Article
Immunology
Casimiro Luca Gigliotti, Elena Boggio, Francesco Favero, Danny Incarnato, Claudio Santoro, Salvatore Oliviero, Jose Maria Rojo, Silvia Zucchelli, Francesca Persichetti, Gianluca Baldanzi, Umberto Dianzani, Davide Cora
Summary: ICOS and CD28 costimulatory signals play distinct roles in the activation of naive T cells by modulating different sets of immunological and immunometabolic genes.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Mackenzie M. Honikel, Scott H. Olejniczak
Summary: T cell engineering strategies, particularly CAR-T cell therapy, have shown great success in treating human cancer. The inclusion of a co-stimulatory domain in CARs plays a crucial role in CAR-T cell activation, proliferation, and anti-tumor efficacy. Currently, CAR-T therapy is FDA approved for hematological malignancies, and ongoing research explores the potential of multiple co-stimulatory molecules or domains to enhance CAR-T cell function.
Article
Immunology
Yannick D. Muller, Duy P. Nguyen, Leonardo M. R. Ferreira, Patrick Ho, Caroline Raffin, Roxxana Valeria Beltran Valencia, Zion Congrave-Wilson, Theodore L. Roth, Justin Eyquem, Frederic Van Gool, Alexander Marson, Laurent Perez, James A. Wells, Jeffrey A. Bluestone, Qizhi Tang
Summary: This study revealed a fundamental difference between CD28-TMD and CD8-TMD, indicating that CD28-TMD can modulate CAR T-cell activities by engaging endogenous partners.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Multidisciplinary Sciences
Joni Vuorio, Jana Skerlova, Milan Fabry, Vaclav Veverka, Ilpo Vattulainen, Pavlina Rezacova, Hector Martinez-Seara
Summary: This study reveals that CD44 receptor has multiple distinct binding sites for hyaluronan, which are modulated by N-glycosylation. Non-glycosylated CD44 prefers a canonical sub-micromolar binding site, while glycosylated CD44 binds hyaluronan through a different micromolar binding site. The findings demonstrate how glycosylation can alter receptor affinity and emphasize the importance of considering glycosylation in protein function and structure determination.
SCIENTIFIC REPORTS
(2021)
Article
Immunology
Lisa Sandner, Marlis Alteneder, Ramona Rica, Barbara Woller, Eleonora Sala, Tobias Frey, Anela Tosevska, Ci Zhu, Moritz Madern, Matarr Khan, Pol Hoffmann, Alexandra Schebesta, Ichiro Taniuchi, Michael Bonelli, Klaus Schmetterer, Matteo Iannacone, Mirela Kuka, Wilfried Ellmeier, Shinya Sakaguchi, Ruth Herbst, Nicole Boucheron
Summary: This study identifies the guanine nucleotide exchange factor Rin-like (Rinl) as a negative regulator of Tfh cell development. Loss of Rinl leads to an increase in Tfh cells and affects CD28 internalization and signaling pathways in CD4(+) T cells.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Multidisciplinary Sciences
Tetsuya Yoshimoto, Mizuho Kittaka, Andrew Anh Phuong Doan, Rina Urata, Matthew Prideaux, Roxana E. Rojas, Clifford Harding, W. Henry Boom, Lynda F. Bonewald, Edward M. Greenfield, Yasuyoshi Ueki
Summary: In the context of periodontal infection, the MYD88 pathway in osteocytes plays a dominant role in regulating osteolysis caused by bacterial infection. Matrix-embedded osteocytes stimulated with bacterial pathogen-associated molecular patterns (PAMPs) directly drive bone resorption through an MYD88-regulated signaling pathway. Mice lacking MYD88 primarily in osteocytes protect against bone loss caused by bacterial PAMPs injections and resist alveolar bone resorption induced by oral Porphyromonas gingivalis (Pg) infection. Targeted restoration of MYD88 in osteocytes leads to osteolysis with inflammatory cell infiltration. In vitro, bacterial PAMPs induce higher expression of the cytokine RANKL in osteocytes compared to osteoblasts. Activation of the osteocyte MYD88 pathway up-regulates RANKL by increasing binding of transcription factors CREB and STAT3 to Rankl enhancers and suppressing K48-ubiquitination of CREB/CREB binding protein and STAT3. Blocking MYD88 prevents jawbone loss in Pg-driven periodontitis. These findings suggest that MYD88 and downstream RANKL regulators in osteocytes are potential therapeutic targets for osteolysis in periodontitis and osteomyelitis.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Bhairavi Swaminathan, Seock-Won Youn, L. A. Naiche, Jing Du, Stephanie R. Villa, Jordan B. Metz, Huijuan Feng, Chaolin Zhang, Raphael Kopan, Peter A. Sims, Jan K. Kitajewski
Summary: Through transcriptional analysis, it was found that Notch signaling controls sprouting angiogenesis by suppressing tip cell formation, migration, and proliferation, while promoting barrier formation. This process is achieved by regulating different target genes. Particularly, the effector RND1 in the GPCR signaling pathway plays an important role in the Notch signaling regulation process.
SCIENTIFIC REPORTS
(2022)
Article
Multidisciplinary Sciences
Simon Zenke, Mauricio P. Sica, Florian Steinberg, Julia Braun, Alicia Zink, Alina Gavrilov, Alexander Hilger, Aditya Arra, Monika Brunner-Weinzierl, Roland Elling, Niklas Beyersdorf, Tim Laemmermann, Cristian R. Smulski, Jan C. Rohr
Summary: The study reveals that T cells control the abundance of immunoregulatory ligands differently through competitive antagonistic receptor trogocytosis, with CD28 and CTLA4 playing distinct roles in this process.
NATURE COMMUNICATIONS
(2022)
Article
Oncology
Justin C. Boucher, Gongbo Li, Hiroshi Kotani, Maria L. Cabral, Dylan Morrissey, Sae Bom Lee, Kristen Spitler, Nolan J. Beatty, Estelle Cervantes, Bishwas Shrestha, Bin Yu, Aslamuzzaman Kazi, Xuefeng Wang, Said M. Sebti, Marco L. Davila
Summary: Mutating the CD28 endodomain of CAR T cells optimized costimulation, leading to improved function and survival rates, which lays the foundation for enhancing CAR T-cell therapies.
CANCER IMMUNOLOGY RESEARCH
(2021)
Article
Immunology
Leena Halim, Kushal K. Das, Daniel Larcombe-Young, Adam Ajina, Andrea Candelli, Reuben Benjamin, Richard Dillon, David M. Davies, John Maher
Summary: This study demonstrates the enhanced anti-tumor activity of CAR T-cells through dual co-stimulation provided by a parallel CAR architecture. CD19-specific CAR and pCAR T-cells showed broad binding ability and avidity for CD19-expressing tumor cells. Each pCAR showed significant improvement in tumor re-stimulation potential and therapeutic efficacy compared to unmodified or mutated CARs.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Multidisciplinary Sciences
Florian A. Lempp, Leah B. Soriaga, Martin Montiel-Ruiz, Fabio Benigni, Julia Noack, Young-Jun Park, Siro Bianchi, Alexandra C. Walls, John E. Bowen, Jiayi Zhou, Hannah Kaiser, Anshu Joshi, Maria Agostini, Marcel Meury, Exequiel Dellota, Stefano Jaconi, Elisabetta Cameroni, Javier Martinez-Picado, Julia Vergara-Alert, Nuria Izquierdo-Useros, Herbert W. Virgin, Antonio Lanzavecchia, David Veesler, Lisa A. Purcell, Amalio Telenti, Davide Corti
Summary: The study reveals that C-type lectin receptors and other factors can serve as attachment receptors for SARS-CoV-2 infection, enhancing ACE2-mediated infection and modulating the neutralizing activity of antibodies.
Article
Immunology
Sarah Albogami, Ian Todd, Ola Negm, Lucy C. Fairclough, Patrick J. Tighe
Summary: This study manipulated the PLAD of TNFR1 through mutations, finding that alterations in key amino acids affect homologous interactions of PLAD but do not impact its function as a TNFR antagonist. Some mutant PLADs even exhibited stronger antagonistic activity compared to the wild-type PLAD.
Article
Multidisciplinary Sciences
Hong Sik Yoo, Adrienne Rodriguez, Dongjoo You, Rebecca A. Lee, Michael A. Cockrum, Jack A. Grimes, Jen-Chywan Wang, Sona Kang, Joseph L. Napoli
Summary: Insulin reduces the transcription of CYP26A1, resulting in decreased oxidation of retinoic acid (RA). Factors such as glucocorticoids and SNP rs2068888 also affect the expression of CYP26A1. Regulating the transcription of CYP26A1 contributes to maintaining the homeostasis of RA during changes in energy availability.
Correction
Multidisciplinary Sciences
Patrick Han, Douglas Hanlon, Najla Arshad, Jung Seok Lee, Kazuki Tatsuno, Eve Robinson, Renata Filler, Olga Sobolev, Christine Cote, Felix Rivera-Molina, Derek Toomre, Tarek Fahmy, Richard Edelson
Summary: Platelets can activate a cross-presentation program in monocytes, leading to rapid maturation into physiological DCs. These DCs are more effective in generating tumor-specific T cell immunity than cytokine-derived DCs. Platelets mediate a cytokine-independent, physiologic maturation of DC, suggesting a novel strategy for DC-based immunotherapies.
Article
Oncology
Shishuo Sun, Chao Huang, Mengmeng Lu, Heng Xu, Yifan Yuan, Wanxin Zhao, Xiaolei Hu, Bixi Wang, Wei Zhang, Xiaoge Gao, Junnian Zheng, Lishan Su, Qing Zhang
Summary: The costimulatory domains (CSD) of 4-1BB and CD28 are commonly used in CAR-engineered T cells. While these CART cells have shown good efficacy in blood cancers, their effectiveness against solid tumors is limited. HVEM, a costimulatory molecule with a unique signaling pathway, has been found to enhance cytokine release and cytotoxicity in CAR T cells. HVEM-CAR T cells also demonstrated superior therapeutic efficacy in mouse tumor models, with improved functionality and persistence in tumor tissue compared to other CSD-based CAR T cells.
CANCER IMMUNOLOGY RESEARCH
(2023)
Article
Chemistry, Multidisciplinary
Alec T. Salminen, Jingkai Zhang, Gregory R. Madejski, Tejas S. Khire, Richard E. Waugh, James L. McGrath, Thomas R. Gaborski
Article
Virology
Petrus Jansen van Vuren, Jason T. Ladner, Antoinette A. Grobbelaar, Michael R. Wiley, Sean Lovett, Mushal Allam, Arshad Ismail, Chantel le Roux, Jacqueline Weyer, Naazneen Moolla, Nadia Storm, Joe Kgaladi, Mariano Sanchez-Lockhart, Ousman Conteh, Gustavo Palacios, Janusz T. Paweska
Article
Virology
Eva Ramirez de Arellano, Mariano Sanchez-Lockhart, Maria J. Perteguer, Maggie Bartlett, Marta Ortiz, Pamela Campioli, Ana Hernandez, Jeanette Gonzalez, Karla Garcia, Manolo Ramos, Miguel Angel Jimenez-Clavero, Antonio Tenorio, Ma Paz Sanchez-Seco, Felix Gonzalez, Juan Emilio Echevarria, Gustavo Palacios, Anabel Negredo
Article
Chemistry, Multidisciplinary
Shaheen A. Farhadi, Margaret M. Fettis, Renjie Liu, Gregory A. Hudalla
FRONTIERS IN CHEMISTRY
(2020)
Review
Microbiology
Nicholas Di Paola, Mariano Sanchez-Lockhart, Xiankun Zeng, Jens H. Kuhn, Gustavo Palacios
NATURE REVIEWS MICROBIOLOGY
(2020)
Article
Infectious Diseases
Patrick L. Iversen, Christopher D. Kane, Xiankun Zeng, Rekha G. Panchal, Travis K. Warren, Sheli R. Radoshitzky, Jens H. Kuhn, Rajini R. Mudhasani, Christopher L. Cooper, Amy C. Shurtleff, Farooq Nasar, Melek M. E. Sunay, Allen J. Duplantier, Brett P. Eaton, Elizabeth E. Zumbrun, Sandra L. Bixler, Shannon Martin, J. Matthew Meinig, Chih-Yuan Chiang, Mariano Sanchez-Lockhart, Gustavo F. Palacios, Jeffrey R. Kugelman, Karen A. Martins, Margaret L. Pitt, Ian Crozier, David L. Saunders
LANCET INFECTIOUS DISEASES
(2020)
Article
Immunology
Scott A. Leddon, Margaret M. Fettis, Kristin Abramo, Ryan Kelly, David Oleksyn, Jim Miller
FRONTIERS IN IMMUNOLOGY
(2020)
Article
Virology
Unai Perez-Sautu, Se Hun Gu, Katie Caviness, Dong Hyun Song, Yu-Jin Kim, Nicholas Di Paola, Daesang Lee, Terry A. Klein, Joseph A. Chitty, Elyse Nagle, Heung-Chul Kim, Sung-Tae Chong, Brett Beitzel, Daniel S. Reyes, Courtney Finch, Russ Byrum, Kurt Cooper, Janie Liang, Jens H. Kuhn, Xiankun Zeng, Kathleen A. Kuehl, Kayla M. Coffin, Jun Liu, Hong Sang Oh, Woong Seog, Byung-Sub Choi, Mariano Sanchez-Lockhart, Gustavo Palacios, Seong Tae Jeong
Article
Cell Biology
Luis. F. Delgadillo, Elena. B. Lomakina, Julia Kuebel, Richard E. Waugh
Summary: The study explores the impact of damaging the endothelial glycocalyx layer (EGL) on leukocyte adhesion and barrier dysfunction. Results show that removing both hyaluronic acid (HA) and heparan sulfate (HS) from the EGL structure leads to increased leukocyte adhesion and decreased endothelial barrier properties. Additionally, disruption of the EGL may predispose endothelial cells to increased fluid leakage.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2021)
Article
Immunology
Ashley J. Russo, Swathy O. Vasudevan, Santiago P. Mendez-Huergo, Puja Kumari, Antoine Menoret, Shivalee Duduskar, Chengliang Wang, Juan M. Perez Saez, Margaret M. Fettis, Chuan Li, Renjie Liu, Arun Wanchoo, Karthik Chandiran, Jianbin Ruan, Sivapriya Kailasan Vanaja, Michael Bauer, Christoph Sponholz, Gregory A. Hudalla, Anthony T. Vella, Beiyan Zhou, Sachin D. Deshmukh, Gabriel A. Rabinovich, Vijay A. Rathinam
Summary: Studies have identified galectin-1 as a new DAMP that promotes inflammation by inhibiting CD45. The release of galectin-1 during cytosolic LPS sensing is detrimental and affects endotoxin shock.
Article
Cell & Tissue Engineering
Bryant J. Kane, Margaret M. Fettis, Shaheen A. Farhadi, Renjie Liu, Gregory A. Hudalla
Summary: Thiol-Michael addition bioconjugation leads to a PEG-cross-linked Gal1 homodimer with improved extracellular signaling activity that does not require a reducing environment to be functional.
CELLULAR AND MOLECULAR BIOENGINEERING
(2021)
Article
Chemistry, Medicinal
Adrian D. Hobson, Michael J. McPherson, Martin E. Hayes, Christian Goess, Xiang Li, Jian Zhou, Zhongyuan Wang, Yajie Yu, Jindong Yang, Liang Sun, Qiang Zhang, Pei Qu, Shi Yang, Axel Hernandez, Shaughn H. Bryant, Suzanne L. Mathieu, Agnieszka K. Bischoff, Julia Fitzgibbons, Ling C. Santora, Lu Wang, Margaret M. Fettis, Xiaofeng Li, Christopher C. Marvin, Zhi Wang, Meena V. Patel, Diana L. Schmidt, Tongmei Li, John T. Randolph, Rodger F. Henry, Candace Graff, Yu Tian, Ana L. Aguirre, Anurupa Shrestha
Summary: This study employed a convergent synthetic route to evaluate a series of glucocorticoid receptor modulators, and found that the evaluation of nonconjugated small molecules was suboptimal, leading to the use of antibody conjugation for evaluation. By screening in two mouse models, a promising payload was identified and conjugated with a human antibody.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Engineering, Biomedical
Evelyn Bracho-Sanchez, Fernanda G. Rocha, Sean K. Bedingfield, Brittany D. Partain, Sabrina L. Macias, Maigan A. Brusko, Juan M. Colazo, Margaret M. Fettis, Shaheen A. Farhadi, Eric Y. Helm, Kevin Koenders, Alexander J. Kwiatkowski, Antonietta Restuccia, Bethsymarie Soto Morales, Arun Wanchoo, Dorina Avram, Kyle D. Allen, Craig L. Duvall, Shannon M. Wallet, Gregory A. Hudalla, Benjamin G. Keselowsky
Summary: In this study, a fusion protein of the immunosuppressive enzyme IDO and the tissue-anchoring protein Gal3 was developed to locally suppress inflammation. The fusion protein remained in inflamed tissues and joints for about 1 week, providing long-lasting local anti-inflammatory effects without causing systemic immune suppression. This approach shows promise for the treatment of inflammatory diseases.
NATURE BIOMEDICAL ENGINEERING
(2023)
Article
Chemistry, Medicinal
Adrian D. Hobson, Jianwen Xu, Dennie S. Welch, Christopher C. Marvin, Michael J. Mcpherson, Bradley Gates, Xiaoli Liao, Markus Hollmann, Michael J. Gattner, Kristina Dzeyk, Hetal Sarvaiya, Vikram M. Shenoy, Margaret M. Fettis, Agnieszka K. Bischoff, Lu Wang, Ling C. Santora, Lu Wang, Julia Fitzgibbons, Paulin Salomon, Axel Hernandez Jr, Ying Jia, Christian A. Goess, Suzanne L. Mathieu, Shaughn H. Bryant, Mary E. Larsen, Baoliang Cui, Yu Tian
Summary: Stable attachment of drug-linkers to the antibody is achieved by ring hydrolysis of the succinimide ring. The succinimide ring open form is in equilibrium with the ring closed form, but this equilibrium is completely removed by replacing maleimide with bromoacetamide. This replacement also offers multiple benefits, especially regarding the homogeneity of the ADC structure. In combination with a short, hydrophilic linker and phosphate prodrug on the payload, this enables the development of a stable ADC (ABBV-154) suitable for long-term subcutaneous self-administration.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Adrian D. Hobson, Jianwen Xu, Christopher C. Marvin, Michael J. McPherson, Markus Hollmann, Michael Gattner, Kristina Dzeyk, Margaret M. Fettis, Agnieszka K. Bischoff, Lu Wang, Julia Fitzgibbons, Lu Wang, Paulin Salomon, Axel Hernandez Jr, Ying Jia, Hetal Sarvaiya, Christian A. Goess, Suzanne L. Mathieu, Ling C. Santora
Summary: To enable subcutaneous dosing, biotherapeutics need to have properties that allow high-concentration formulation and long-term stability in the formulation buffer. The introduction of drug-linkers in ADCs can increase hydrophobicity and aggregation, which are detrimental to subcutaneous dosing properties. This study demonstrates how the physicochemical properties of ADCs can be controlled by the drug-linker chemistry and prodrug chemistry, resulting in significantly improved solution stability. The use of an accelerated stress test in a minimal formulation buffer is crucial for achieving this optimization.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)