with cytomegalovirus (CMV). IgG and IgM levels, immune activation, inflammation and T-cell death in c-ART-suppressed individuals with CD4+ T-cell counts >350 cells/μL (immunoconcordant, n = 133) or <350 cells/μL (immunodiscordant, n = 95) were analyzed to evaluate the effect of CMV humoral response on immune recovery...
2017: PloS One
https://www.readbyqxmd.com/read/28932640/co-delivery-of-the-nkt-agonist-%C3%AE-galactosylceramide-and-tumor-antigens-to-cross-priming-dendritic-cells-breaks-tolerance-to-self-antigens-and-promotes-antitumor-responses
#8
Reem Ghinnagow, Julie De Meester, Luis Javier Cruz, Caroline Aspord, Stéphanie Corgnac, Elodie Macho-Fernandez, Daphnée Soulard, Josette Fontaine, Laurence Chaperot, Julie Charles, Fabrice Soncin, Fathia Mami-Chouaib, Joel Plumas, Christelle Faveeuw, François Trottein
Vaccines designed to abrogate the tolerance of tumor self-antigens and amplify cytotoxic CD8(+) T cells (CTLs) have promise for the treatment of cancer. Type I natural killer (NKT) cells have attracted considerable interest in the cancer therapy field. In the current study, we have exploited the unique ability of NKT cells to serve as T-helper cells to license dendritic cells (DCs) for cross priming with the aim to generate efficient CTL antitumor responses. To this end, we designed a nanoparticle-based vaccine to target cross-priming DCs via the Clec9a endocytic pathway...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28931520/dna-priming-increases-frequency-of-t-cell-responses-to-a-vsv-hiv-vaccine-with-specific-enhancement-of-cd8-t-cell-responses-by-il-12-pdna
#9
Shuying S Li, Nidhi K Kochar, Marnie Elizaga, Christine M Hay, Gregory J Wilson, Kristen W Cohen, Stephen C De Rosa, Rong Xu, Ayuko Ota-Setlik, Daryl Morris, Greg Finak, Mary Allen, Hong-Van Tieu, Ian Frank, Magdalena E Sobieszczyk, Drew Hannaman, Raphael Gottardo, Peter B Gilbert, Georgia D Tomaras, Lawrence Corey, David K Clarke, Michael A Egan, John H Eldridge, M Juliana McElrath, Nicole Frahm
HVTN 087 assessed the effect of increasing doses of pIL-12 adjuvant on the immunogenicity of a HIV-1 multi-antigen (MAG) DNA vaccine delivered by electroporation and boosted with an attenuated VSV-Gag vaccine. We randomized 100 healthy adults to receive placebo, or 3mg HIV-MAG (gag/pol, env, nef/tat/vif) DNA vaccine co-administered with pIL-12 at 0μg, 250μg, 1,000μg or 1,500μg intramuscularly by electroporation at 0, 1 and 3 months followed by intramuscular inoculation with 3.4×10(7) PFU VSV-Gag vaccine at 6 months...
September 20, 2017: Clinical and Vaccine Immunology: CVI
https://www.readbyqxmd.com/read/28930701/leukocyte-telomere-length-t-cell-composition-and-dna-methylation-age
#10
Brian H Chen, Cara L Carty, Masayuki Kimura, Jeremy D Kark, Wei Chen, Shengxu Li, Tao Zhang, Charles Kooperberg, Daniel Levy, Themistocles Assimes, Devin Absher, Steve Horvath, Alexander P Reiner, Abraham Aviv
Both leukocyte telomere length (LTL) and DNA methylation age are strongly associated with chronological age. One measure of DNA methylation age─ the extrinsic epigenetic age acceleration (EEAA)─ is highly predictive of all-cause mortality. We examined the relation between LTL and EEAA. LTL was measured by Southern blots and leukocyte DNA methylation was determined using Illumina Infinium HumanMethylation450 BeadChip in participants in the Women's Health Initiative (WHI; n=804), the Framingham Heart Study (FHS; n=909) and the Bogalusa Heart study (BHS; n=826)...
September 20, 2017: Aging
https://www.readbyqxmd.com/read/28930685/human-tissue-resident-memory-t-cells-are-defined-by-core-transcriptional-and-functional-signatures-in-lymphoid-and-mucosal-sites
#11
Brahma V Kumar, Wenji Ma, Michelle Miron, Tomer Granot, Rebecca S Guyer, Dustin J Carpenter, Takashi Senda, Xiaoyun Sun, Siu-Hong Ho, Harvey Lerner, Amy L Friedman, Yufeng Shen, Donna L Farber
Tissue-resident memory T cells (TRMs) in mice mediate optimal protective immunity to infection and vaccination, while in humans, the existence and properties of TRMs remain unclear. Here, we use a unique human tissue resource to determine whether human tissue memory T cells constitute a distinct subset in diverse mucosal and lymphoid tissues. We identify a core transcriptional profile within the CD69(+) subset of memory CD4(+) and CD8(+) T cells in lung and spleen that is distinct from that of CD69(-) TEM cells in tissues and circulation and defines human TRMs based on homology to the transcriptional profile of mouse CD8(+) TRMs...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28930287/exposure-to-human-alveolar-lining-fluid-enhances-mycobacterium-bovis-bcg-vaccine-efficacy-against-mycobacterium-tuberculosis-infection-in-a-cd8-t-cell-dependent-manner
#12
J I Moliva, A P Hossfeld, C H Canan, V Dwivedi, M D Wewers, G Beamer, J Turner, J B Torrelles
Current tuberculosis (TB) treatments include chemotherapy and preventative vaccination with Mycobacterium bovis Bacillus Calmette-Guérin (BCG). In humans, however, BCG vaccination fails to fully protect against pulmonary TB. Few studies have considered the impact of the human lung mucosa (alveolar lining fluid (ALF)), which modifies the Mycobacterium tuberculosis (M.tb) cell wall, revealing alternate antigenic epitopes on the bacterium surface that alter its pathogenicity. We hypothesized that ALF-induced modification of BCG would induce better protection against aerosol infection with M...
September 20, 2017: Mucosal Immunology
https://www.readbyqxmd.com/read/28929596/hypogammaglobulinemia-in-children-a-warning-sign-to-look-deeply
#13
Karina Mescouto de Melo, Maria Isabel de Moraes-Pinto, Luís E C Andrade, Reinaldo Salomão, Milena K C Brunialti, Vanessa S Ferreira, Beatriz T Costa-Carvalho
This study investigated phenotypic and functional characteristics of lymphocytes in children with common variable immunodeficiency (CVID) and unclassified hypogammaglobulinemia (UH), as well as B-cell subsets in non-consanguineous parents. Blood samples of 30 children, CVID (n = 9), UH (n = 9), healthy donors HD (n = 12), and 19 adults (parents and controls) were labeled by a combination of surface markers to identify CD4, CD8 T-cell and B-cell subpopulations. T-cell cytokine production in children was analyzed in vitro after stimulation with phytohemagglutinin (PHA) and tetanus toxoid...
October 2017: APMIS: Acta Pathologica, Microbiologica, et Immunologica Scandinavica
https://www.readbyqxmd.com/read/28928269/perturbed-cd8-t-cell-immunity-across-universal-influenza-epitopes-in-the-elderly
#14
Thi H O Nguyen, Sneha Sant, Nicola L Bird, Emma J Grant, E Bridie Clemens, Marios Koutsakos, Sophie A Valkenburg, Stephanie Gras, Martha Lappas, Anthony Jaworowski, Jane Crowe, Liyen Loh, Katherine Kedzierska
Influenza epidemics lead to severe illness, life-threatening complications, and deaths, especially in the elderly. As CD8(+) T cells are associated with rapid recovery from influenza, we investigated the effects of aging on antigen-specific CD8(+) T cells across the universal influenza epitopes in humans. We show that aging is characterized by altered frequencies in T cell subsets, with naive T cells being partially replaced by activated effector/memory populations. Although we observed no striking differences in TCR signaling capacity, T cells in the elderly had increased expression of transcription factors Eomes and T-bet, and such changes were most apparent in CD8(+) T cells...
September 19, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28927891/vitiligo-skin-is-imprinted-with-resident-memory-cd8-t-cells-expressing-cxcr3
#15
Katia Boniface, Clément Jacquemin, Anne-Sophie Darrigade, Benoît Dessarthe, Christina Martins, Nesrine Boukhedouni, Charlotte Vernisse, Alexis Grasseau, Denis Thiolat, Jérôme Rambert, Fabienne Lucchese, Antoine Bertolotti, Khaled Ezzedine, Alain Taieb, Julien Seneschal
Vitiligo is a chronic auto-immune depigmenting skin disorder that results from a loss of melanocytes. Multiple combinatorial factors have been involved in disease development, with a prominent role of the immune system, in particular T cells. After repigmentation, vitiligo frequently recurs in the same area, suggesting that vitiligo could involve the presence of resident memory T cells (TRM). We sought to perform a thorough characterization of the phenotype and function of skin memory T cells in vitiligo. We show that stable and active vitiligo perilesional skin is enriched with a population of CD8 TRM expressing both CD69 and CD103 compared to psoriasis and control unaffected skin...
September 16, 2017: Journal of Investigative Dermatology
https://www.readbyqxmd.com/read/28924369/il-12-influence-mtor-to-modulate-cd8-t-cells-differentiation-through-t-bet-and-eomesodermin-in-response-to-invasive-pulmonary-aspergillosis
#16
Hao Wang, Jingdong Li, Qiyang Han, Fei Yang, Yu Xiao, Meng Xiao, Yingchun Xu, Longxiang Su, Na Cui, Dawei Liu
Objective: To investigate whether mTOR signaling pathway regulate the proliferation and differentiation of CD8(+) T cells by transcription factors T-bet and Eomes, and explore the role of IL-12 in this biological procedure. Methods: Aspergillus fumigatus spore suspension nasal inhalation was used to establish the invasive pulmonary aspergillosis (IPA) mouse model. After inoculation, rapamycin (2mg/kg) each day or IL-12 (5ug/kg) every other day was given for 7 days. The blood samples were obtained before the mice sacrificed and lung specimens were taken...
2017: International Journal of Medical Sciences
https://www.readbyqxmd.com/read/28924019/kinetics-and-biomarkers-of-severe-cytokine-release-syndrome-after-cd19-chimeric-antigen-receptor-modified-t-cell-therapy
#17
Kevin A Hay, Laïla-Aïcha Hanafi, Daniel Li, Juliane Gust, W Conrad Liles, Mark M Wurfel, José A López, Junmei Chen, Dominic Chung, Susanna Harju-Baker, Sindhu Cherian, Xueyan Chen, Stanley R Riddell, David G Maloney, Cameron J Turtle
Lymphodepletion chemotherapy followed by infusion of CD19-specific chimeric antigen receptor-modified T cells (CAR-T) has produced impressive antitumor responses in patients with refractory CD19(+) B cell malignancies, but is often associated with cytokine release syndrome (CRS). Our understanding of CRS continues to evolve, and identification of the kinetics of CRS and predictive clinical and laboratory biomarkers of severity are needed to evaluate strategies to mitigate toxicity. We report the clinical presentation and identify biomarkers of severe CRS in 133 adult patients who received CD19 CAR-T cells...
September 18, 2017: Blood
https://www.readbyqxmd.com/read/28920005/the-frequency-of-neoantigens-per-somatic-mutation-rather-than-overall-mutational-load-or-number-of-predicted-neoantigens-per-se-is-a-prognostic-factor-in-ovarian-clear-cell-carcinoma
#18
Hirokazu Matsushita, Kosei Hasegawa, Katsutoshi Oda, Shogo Yamamoto, Akira Nishijima, Yuichi Imai, Kayo Asada, Yuji Ikeda, Takahiro Karasaki, Keiichi Fujiwara, Hiroyuki Aburatani, Kazuhiro Kakimi
Neoantigens derived from tumor-specific somatic mutations are excellent targets for anti-tumor immune responses. In ovarian clear cell carcinoma (OCCC), checkpoint blockade yields durable responses in a subset of patients. To approach the question of why only some patients respond, we first investigated neoantigen loads and immune signatures using exome sequencing and expression array data for 74 OCCC patients treated conventionally. Neither the number of missense mutations nor total predicted neoantigens assessed in the tumor correlated with clinical outcomes...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28919997/increased-infiltration-and-tolerised-antigen-specific-cd8-tem-cells-in-tumor-but-not-peripheral-blood-have-no-impact-on-survival-of-hcmv-glioblastoma-patients
#19
M Bahador, A Gras Navarro, M A Rahman, M Dominguez-Valentin, S Sarowar, E Ulvestad, G Njølstad, S A Lie, E K Kristoffersen, E Bratland, M Chekenya
Human cytomegalovirus (HCMV) antigens in glioblastoma (GBM) present opportunities for personalised immunotherapy. However, their presence in GBM tissue is still under debate, and evidence of their impact on functional immune responses and prognosis is sparse. Here, we investigated the presence of pp65 (UL83) and immediate early 1 (IE-1) HCMV antigens in a cohort of Norwegian GBM patients (n = 177), using qPCR, immunohistochemistry, and serology. HCMV status was then used to investigate whether viral antigens influenced immune cell phenotype, infiltration, activation and patient survival...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28918040/codon-optimized-p1a-encoding-dna-vaccine-toward-a-therapeutic-vaccination-against-p815-mastocytoma
#20
Alessandra Lopes, Kevin Vanvarenberg, Véronique Préat, Gaëlle Vandermeulen
DNA vaccine can be modified to increase protein production and modulate immune response. To enhance the efficiency of a P815 mastocytoma DNA vaccine, the P1A gene sequence was optimized by substituting specific codons with synonymous ones while modulating the number of CpG motifs. The P815A murine antigen production was increased with codon-optimized plasmids. The number of CpG motifs within the P1A gene sequence modulated the immunogenicity by inducing a local increase in the cytokines involved in innate immunity...
September 15, 2017: Molecular Therapy. Nucleic Acids
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