Review
Biochemistry & Molecular Biology
Raquel Gomez-Bris, Angela Saez, Beatriz Herrero-Fernandez, Cristina Rius, Hector Sanchez-Martinez, Jose M. Gonzalez-Granado
Summary: Inflammatory bowel disease (IBD) refers to chronic immune-mediated idiopathic inflammation of the gastrointestinal tract, presenting as Crohn's disease (CD) or ulcerative colitis (UC). It is characterized by exacerbated innate and adaptive immunity in the gut, along with microbiota dysbiosis and disruption of the intestinal barrier, leading to increased bacterial exposure. CD4 T-cells play a crucial role in the development of IBD, with various phenotypes and interactions with other immune cells determining the progression of the disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Gastroenterology & Hepatology
Dominik Aschenbrenner, Maria Quaranta, Soumya Banerjee, Nicholas Ilott, Joanneke Jansen, Boyd Steere, Yin-Huai Chen, Stephen Ho, Karen Cox, Carolina V. Arancibia-Carcamo, Mark Coles, Eamonn Gaffney, Simon Pl Travis, Lee Denson, Subra Kugathasan, Jochen Schmitz, Fiona Powrie, Stephen N. Sansom, Holm H. Uhlig
Summary: Dysregulated immune responses are the cause of IBDs, with IL-10 and IL-1 identified as critical regulators of monocyte IL-23 production. The study differentiates between homeostatic IL-23 production and hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn's disease and anti-TNF treatment non-responsiveness. Subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1 alpha/IL-1 beta-targeting therapies upstream of IL-23 are identified.
Article
Multidisciplinary Sciences
Tomas Raul Wiche Salinas, Yuwei Zhang, Daniele Sarnello, Alexander Zhyvoloup, Laurence Raymond Marchand, Augustine Fert, Delphine Planas, Manivel Lodha, Debashree Chatterjee, Katarzyna Karwacz, Sally Oxenford, Jean-Pierre Routy, David Irlbeck, Heather Amrine-Madsen, Petronela Ancuta, Ariberto Fassati
Summary: Th17 cells are highly susceptible to HIV-1 infection and play a crucial role in viral persistence and disease progression. The master transcriptional regulator RORC2 is essential for Th17 cell differentiation and functions as a key host cofactor for HIV replication. Pharmacological inhibition of RORC2 may be a potential cell-specific target for HIV-1 therapy.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Immunology
Tiago S. Medina, Alex Murison, Michelle Smith, Gabriela S. Kinker, Ankur Chakravarthy, Glauco A. F. Vitiello, Williams Turpin, Shu Yi Shen, Helen L. Yau, Olga F. Sarmento, William Faubion, Mathieu Lupien, Mark S. Silverberg, Cheryl H. Arrowsmith, Daniel D. De Carvalho
Summary: This study characterized the chromatin landscape and heterogeneity of CD4 T cells in IBD patients using ATAC-Seq and single cell RNA-Seq. The results showed that the chromatin accessibility profiles of CD4 T cells from inflamed intestinal biopsies were associated with genes related to inflammatory processes. Integration of chromatin profiles revealed a higher predominance of pathogenic Th17 cells in inflamed biopsies and colocalization of IBD risk loci with accessible chromatin changes near Th17-related genes.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Immunology
Christopher Sie, Ravi Kant, Christian Peter, Andreas Muschaweckh, Monika Pfaller, Lucy Nirschl, Helena Dominguez Moreno, Tereza Chadimova, Gildas Lepennetier, Tanja Kuhlmann, Rupert Ollinger, Thomas Engleitner, Roland Rad, Thomas Korn
Summary: Th17 cells have an intrinsic feedback mechanism to control their pathogenicity, involving the production of IL-24 and secretion of IL-10. IL-24 interacts with Grim19 on the inner mitochondrial membrane to promote STAT3 accumulation in the mitochondrial compartment, which serves as a rheostat to regulate nuclear STAT3 activity. This mechanism plays an important role in restricting immunopathology associated with Th17 cells.
JOURNAL OF EXPERIMENTAL MEDICINE
(2022)
Article
Rheumatology
Anne Filleron, Tu Anh Tran, Audrey Hubert, Alexia Letierce, Guillaume Churlaud, Isabelle Kone-Paut, David Saadoun, Renaud Cezar, Pierre Corbeau, Michelle Rosenzwajg
Summary: This study found a bias towards Th17 polarization in pediatric BD patients, and Tregs can limit the differentiation of CD4(+) T cells into Th1 and Th17 cells.
Review
Immunology
Egle Kvedaraite
Summary: Neutrophils, the most abundant white blood cells in human blood, play important roles in inflammation, tissue repair, infection, cancer, and chronic inflammatory diseases. Their immune responses and ability to influence T cells in inflammatory bowel disease have been recognized and studied in recent years.
Article
Cell Biology
Chunyue Hao, Wei Wang, Bin Zhan, Zixia Wang, Jingjing Huang, Ximeng Sun, Xinping Zhu
Summary: The study demonstrates that the Trichinella-derived protein rTsPmy can ameliorate disease progression and reduce inflammatory responses in experimental colitis, by specifically promoting the expansion and differentiation of regulatory T cells in the inflamed colon. These findings provide insights into the immunological mechanisms involved in the therapeutic effect of helminth-derived proteins in inflammatory bowel diseases.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Immunology
Mobina Jalalvand, Samaneh Enayati, Maryam Akhtari, Elham Madreseh, Ahmadreza Jamshidi, Elham Farhadi, Mahdi Mahmoudi, Aliakbar Amirzargar
Summary: This meta-analysis aimed to determine the frequency of peripheral blood regulatory T cells (Tregs) in inflammatory bowel disease (IBD) patients. The results showed no significant difference in the frequency of PB Tregs between IBD cases and control subjects. However, the frequency of CD4+CD25+CD127- and CD4+CD25+FoxP3+ Tregs were significantly lower in IBD cases. Additionally, UC cases and active IBD cases showed a significantly lower frequency of Treg cells.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2023)
Review
Gastroenterology & Hepatology
Bram Verstockt, Azucena Salas, Bruce E. Sands, Clara Abraham, Haim Leibovitzh, Markus Neurath, Niels Vande Casteele
Summary: IL-12 and IL-23 play a crucial role in intestinal homeostasis and inflammation, and are implicated in the pathogenesis of inflammatory bowel disease. Monoclonal antibodies targeting IL-12 and/or IL-23 have been developed for the treatment of Crohn's disease and ulcerative colitis. This Review summarizes the biological characteristics of IL-12 and IL-23, discusses their role in intestinal homeostasis and inflammation, and highlights the development of drugs targeting IL-12 and/or IL-23.
NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY
(2023)
Review
Pharmacology & Pharmacy
Saima Akhter, Farhin Montaha Tasnin, Mohammad Nazmul Islam, Abdur Rauf, Saikat Mitra, Talha Bin Emran, Fahad A. Alhumaydhi, Anees Ahmed Khalil, Abdullah S. M. Aljohani, Waleed Al Abdulmonem, Muthu Thiruvengadam
Summary: The IL-17 cytokine family plays a critical role in inflammatory and autoimmune diseases, and dysregulation may lead to the development of various conditions. Understanding the role of IL-17 in these diseases is crucial for developing targeted therapeutic strategies.
CURRENT PHARMACEUTICAL DESIGN
(2023)
Review
Immunology
Jianli Zhou, Qiao Zhang, Yuzhen Zhao, Yuchen Song, Yanan Leng, Moxian Chen, Shaoming Zhou, Zhaoxia Wang
Summary: Inflammatory bowel disease (IBD) is a group of chronic diseases including Crohn's disease and ulcerative colitis, which have a global impact on both children and adults. The burden of IBD is increasing worldwide, and the costs associated with it are high. The pathogenesis of IBD is still unclear, but is believed to be related to environmental factors, gut microbiota, immune imbalance, and genetic susceptibility. This article reviews the research progress on alternative splicing events, splicing factors, and splicing mutations associated with IBD.
FRONTIERS IN IMMUNOLOGY
(2023)
Review
Medicine, Research & Experimental
Yaoyao Chang, Lixiang Zhai, Jiao Peng, Haiqiang Wu, Zhaoxiang Bian, Haitao Xiao
Summary: IBD is a chronic inflammatory intestinal disorder with limited treatment options, and correcting the imbalance of Th17/Treg has been shown to be effective in preventing and treating IBD. Phytochemicals derived from natural products have been recognized as potent regulators of Th17/Treg and may offer protective benefits against colonic inflammation, showing great potential for the development of new drugs for IBD treatment.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Review
Immunology
Marcela Laukova, Arielle Glatman Zaretsky
Summary: Foxp3(+) T regulatory cells are essential for suppressing inflammation and maintaining tissue homeostasis. In particular, these cells play a critical role in maintaining the intestinal environment by mediating interactions with the microbiota, supporting barrier integrity, and regulating the immune system. Developing T regulatory cell therapies for intestinal inflammatory diseases, such as inflammatory bowel disease, is of particular interest.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2023)
Review
Pharmacology & Pharmacy
Andrea Cassinotti, Francesco Passamonti, Sergio Segato
Summary: Cell-based therapies have been explored in immune-mediated inflammatory diseases, including inflammatory bowel disease (IBD). The most studied treatment in IBD involves stem cells, with recent studies also focusing on regulatory cells such as T-reg and Tr1 cells. Preclinical research is also being conducted on induced pluripotent stem cells in animal models related to colitis.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Immunology
Avery J. Lam, Manjurul Haque, Kirsten A. Ward-Hartstonge, Prakruti Uday, Christine M. Wardell, Jana K. Gillies, Madeleine Speck, Majid Mojibian, Ramon I. Klein Geltink, Megan K. Levings
Summary: The study demonstrates that ablation of PTEN does not affect the overall function and stability of human Tregs, but selectively impairs their ability to suppress antigen-presenting cells. These findings highlight the functional necessity of PTEN-regulated PI3K-AKT activity for optimal human Treg function.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Emma Proics, Marion David, Majid Mojibian, Madeline Speck, Nadia Lounnas-Mourey, Adeline Govehovitch, Wissam Baghdadi, Justine Desnouveaux, Herve Bastian, Laura Freschi, Geoffrey Privat, Cedric Pouzet, Mauro Grossi, Pierre Heimendinger, Tobias Abel, David Fenard, Megan K. Levings, Francois Meyer, Celine Dumont
Summary: This publication reports the preclinical characterization of Tregs transduced with a CAR lentiviral vector. The results demonstrated the specificity, immunosuppressive function, and safety of the transduced Tregs. The study also showed that the transduced Tregs effectively prevented graft-versus-host disease in mice and remained stable without switching to a proinflammatory phenotype. Furthermore, concomitant tacrolimus did not impair the survival or inhibitory function of the transduced Tregs.
Review
Endocrinology & Metabolism
Adam Ramzy, Paul J. Belmonte, Mitchell J. S. Braam, Shogo Ida, Emily M. Wilts, Megan K. Levings, Alireza Rezania, Timothy J. Kieffer
Summary: Insulin injections have saved many lives, but glycemic instability remains a challenge for people with diabetes. Islet transplantation research suggests that replacing insulin-producing beta cells can restore normal blood sugar levels. Pluripotent stem cells could provide an unlimited supply of beta cells, but more research and development is needed.
Article
Immunology
Dominic A. Boardman, May Q. Wong, William D. Rees, Dan Wu, Megan E. Himmel, Paul C. Orban, Jens Vent-Schmidt, Nicholas C. Zachos, Theodore S. Steiner, Megan K. Levings
Summary: Regulatory T cell (Treg) therapy is a promising strategy for treating inflammatory bowel disease (IBD). A novel chimeric antigen receptor (CAR) specific for flagellin derived from Escherichia coli H18 (FliC) was developed to confer FliC-specificity to human Tregs. FliC-CAR Tregs showed specificity and functionality, and demonstrated potential in treating IBD by suppressing inflammation and promoting the establishment of colon-derived epithelial cell monolayers.
JOURNAL OF AUTOIMMUNITY
(2023)
Editorial Material
Surgery
Manjurul Haque, Dominic A. Boardman, Megan K. Levings
AMERICAN JOURNAL OF TRANSPLANTATION
(2023)
Review
Immunology
Torin Halvorson, Karoliina Tuomela, Megan K. Levings
Summary: Regulatory T cells (Tregs) are important for maintaining immune homeostasis, but they can also hinder anti-tumor immunity. Targeting metabolic pathways can selectively promote or inhibit Treg function, offering potential therapeutic opportunities. This review explores the current understanding of Treg metabolism and discusses emerging metabolic targeting strategies in transplantation, autoimmunity, and cancer. Manipulating Treg metabolism during ex vivo expansion for adoptive cell therapy (ACT) and modulating Treg metabolism in disease states through nutritional and pharmacological interventions are also discussed.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2023)
Editorial Material
Immunology
Karoliina Tuomela, Megan K. Levings
Summary: A recent study reveals that lactic acid, through a pH-dependent mechanism, promotes the differentiation of conventional CD4(+) T cells into Tregs, contributing to the accumulation of Tregs within tumors. This finding adds to the understanding of lactic acid's role in maintaining an immunosuppressive tumor microenvironment.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2023)
Review
Immunology
Karoliina Tuomela, Kevin Salim, Megan K. Levings
Summary: Regulatory T cells (Tregs) have been recognized as critical cells for immune homeostasis regulation. The development of designer Tregs has gone through three eras: FOXP3 engineering, antigen-specificity, and advanced genome-editing techniques, providing new opportunities for treating immune-mediated diseases.
IMMUNOLOGICAL REVIEWS
(2023)
Article
Immunology
Esther Bernaldo-de-Quiros, Manuela Camino, Marta Martinez-Bonet, Juan Miguel Gil-Jaurena, Nuria Gil, Diana Hernandez-Florez, Maria Eugenia Fernandez-Santos, Laura Butragueno, I. Esme Dijke, Megan K. Levings, Lori J. West, Marjorie Pion, Rafael Correa-Rocha
Summary: This study developed a new approach to obtain large quantities of high-purity Tregs from routine surgeries, which could be used for cellular therapy to prevent transplant rejection. The initial results of the clinical trial showed that the administration of thyTregs in infants undergoing heart transplantation had no adverse effects and maintained a stable Treg frequency in the peripheral blood.
JOURNAL OF EXPERIMENTAL MEDICINE
(2023)
Article
Immunology
Cara E. Ellis, Majid Mojibian, Shogo Ida, Vivian C. W. Fung, Sos Skovso, Emma McIver, Shannon O'Dwyer, Travis D. Webber, Mitchell J. S. Braam, Nelly Saber, Shugo Sasaki, Francis C. Lynn, Timothy J. Kieffer, Megan K. Levings
Summary: This study used A2-CAR T cells to investigate the rejection of insulin-producing cells and successfully addressed the issue of complications from xenogeneic graft-versus-host disease.
Article
Immunology
Ji-Young V. Kim, Sara Assadian, Zsuzsanna Hollander, Paloma Burns, Casey P. Shannon, Karen Lam, Mustafa Toma, Andrew Ignaszewski, Ross A. Davies, Diego Delgado, Haissam Haddad, Debra Isaac, Daniel Kim, Alice Mui, Miroslaw Rajda, Lori West, Michel White, Shelley Zieroth, Paul A. Keown, W. Robert McMaster, Raymond T. Ng, Bruce M. McManus, Megan K. Levings, Scott J. Tebbutt
Summary: This study demonstrates that gene expression associated with CD4+ Tconv and Treg can identify patients at risk of ACR. Complementing HEARTBiT with TGS improves the classification of ACR.
Article
Medicine, Research & Experimental
Isaac Rosado-Sanchez, Manjurul Haque, Kevin Salim, Madeleine Speck, Vivian C. W. Fung, Dominic A. Boardman, Majid Mojibian, Giorgio Raimondi, Megan K. Levings
Summary: Tregs expressing chimeric antigen receptors (CAR-Tregs) were studied to understand the relationship between CAR structure and Treg function. CD28-encoding CARs showed advantages in xenogeneic, immunodeficient mice, but the interactions with antigen-presenting cells (APCs) and donor specific antibodies were not fully represented. In vitro, CD28-encoding CARs had superior antigen-specific suppression, proliferation, and cytokine production. However, in vivo, Tregs expressing CARs encoding CD28, ICOS, programmed cell death 1, and GITR extended skin allograft survival, while CARs encoding 4-1BB or OX40 did not. Analysis of a CAR encoding CD3 zeta but no costimulatory domain revealed that exogenous costimulation from APCs can compensate for the lack of a CAR-encoded CD28 domain. This study has important implications for the design of CARs for clinical use in Tregs.
Article
Medicine, Research & Experimental
Justin A. Spanier, Vivian Fung, Christine M. Wardell, Mohannad H. Alkhatib, Yixin Chen, Linnea A. Swanson, Alexander J. Dwyer, Matthew E. Weno, Nubia Silva, Jason S. Mitchell, Paul C. Orban, Majid Mojibian, C. Bruce Verchere, Brian T. Fife, Megan K. Levings
Summary: Engineering Tregs with specific recognition for islet antigens using a chimeric antigen receptor (CAR) is a promising therapeutic approach for preventing autoimmune diabetes.
JOURNAL OF CLINICAL INVESTIGATION
(2023)