Immunology
Abstract
The success of allogeneic hematopoietic cell transplantation (allo-HCT) is limited by acute graft-versus-host disease (aGVHD). We have previously reported that neutrophils can exacerbate tissue damage caused by conditioning regimens. Pegtarazimod is a synthetic peptide, derived from the capsid protein of human astrovirus serotype 1, that was shown to reduce neutrophil effector functions. Therefore, we evaluated the therapeutic activity of pegtarazimod against aGVHD. Pegtarazimod significantly reduced aGVHD-related mortality, histological aGVHD severity, and pro-inflammatory cytokines in multiple in vivo mouse models, while maintaining the anti-leukemia effect. Mechanistically, pegtarazimod reduced inflammation by decreasing ROS production as investigated using allo-HCT recipient mice with genetic inactivation of NADPH oxidase (NOX2) in the bone marrow. In addition to the anti-inflammatory effect, pegtarazimod protected intestinal organoids against TNF-induced toxicity and oxidative DNA damage. In the phase-2 clinical trial AURORA, pegtarazimod treatment was well-tolerated in patients with corticosteroid-refractory (SR) aGVHD (NCT06343792) with an overall response rate (ORR) of 4/7 patients at day 28. In summary, pegtarazimod reduced aGVHD in mice by suppressing pro inflammatory neutrophil effector functions and preserving enterocyte integrity. The clinical trial data support tolerability of pegtarazimod in aGVHD patients and further studies are needed to determine efficacy.
Authors
Verena Holzmüller, Jana Gawron, Ann-Cathrin Burk, Anna-Verena Stell, Anna-Sophia Baur, Alexander Zähringer, Viktor Fetsch, Annika Mäder, Alina Hartmann, Nana Talvard-Balland, Neel Krishna, Kenji Cunnion, Ulrich Thienel, Paolo Martini, Lindsey Glenn, James L.M. Ferrara, Monzr M. Al Malki, Hannah Choe, José Antonio Pérez-Simón, Annette Schmitt-Graeff, Joerg Buescher, Natalie Köhler, Zohreh Mansoori Moghadam, Philipp Henneke, Geoffroy Andrieux, Melanie Boerries, Robert Zeiser
Abstract
Background Autoimmune diseases (ADs) often co-occur within individuals and families, indicating shared genetic risk factors. However, the composition of genetic overlap across autoimmunity is largely unknown. Methods This nationwide study included 6,336,615 individuals born in Sweden between 1932 and 1983, comprising 3,839,400 full-sibling pairs. Based on national heath-registers, 22 ADs were identified from 1969-2013. Aggregation and co-aggregation of ADs among siblings was used to estimate pairwise genetic correlations of ADs under a liability-threshold model. Network analysis and principal component analysis was used to characterize the structure of shared genetic risk across ADs. Results A total of 707,995 individuals (11.2%) were diagnosed with at least one AD. The studied ADs formed a network of significant genetic correlations (mean rg = 0.24, range 0.08-0.84) with clusters of more closely related ADs (rg ≥ 0.3). We found no evidence of a significant universal factor predisposing to autoimmunity. Conclusions This study demonstrates that ADs share substantial cluster-specific genetic overlap that largely aligns with affected tissue types, leading to distinct groupings of connective tissue diseases, gastrointestinal disorders, and endocrinopathies, whereas diseases of the nervous system show limited genetic cohesion. This suggests that shared biological mechanisms may drive coaggregation within disease groups. Clinically, these insights highlight the importance of monitoring patients and their relatives for related autoimmune disorders. Funding The Swedish Society of Medicine, Region Värmland's County Research Council, The Swedish Research Council, the Knut and Alice Wallenberg Foundation, The Regional Agreement on medical training and Clinical research (ALF) between Stockholm County Council and Karolinska Institutet
Authors
Daniel Eriksson, Ralf Kuja-Halkola, Marie E. Holmqvist, Henrik Larsson, Agnieszka Butwicka, Soffia Gudbjörnsdottir, Olle Kämpe, Sophie Bensing, Jakob Skov
Abstract
TRAIL is a TNF family ligand that trimerizes TRAIL-R1 (DR4) or TRAIL-R2 (DR5) to induce apoptosis, necroptosis, and/or NF-κB activation in receptor-bearing cells. We previously identified TRAILshort as a splice variant of TRAIL that lacks cysteine 230, cannot trimerize, and acts as a dominant-negative ligand that blocks TRAIL-mediated apoptosis. TRAILshort is expressed on cell surfaces and within extracellular vesicles, enabling it to confer TRAIL resistance to both producing and bystander cells. In this study, we showed that elevated TRAILshort levels were associated with chronic viral infections, cancer, and autoimmune diseases, suggesting a link to impaired immune regulation. Using unbiased phosphoproteomics and mechanistic studies, we demonstrated that TRAILshort binding to DR5 recruited and activated the phosphatase Src homology region 2 domain–containing phosphatase 1 (SHP-1), leading to zeta-chain-associated protein kinase 70 (ZAP-70) dephosphorylation, disruption of ZAP-70–CD3ζ interactions, and impaired T cell receptor signaling, thereby reducing T cell activation, proliferation, and cytokine production in response to antigen or CD3/CD28 ligation. Genetic or pharmacologic SHP-1 inhibition reverses these effects. In humanized mouse models, TRAILshort promoted the persistence of transformed mouse embryonic fibroblasts (MEFs) and L428 and antagonized CD19-directed CAR T cell activity, revealing TRAILshort as an immunomodulator of T cell function with therapeutic implications, including blocking TRAILshort to restore T cell immunity or delivering TRAILshort to enforce tolerance.
Authors
Shahrzad Jalali, Sekar Natesampillai, Zilin Nie, Ying Zhang, Ismail Can, Aswath P. Chandrasekar, Brianna M. Hameister, Cristina Correia, Tuantuan V. Zhao, Dong-Gi Mun, Enrique Garcia-Rivera, Robert Matson, Ashton Krogman, Mark A. Maynes, Robin Batchelor, Dileep D. Monie, Hu Li, Atta Behfar, Saad S. Kenderian, Akhilesh Pandey, Stephen M. Ansell, Timucin Taner, Cornelia Weyand, Daniel D. Billadeau, Andrew D. Badley
Abstract
Orphan GPCRs of the GPRC5 family regulate macrophage activity and vascular contractility by dimerizing with other GPCRs, but pharmacological modulation of this process has not been explored. We previously identified the dimerization interface of receptor GPRC5B and show here that both its mutation and inhibition by a decoy peptide disturbed the interaction with the prostaglandin E2 receptor EP2 in macrophages, resulting in reduced EP2 signaling, enhanced migration and phagocytosis, and protection from bacterial peritonitis in mice. Furthermore, we show that a similar interface exists in related receptor GPRC5C, and, the same as in GPRC5B, mutation or inhibition by decoy peptide improved host defense. Through a virtual docking screen, we identified a small molecule inhibitor of both GPRC5B and GPRC5C dimerization, K303MP20, and showed that it reduced EP2 signaling, enhanced macrophage activity, and improved host defense in bacterial peritonitis and influenza A infection. Interestingly, K303MP20 not only blocked dimerization between GPRC5B/C and EP2, but also with prostacyclin receptor IP and angiotensin II receptor AT1, resulting in reduced AT1-dependent contraction and enhanced IP-dependent relaxation in human and murine smooth muscle cells. In vivo, K303MP20 did not affect basal blood pressure, but protected mice from angiotensin II–induced hypertension. Taken together, inhibition of orphan GPCR dimerization by small molecules is feasible and improves infection control and arterial hypertension.
Authors
Jeonghyeon Kwon, Margherita Persechino, Jingchen Shao, Jamal Shamsara, Birgit Spitznagel, Isabelle Salwig, Miloslav Sanda, Stefan Offermanns, Peter Kolb, Nina Wettschureck
Abstract
Authors
S. Marina Casalino-Matsuda, Vijeeth Guggilla, Catherine A. Gao, Kaitlyn E. DeMeulenaere, Luisa Cusick, Samuel W. Fenske, Zhan Yu, Ziyan Lu, Suchitra Swaminathan, Rogan A. Grant, Maxwell J. Schleck, Murali Prakriya, Sudarshan Hebbar, Kenneth Stauderman, Helen K. Donnelly, Chiagozie I. Pickens, Luisa Morales-Nebreda, The NU SCRIPT Study Investigators, Richard G. Wunderink, Alexander V. Misharin, Benjamin D. Singer, G.R. Scott Budinger
Abstract
During early pregnancy, maternal blood surrounds the embryo before the placenta is fully developed, requiring tight regulation of maternal blood flow into the placental vasculature. We identify placental microthrombi (PMTs) as essential structures guiding this process. PMTs contain platelets, coagulation factors, and complement proteins, and their formation depends on maternal platelet activation by thrombin through the protease-activated receptor PAR4 (F2rl3). Deficiency of PAR4 abolished PMTs and caused excessive bleeding at the implantation site. C3 deficiency also led to increased bleeding events, indicating that complement activation contributes to thrombosis in the placental circulation. Conversely, dysregulated complement activation in CMP-sialic acid synthase-deficient (Cmas-/-) mice led to widespread thrombosis and failed placental development. Strikingly, platelet activation via PAR4 was necessary to localize complement activation to trophoblast surfaces, thereby coupling coagulation and complement in PMT formation. Depletion of maternal platelets mitigated complement-driven thromboinflammation in Cmas-/- pregnancies, restoring placental growth. These findings uncover a critical cooperation between platelets, coagulation, and complement in establishing maternal blood flow to the placenta. Successful pregnancy therefore requires not only activation but also tight regulation of these systems to balance necessary PMT formation with the prevention of pathological thrombosis.
Authors
Arno Smid, Lisa Schumann, Olga Oleshko, Ulrike Peters-Bernard, Kerstin Flächsig-Schulz, Melissa Whitehead, Emma Arndt, Korbinian Brand, Sonja Werwitzke, Andreas Klos, Bryan Paul Morgan, Wioleta M. Zelek, Andreas Tiede, Markus Abeln
Abstract
Ex vivo engineering strategies for adoptive αβ T-cell therapies increasingly use pharmacological modulation to improve survival, expansion, and antitumor activity. Short-term exposure to the BCL-2 inhibitor venetoclax during αβ T-cell manufacturing enhances apoptotic priming and effector persistence, suggesting a route to strengthen other T-cell lineages. γδ T cells share cytotoxic properties with αβ T cells but recognize targets independently of major histocompatibility complex (MHC) and show low alloreactivity, supporting off-the-shelf use in acute myeloid leukemia (AML). Whether such conditioning benefits γδ T cells was unknown. Here, we show that ex vivo venetoclax pretreatment enhances the antileukemic efficacy of therapeutic γδ T cells and chimeric antigen receptor (CAR) γδ T cells. Venetoclax-pretreated γδ T cells displayed increased cytotoxicity and proliferation with reduced exhaustion, yielding superior control of AML blasts and xenografts. These functional gains coincided with elevated mitochondrial content and a fatty acid oxidation metabolic profile. In vivo, venetoclax-pretreated γδ T cells achieved durable disease suppression, and the same conditioning improved CAR γδ T-cell efficacy. Together, these results show that short-term BCL-2 inhibition enhances γδ T-cell cytotoxicity and persistence. Incorporating venetoclax pretreatment into γδ T-cell manufacturing may improve therapeutic efficacy and inform next-generation γδ T-cell therapies for AML.
Authors
Xingchi Chen, Lin Zhang, Bingbing Yan, Yinqiang Sui, Weiwei Ma, Hui Zhao, Yining Wang, Kepeng Yang, Jiewen Ma, Baolin Tang, Yonghui Zhang, Xiaoyu Zhu
Abstract
Regulatory T cells (Tregs) maintain immune tolerance through mechanisms tightly coupled to cellular metabolism. Whereas glycolysis supports Treg migration, lipid metabolism sustains their suppressive phenotype. Here, we identify the sterol regulatory element–binding protein 1c (SREBP1c) as a central regulator of Treg immunobiology. Tregs from Srebp1c-deficient mice displayed impaired suppressive function, reduced frequencies in circulation and lymphoid tissues, and diminished expression of functional markers. These defects stemmed from intrinsic metabolic rewiring rather than systemic alterations, as both ex vivo Tregs (CD4+CD25hiFoxP3+) and in vitro-derived Tregs lacking Srebp1c were shifted toward glycolysis. Integrated transcriptomic and lipidomic analyses revealed that Srebp1c-deficient Tregs exhibited defective phospholipid remodeling, with an accumulation of lysophosphatidylcholines over phosphatidylcholines, which we attributed to enhanced cytosolic phospholipase A2 (cPLA2α) activity and disruption of the Lands cycle. Altered lipid composition impaired adenosine-mediated immunosuppression by reducing CD73 expression and extracellular adenosine generation. Accordingly, pharmacological inhibition of cPLA2α restored adenosine signaling, CD73 expression, and Treg suppressive capacity. Thus, by preserving phospholipid homeostasis, SREBP1c functions as an immunometabolic checkpoint that links lipid metabolism to adenosine-dependent Treg suppression.
Authors
Fabrizia Bonacina, Claudio Procaccini, Marta Iaia, Arianna Moretti, Monika Svecla, Silvia Pedretti, Jeroen F.J. Bogie, Giovani Battista Vingiani, Annalisa Moregola, Francesca Genova, Claudia Russo, Giusy De Rosa, Claudia La Rocca, Giada Mondanelli, Marco Gargaro, Nico Mitro, Giuseppe Matarese, Giuseppe Danilo Norata
Abstract
Resistance to antiangiogenics is a major challenge in cancer therapy. These agents can either normalize or exacerbate tumor vascular abnormality and hypoxia. The mechanisms of resistance remain unclear in the latter setting. By integrating data from mouse models and clinical trials, we showed that hypoxia-inducing anti-VEGF therapy upregulated programmed cell death ligand 1 (PD-L1), yet failed to sensitize tumors to PD-L1 blockade. Mechanistically, early hypoxic stress triggered epithelial osteopontin (SPP1) production, which recruited monocytes and skewed macrophages toward M2 states, suppressing T cell cytotoxicity. Pharmacological SPP1 depletion impeded the development of hypoxia, reduced M2 infiltration, restored T cell activity, and enabled synergy between antiangiogenics and anti–PD-L1. Genetic dissection — tumor-epithelial Spp1-KO grafts and bone marrow chimeras generated by lethal irradiation and reconstitution with Spp1–/– or WT hematopoietic donors — showed that myeloid SPP1 contributed only marginally compared with epithelial SPP1. These findings identified SPP1 as a central mediator of resistance to hypoxia-inducing antiangiogenics, contributed to a comprehensive model of antiangiogenic resistance, and supported SPP1-targeted strategies to personalize immunotherapy and antiangiogenic therapy according to tumor hypoxia.
Authors
Jose Luis Ruiz-Sepulveda, Maria J. Bueno, Silvana Mouron, Veronica Jimenez-Renard, Manuel Muñoz, Manuel Moradiellos, Leonardo D. Garma, Luis García-Jimeno, Adam W. Watson, Ghassan Mouneimne, Solip Park, Rebeca Jimeno, Miguel Quintela-Fandino
Abstract
Oral antibiotics can predispose to joint inflammation, but this phenomenon remains poorly understood. Here, we leverage mouse models of alphavirus-induced arthritis to investigate the roles of gut commensals, metabolites, and host immune mechanisms in promoting musculoskeletal inflammation. Mice treated with a short course of oral antibiotics exhibited worsened arthritis after chikungunya (CHIKV) or Mayaro virus infections. This phenotype was associated with loss of short-chain fatty acids (SCFAs), greater intestinal permeability, and activation of gut-associated immune cells and required TLR4 signaling, MyD88 expression, monocytes, antigen-specific and bystander CD4+ T cells, and proinflammatory cytokines. Administration of exogenous SCFAs or colonization of mice with bacterial species that generate SCFAs mitigated CHIKV-induced joint inflammation. scRNA-seq revealed that gut-derived SCFAs ameliorate the inflammatory phenotype of synovial CD4+ T cells, infiltrating monocytes, and resident osteoclast-like cells. Thus, antibiotic-triggered gut dysbiosis exacerbates alphavirus arthritis by shaping the inflammatory profile of both infiltrating and resident immune cells in joint tissues.
Authors
Fang R. Zhao, Maksim Kleverov, Emma S. Winkler, Russell B. Williams, Hana Janova, Lindsay Droit, Leran Wang, Ting-ting Li, Leah Heath, Ana Jung, Matthias Mack, Megan T. Baldridge, Thaddeus S. Stappenbeck, Larissa B. Thackray, Chyi-Song Hsieh, Scott A. Handley, Chun-Jun Guo, Michael A. Fischbach, Maxim N. Artyomov, Michael S. Diamond
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)