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https://www.readbyqxmd.com/read/29751636/design-synthesis-and-evaluation-of-novel-immunomodulatory-small-molecules-targeting-the-cd40%C3%A2-cd154-costimulatory-protein-protein-interaction
#1
Damir Bojadzic, Jinshui Chen, Oscar Alcazar, Peter Buchwald
We report the design, synthesis, and testing of novel small-molecule compounds targeting the CD40⁻CD154 (CD40L) costimulatory interaction for immunomodulatory purposes. This protein-protein interaction (PPI) is a TNF-superfamily (TNFSF) costimulatory interaction that is an important therapeutic target since it plays crucial roles in the activation of T cell responses, and there is resurgent interest in its modulation with several biologics in development. However, this interaction, just as all other PPIs, is difficult to target by small molecules...
May 11, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29731087/seven-years-of-experiences-of-preclinical-experiments-of-xeno-heart-transplantation-of-pig-to-non-human-primate-cynomolgus-monkey
#2
S J Lee, J S Kim, H K Chee, I J Yun, K S Park, H S Yang, J H Park
BACKGROUND: The absolute shortage of donors compared with patients requiring transplantation is currently an unsolved problem, and the only possible solution may be xenotransplantation. To establish a successful clinical trial, a preclinical study using nonhuman primates is essential. Starting in November 2011, our team initiated heterotopic abdominal heart xenotransplantation, the first in the Republic of Korea. We present here the initial 7-year results. METHODS: A total of 22 xenotransplantation procedures have been performed since 2011...
May 2018: Transplantation Proceedings
https://www.readbyqxmd.com/read/29722117/upregulation-of-cd80-on-glomerular-podocytes-plays-an-important-role-in-development-of-proteinuria-following-pig-to-baboon-xeno-renal-transplantation-an-experimental-study
#3
Christopher J Rivard, Tatsu Tanabe, Miguel A Lanaspa, Hironosuke Watanabe, Shunichiro Nomura, Ana Andres-Hernando, Krystle Garth, Mitsuhiro Sekijima, Takuji Ishimoto, Yuichi Ariyoshi, Gabriela E Garcia, Jigesh Shah, Lennan Boyd, Masayuki Tasaki, Thomas Pomposelli, Akira Shimizu, David H Sachs, Richard J Johnson, Kazuhiko Yamada
We have previously reported that co-transplantation of the kidney with vascularized donor thymus from α-1, 3-galactosyl transferase gene knockout pigs, with an anti-CD154 with rituximab-based regimen led to improved xenograft survival in baboons with donor-specific unresponsiveness. However, nephrotic syndrome emerged as a complication in which the glomeruli showed mild mesangial expansion with similarities to minimal change disease (MCD) in humans. Since MCD is associated with CD80 expression in glomeruli and elevated urinary excretion, we evaluated a potential role for CD80 in xenograft nephropathy...
May 2, 2018: Transplant International: Official Journal of the European Society for Organ Transplantation
https://www.readbyqxmd.com/read/29665205/characterization-of-the-in-vitro-and-in-vivo-properties-of-cfz533-a-blocking-and-non-depleting-anti-cd40-monoclonal-antibody
#4
Jacinda Ristov, Pascal Espie, Peter Ulrich, Denise Sickert, Thierry Flandre, Mirela Dimitrova, Dorothee Müller-Ristig, Doris Weider, Gautier Robert, Patrick Schmutz, Barbara Greutmann, Francisco Cordoba-Castro, Martin A Schneider, Max Warncke, Frank Kolbinger, Serge Cote, Christoph Heusser, Christian Bruns, James S Rush
The CD40-CD154 co-stimulatory pathway is essential for T cell-dependent immune responses, development of humoral memory and antigen presenting cell function. These immune functions have been implicated in the pathology of multiple autoimmune diseases as well as allograft rejection. We have generated CFZ533, a fully human, pathway blocking anti-CD40 monoclonal antibody that has been modified with a N297A mutation to render it unable to mediate Fcγ-dependent effector functions. CFZ533 inhibited CD154-induced activation of human leukocytes in vitro, but failed to induce human leukocyte activation...
April 17, 2018: American Journal of Transplantation
https://www.readbyqxmd.com/read/29625147/the-role-of-t-reg-population-in-pathogenesis-of-crimean-congo-hemorrhagic-fever
#5
Umut Gazi, Derya Yapar, Djursun Karasartova, Ayse Semra Gureser, Ozlem Akdogan, Ozgur Unal, Nurcan Baykam, Aysegul Taylan Ozkan
Crimean-Congo hemorrhagic fever (CCHF) is a severe human infection caused by CCHF virus (CCHFV). Today, although the literature on CCHF pathogenesis is still limited, it is thought to be associated with immunosuppression in the early phase of infection followed by pro-inflammatory immune response that may lead to fatal outcomes. The aim of this study is to investigate the role of regulatory T-cells (Treg cells) in the pathogenesis of CCHFV. Peripheral blood mononuclear cell samples collected from 14 acute CCHF patients with mild disease course and 13 healthy subjects were included in this study...
April 3, 2018: Virus Research
https://www.readbyqxmd.com/read/29611226/susceptibility-of-a-fumigatus-specific-t-cell-assays-to-pre-analytic-blood-storage-and-pbmc-cryopreservation-greatly-depends-on-readout-platform-and-analytes
#6
Chris D Lauruschkat, Sebastian Wurster, Lukas Page, Maria Lazariotou, Mariola Dragan, Philipp Weis, Andrew J Ullmann, Hermann Einsele, Jürgen Löffler
Mould specific T-cells detectable by flow cytometry or ELISPOT were proposed as a novel biomarker in invasive aspergillosis. To define protocols facilitating sample shipment and longitudinal analysis, this study evaluated the susceptibility of different functional assays for A. fumigatus specific T-cell quantification and characterisation to pre-analytic delays. PBMCs from six healthy donors were analysed after immediate isolation, after 6 hours whole blood storage or after cryopreservation using three different common media...
April 3, 2018: Mycoses
https://www.readbyqxmd.com/read/29582477/immune-molecular-profiling-of-whole-blood-drawn-from-a-non-human-primate-cardiac-xenograft-model-treated-with-anti-cd154-monoclonal-antibodies
#7
Sun A Ock, Keon Bong Oh, Seongsoo Hwang, Ik Jin Yun, Curie Ahn, Hyun Ken Chee, Hwajung Kim, Imran Ullah, Gi-Sun Im, Eung Woo Park
Most studies of xenografts have been carried out with complex immunosuppressive regimens to prevent immune rejection; however, such treatments may be fatal owing to unknown causes. Here, we performed immune molecular profiling following anti-CD154 monoclonal antibody (mAb) treatment in heterotopic abdominal cardiac xenografts from α-1,3-galactosyltransferase-knockout pigs into cynomolgus monkeys to elucidate the mechanisms mediating the undesirable fatal side effects of immunosuppressive agents. Blood samples were collected from healthy monkeys as control and then at 2 days after xenograft transplantation and just before humane euthanasia; 94 genes related to the immune system were analyzed...
March 26, 2018: Xenotransplantation
https://www.readbyqxmd.com/read/29577371/role-of-t-bet-the-master-regulator-of-th1-cells-in-the-cytotoxicity-of-murine-cd4-t-cells
#8
Koji Eshima, Kana Misawa, Chihiro Ohashi, Kazuya Iwabuchi
Although CD4+ T cells are generally regarded as helper T cells, some activated CD4+ T cells exert cytotoxicity. Since CD4+ cytotoxic T lymphocytes (CTLs) often secrete IFN-γ, CTL activity among CD4+ T cells may be attributable to Th1 cells, where a T-box family molecule, T-bet serves as the "master regulator". However, although the essential contribution of T-bet to the expression of IFN-γ has been well-documented, it remains unclear if T-bet is involved in CD4+ T cell-mediated cytotoxicity. In this study, in order to investigate the ability of T-bet to confer cytolytic activity on CD4+ T cells, we introduced the T-bet gene into non-cytocidal CD4+ T cell lines and analyzed their cytolytic function...
March 25, 2018: Microbiology and Immunology
https://www.readbyqxmd.com/read/29567905/diminished-cd40l-expression-on-t-cells-in-a-case-of-disseminated-cryptococcosis
#9
Supreet Kumar Mohanty, Deepshi Thakral, Devika Gupta, Prabin Kumar, Dipendra Kumar Mitra
X-linked hyperimmunoglobulin M (HIGM) syndrome may increase the susceptibility of patients to disseminated cryptococcal infections primarily due to CD40L deficiency that causes defective cross talk between T- and B-cells, thus preventing class switching. In HIGM syndrome, serum IgM levels are elevated with severe reduction in serum immunoglobulin G (IgG) and IgA levels. In addition, the expression of CD40L (CD154) on in vitro-activated T-cells is severely reduced or absent. Here, we describe a rare, and perhaps, the first reported case in India of a 3-year-old male child with X-linked HIGM immunodeficiency syndrome who developed disseminated Cryptococcosis...
January 2018: Indian Journal of Pathology & Microbiology
https://www.readbyqxmd.com/read/29565449/dna-damage-induced-by-human-cd40-ligand-mutant-promotes-senescence-and-induces-demethylation-of-gata4-in-lung-cancer
#10
Yue Li, Yunyan Wei, Weiwei Yuan, Qiqing Huang, Yaya Zhao, Weihong Zhao, Wei Xu, Jianqing Wu
The ligand of CD40, known as CD154 or CD40L, is the key to immunostimulatory and anticancer activity, but how CD40L affects cellular senescence is unclear. Thus, we studied a membrane‑stable mutant form CD40L (CD40L‑M) to explore tumor growth and cellular senescence in CD40‑positive NSCLC cells. We found that CD40L‑M‑expressing cells had senescent characteristics, including reduced cell proliferation and enlargement, increased SA‑β‑gal staining activity, and overexpression of several cell cycle regulators p53 and p21...
May 2018: Oncology Reports
https://www.readbyqxmd.com/read/29563292/activation-and-induction-of-antigen-specific-t-follicular-helper-cells-t-fh-play-a-critical-role-in-laiv-induced-human-mucosal-anti-influenza-antibody-response
#11
Abdullah Aljurayyan, Suttida Puksuriwong, Muhammad Ahmed, Ravi Sharma, Madhan Krishnan, Salil Sood, Katherine Davies, Devika Rajashekar, Sam Leong, Paul S McNamara, Stephen Gordon, Qibo Zhang
There is increasing interest recently in developing intranasal vaccines against respiratory tract infections. Antibody response is critical in vaccine-induced protection and TFH is considered important in mediating antibody response. Most data supporting the role for TFH in antibody response are from animal studies, and direct evidence from humans is limited, apart from TFH -like cells in blood. We studied activation and induction of TFH and its role on anti-influenza antibody response by live-attenuated influenza vaccine(LAIV) in human nasopharynx-associated lymphoid tissue(NALT)...
March 21, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29550477/rd-05-a-novel-anti-cd154-antibody-efficiently-inhibits-generation-of-anti-drug-antibody-without-the-risk-of-thrombus-formation-in-non-human-primates
#12
Jae-Il Lee, Yun-Jung Choi, Hi-Jung Park, Kyeong Cheon Jung, Seong Hoe Park
Antibody formation against therapeutic agents, such as tumor necrosis factor inhibitors and Factor VIII, that leads to treatment failure has become a major challenge in the treatment of rheumatoid arthritis and hemophilia. It is well known that anti-CD154 antibodies have the highest potential to inhibit these types of adverse immune responses. Nevertheless, the formation of thromboemboli is the major hurdle in the clinical application of these anti-CD154 blocking antibodies. For this, we attempted to derive an idea as to how this major complication can be eliminated...
April 15, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29534920/cardiorespiratory-responses-nitric-oxide-production-and-inflammatory-factors-in-patients-with-myocardial-infarction-after-rehabilitation
#13
José V Subiela, Sonia H Torres, Juan B De Sanctis, Noelina Hernández
There is evidence that myocardial infarction (MI) patients have an inflammatory process that includes skeletal muscles, and exercise has been reported to reduce some inflammatory markers. The aim of this work was to study NO and some inflammatory markers in quadriceps muscle of MI patients before and after cardiac rehabilitation. Muscle biopsy was obtained in17 MI patients before and after CR and only once in 11 healthy subjects. Several cardiorespiratory and metabolic parameters were evaluated and skeletal muscle levels of nitric oxide synthases, nitrate, nitrite, nitrotyrosine, tumor necrosis factor alpha (TNF-α), transforming growth factor beta (TGF-β), interleukin- 6 (IL-6) and CD154...
March 10, 2018: Nitric Oxide: Biology and Chemistry
https://www.readbyqxmd.com/read/29518422/egg-specific-ige-and-basophil-activation-but-not-egg-specific-t-cell-counts-correlate-with-phenotypes-of-clinical-egg-allergy
#14
M Cecilia Berin, Alexander Grishin, Madhan Masilamani, Donald Y M Leung, Scott H Sicherer, Stacie M Jones, A Wesley Burks, Alice K Henning, Peter Dawson, Joanna Grabowska, Charuta Agashe, Wendy F Davidson, Robert A Wood, Hugh A Sampson
BACKGROUND: Egg allergy is phenotypically heterogeneous. A subset of patients with egg allergy can tolerate egg in an extensively heated form. Inclusion of baked egg (BE) into the diet accelerates resolution of egg allergy. Conversely, BE reactivity is associated with persistent disease. The immune basis of this clinical heterogeneity is unknown. OBJECTIVES: We sought to study egg-specific antibody, basophil, and T-cell responses in children with reactivity or tolerance to BE...
March 5, 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29484632/organ-on-chip-recapitulates-thrombosis-induced-by-an-anti-cd154-monoclonal-antibody-translational-potential-of-advanced-microengineered-systems
#15
Riccardo Barrile, Andries D van der Meer, Hyoungshin Park, Jacob P Fraser, Damir Simic, Fang Teng, David Conegliano, Justin Nguyen, Abhishek Jain, Mimi Zhou, Katia Karalis, Donald E Ingber, Geraldine A Hamilton, Monicah A Otieno
Clinical development of Hu5c8, a monoclonal antibody against CD40L intended for treatment of autoimmune disorders, was terminated due to unexpected thrombotic complications. These life-threatening side effects were not discovered during preclinical testing due to the lack of predictive models. In the present study, we describe the development of a microengineered system lined by human endothelium perfused with human whole blood, a "Vessel-Chip." The Vessel-Chip allowed us to evaluate key parameters in thrombosis, such as endothelial activation, platelet adhesion, platelet aggregation, fibrin clot formation, and thrombin anti-thrombin complexes in the Chip-effluent in response to Hu5c8 in the presence of soluble CD40L...
February 27, 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29467769/cd137-cd154-expression-as-a-regulatory-t-cell-treg-specific-activation-signature-for-identification-and-sorting-of-stable-human-tregs-from-in-vitro-expansion-cultures
#16
Anna Nowak, Dominik Lock, Petra Bacher, Thordis Hohnstein, Katrin Vogt, Judith Gottfreund, Pascal Giehr, Julia K Polansky, Birgit Sawitzki, Andrew Kaiser, Jörn Walter, Alexander Scheffold
Regulatory T cells (Tregs) are an attractive therapeutic tool for several different immune pathologies. Therapeutic Treg application often requires prolonged in vitro culture to generate sufficient Treg numbers or to optimize their functionality, e.g., via genetic engineering of their antigen receptors. However, purity of clinical Treg expansion cultures is highly variable, and currently, it is impossible to identify and separate stable Tregs from contaminating effector T cells, either ex vivo or after prior expansion...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29464205/pilot-study-of-delayed-icos-icos-l-blockade-with-%C3%AE-cd40-to-modulate-pathogenic-alloimmunity-in-a-primate-cardiac-allograft-model
#17
Natalie A O'Neill, Tianshu Zhang, Gheorghe Braileanu, Xiangfei Cheng, Alena Hershfeld, Wenji Sun, Keith A Reimann, Sia Dahi, Natalia Kubicki, Wessam Hassanein, Christopher Laird, Arielle Cimeno, Agnes M Azimzadeh, Richard N Pierson
Background: Inducible costimulator (ICOS) is rapidly upregulated with T-cell stimulation and may represent an escape pathway for T-cell costimulation in the setting of CD40/CD154 costimulation blockade. Induction treatment exhibited no efficacy in a primate renal allograft model, but rodent transplant models suggest that the addition of delayed ICOS/ICOS-L blockade may prolong allograft survival and prevent chronic rejection. Here, we ask whether ICOS-Ig treatment, timed to anticipate ICOS upregulation, prolongs NHP cardiac allograft survival or attenuates pathogenic alloimmunity...
February 2018: Transplantation Direct
https://www.readbyqxmd.com/read/29454004/identification-and-analysis-of-peanut-specific-effector-t-and-regulatory-t-cells-in-children-allergic-and-tolerant-to-peanut
#18
Katherine A Weissler, Marjohn Rasooly, Tom DiMaggio, Hyejeong Bolan, Daly Cantave, David Martino, Melanie R Neeland, Mimi L K Tang, Thanh D Dang, Katrina J Allen, Pamela A Frischmeyer-Guerrerio
BACKGROUND: Peanut allergy (PA) is potentially life-threatening and generally persists for life. Recent data suggest the skin might be an important route of initial sensitization to peanut, whereas early oral exposure to peanut is protective. In mice regulatory T (Treg) cells are central to the development of food tolerance, but their contribution to the pathogenesis of food allergy in human subjects is less clear. OBJECTIVE: We sought to quantify and phenotype CD4+ peanut-specific effector T (ps-Teff) cells and peanut-specific regulatory T (ps-Treg) cells in children with and without PA or PS...
May 2018: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29427532/a-pilot-study-of-high-dose-intravenous-immunoglobulin-5-for-autism-impact-on-autism-spectrum-and-markers-of-neuroinflammation
#19
Isaac R Melamed, Melinda Heffron, Alessandro Testori, Kellie Lipe
Research has shown that a subset of the autism spectrum disorder (ASD) population presents with immune dysregulation. To explore this topic further, we investigated the efficacy and tolerability of intravenous immunoglobulin (IVIG) infusion in children with ASD. In this study, participants were recruited based on a diagnosis of autistic disorder, Asperger's disorder, or pervasive developmental disorder not otherwise specified. Participants also showed evidence of immune dysfunction based on abnormal levels of specific biomarkers, including CD40 ligand (CD154), lymphocyte stimulation, and T or B cell dysfunction...
March 2018: Autism Research: Official Journal of the International Society for Autism Research
https://www.readbyqxmd.com/read/29408715/single-cell-profiling-of-peanut-responsive-t-cells-in-patients-with-peanut-allergy-reveals-heterogeneous-effector-t-h-2-subsets
#20
David Chiang, Xintong Chen, Stacie M Jones, Robert A Wood, Scott H Sicherer, A Wesley Burks, Donald Y M Leung, Charuta Agashe, Alexander Grishin, Peter Dawson, Wendy F Davidson, Leah Newman, Robert Sebra, Miriam Merad, Hugh A Sampson, Bojan Losic, M Cecilia Berin
BACKGROUND: The contribution of phenotypic variation of peanut-specific T cells to clinical allergy or tolerance to peanut is not well understood. OBJECTIVES: Our objective was to comprehensively phenotype peanut-specific T cells in the peripheral blood of subjects with and without peanut allergy (PA). METHODS: We obtained samples from patients with PA, including a cohort undergoing baseline peanut challenges for an immunotherapy trial (Consortium of Food Allergy Research [CoFAR] 6)...
January 31, 2018: Journal of Allergy and Clinical Immunology
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