Aug 2026· Journal of Clinical Investigation· 0 citations
Medicine
TL;DR
Pegtarazimod reduced aGVHD in mice by suppressing pro inflammatory neutrophil effector functions and preserving enterocyte integrity and the clinical trial data support tolerability of pegtarazimod in aGVHD patients and further studies are needed to determine efficacy.
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.
Acute graft-versus-host disease (aGVHD) is a major, life-threatening complication in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), and the development of novel molecular-targeted therapies for aGVHD is urgently needed. Thiolutin (THL), a disulfide-containing antibiotic, inhibits the activity of the BRCC3-containing isopeptidase complex and thereby suppresses NLR pyrin domain-containing protein 3 (NLRP3) inflammasome activation. Here, we investigated the effect of THL on aGVHD in a mouse model of allo-HSCT. We found that THL significantly improved survival in aGVHD recipients, reduced weight loss and clinical scores, and attenuated pathological changes in aGVHD target organs, including the liver, small intestine, and colon. Furthermore, THL diminished donor T-cell activation and infiltration into target organs and promoted the expansion of regulatory T cells. THL also inhibited NLRP3 inflammasome activation and reduced the production of proinflammatory cytokines, including tumor necrosis factor (TNF), interferon γ (IFN-γ), interleukin (IL)-2, IL-17A, and IL-1β. This study reveals a previously unrecognized role of THL in regulating aGVHD and highlights its potential as an anti-inflammatory therapeutic agent for clinical development in patients undergoing allo-HSCT.
Xin Li, Ke Zhao, Rui Gao et al.· Blood Science· 0 citations
Acute graft-versus-host disease (aGVHD) remains a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study investigated the preventive effects of paeoniflorin (PF), a natural monoterpene glycoside, on aGVHD.
Candidate herb-derived compounds against aGVHD were screened using SymMap, HERB, ADMETlab, and InflamNat, followed by molecular docking. The preventive effects of PF were evaluated in major histocompatibility complex (MHC)-mismatched murine aGVHD models. An entire-process paeoniflorin (EP-PF) regimen, involving donor pretreatment before transplantation and recipient treatment after transplantation, was proposed for enhancing the preventive effect. Survival, body weight, clinical score, hematopoietic reconstitution, donor T cell infiltration, cytokine and chemokine levels, gut injury, apoptosis, gut microbiota, transcriptomic changes, and graft-versus-tumor (GVT) activity were assessed.
PF was identified as a promising multi-target compound for aGVHD prevention. PF reduced clinical severity, body weight loss, and mortality, while improving hematopoietic recovery and increasing hematopoietic stem/progenitor cell (HSPC) numbers. EP-PF regimen showed stronger protection than recipient-only PF administration. Mechanistically, EP-PF reduced intestinal donor cluster of differentiation 4 (CD4) positive and cluster of differentiation 8 (CD8) positive T cell infiltration, partially restored CD4
+
/CD8
+
T cell balance, and reversed inflammatory transcriptional programs in donor T cells. Moreover, EP-PF balanced serum levels of cytokines and chemokines, preserved gut barrier integrity, reduced intestinal apoptosis, and partially corrected gut microbiota dysbiosis. Importantly, EP-PF preserved donor cell-mediated tumor control in a green fluorescent protein (GFP)-labeled A20 GVT model. PF also directly inhibited the proliferation of hematologic tumor cells and promoted their apoptosis
in vitro
and
in vivo
.
PF prevents experimental aGVHD through coordinated regulation of donor T cell responses, inflammatory mediators, hematopoietic reconstitution, intestinal barrier injury, apoptosis, and gut microbiota, while preserving GVT activity. These findings support PF as a potential prophylactic candidate for allo-HSCT.
Xing-Yu Wan, Nan Li, Yang Gou et al.· Frontiers in Immunology· 0 citations
BACKGROUND
Acute graft-versus-host disease (aGvHD) remains a major complication after allogeneic hematopoietic cell transplantation (alloHCT). Adoptive regulatory T-cell (Treg) therapy may suppress alloreactive T-cell responses, but clinical implementation has been limited by donor-specific manufacturing, prolonged ex vivo expansion, and logistical complexity.
OBJECTIVE
We developed ATreg, a cell therapy product consisting of gp120-activated, polyclonal Tregs derived from HLA-unmatched third-party donors. The primary objective was to assess the safety, tolerability and toxicity of ATreg, hypothesizing that this would be feasable and safe for aGvHD prevention early after alloHCT in patients with hematologic malignancies.
STUDY DESIGN
ATreg-001 is a first-in-human, prospective, open-label, single-arm, multi-center phase 1/2 trial (EU CT number 2024-516599-14-00) conducted at four German centers (Mainz, Dresden, Münster, Dortmund). ATreg was generated from standard non-mobilized apheresis products by Treg isolation followed by 16 hours of gp120-mediated activation in the presence of IL-2, without ex vivo expansion, thereby enhancing suppressive function and (potentially) enabling a therapeutic effect at substantially lower Treg doses. Ten patients received ATreg at 0.1-1.0 × 10⁶ cells/kg body weight on day +10 ± 5 after alloHCT, in addition to standard GvHD prophylaxis, in a dose-escalation design across three cohorts. ATreg was administered within 24 hours after manufacturing. The primary endpoint was the type, incidence, and severity of ATreg-related serious adverse events within 14 days after administration. Secondary endpoints included manufacturing feasibility, aGvHD incidence/severity within 100 days, engraftment, and infections.
RESULTS
ATreg administration was well tolerated, with no infusion-related toxicities or other safety signals attributable to ATreg. All treated patients achieved hematopoietic engraftment and full donor chimerism. Within 100 days after alloHCT, no grade 3-4 aGvHD occurred, the cumulative incidence of grade 2-4 aGvHD was 10%, and no non-relapse mortality was observed.
CONCLUSION
These first clinical data support the feasibility and favorable safety profile of ATreg, a third-party, gp120-activated Treg product requiring no ex vivo expansion, and warrant further evaluation in larger prospective clinical trials.
MAIN POINTS
A. Tuettenberg, L. Ruhnke, J. Schlöder et al.· Transplantation and Cellular...· 0 citations
Background
The resolution of graft-versus-host disease (GVHD) improves survival of patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT). T helper 17 (Th17) cells mediate the progression and severity of GVHD. The differentiation of Th17 cells relies on the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which activates the transcription factor retinoic acid-related orphan receptor γt (RORγt), consolidating the fate of the cell. In this study, we aim to investigate the prophylactic efficacy of itraconazole in GVHD.
Methods
In this study, T cell proliferation and effector T cell subtypes were assessed after in vitro activation or allogeneic stimulation. Itraconazole was administered to mice with GVHD and the effects in vivo were assessed.
Results
Itraconazole treatment decreased type 1 helper (Th1) and Th17 cells during in vitro T cell activation and allogeneic stimulation. In mice with GVHD, combination treatment decreased the clinical and pathological severity of GVHD.
Conclusions
In this study, we show that itraconazole ameliorates GVHD and is associated with reduced phosphorylated STAT3 (pSTAT3) levels and decreased Th17 cell differentiation. Therefore, itraconazole may have potential to ameliorate GVHD and tissue damage.
Y. Kim, Joo-Youn Jhun, S. Han et al.· Clinical transplantation and...· 0 citations
Acute Graft-Versus-Host Disease (GVHD) is a complication of allogeneic blood and marrow transplantation in which alloreactive T cells destroy tissues in the liver, skin, and gastrointestinal tract. The dual energetic demands of activation and proliferation push alloreactive T cells into adopting fatty acid oxidation (FAO), a pathway that then becomes a therapeutic target for mitigating GVHD. Here we demonstrate the results of genetic deletion of FAO machinery in donor T cells, and administration of a novel FAO-targeting pharmaceutical as a GVHD treatment.
We utilized a C57BL/6 donor into B6D2F1/J recipient model of GVHD. Post-transplant, recipient clinical scores were calculated weekly and weight assessed twice weekly. Genetic FAO inhibition was achieved through a T cell-specific knockout (KO) of carnitine palmitoyltransferase 1a in C57BL/6 mice; recipient mice received either KO (n = 16) or wild-type (n = 16) splenic T cells in transplant. For compound testing, recipient mice with wild-type T cell transplants received either the drug (n = 12) or vehicle control (n = 13) intraperitoneally at days 3, 7, and 10 post-transplant.
KO T cell recipients exhibited increased survival (Mantel-Cox p = 0.008). While the ongoing drug treatment experiment has not found a significant survival improvement, the drug-treated group exhibits a trend towards greater weights at day 21 post-transplant (Student’s t-test p = 0.06).
Our results find that genetic inhibition of FAO reduces GVHD; as such, pharmacological inhibition of mitochondrial FAO could theoretically produce the same effect. Although preliminary results do not reveal a survival benefit to drug treatment, optimization of dosing strategy and formulation is underway to clarify the drug’s potential therapeutic benefit. Further investigations will characterize its role in post-transplant weight recovery and impact on specific T cell subpopulations early after transplantation, and determine whether similar effects manifest in human T cells.
Department of Pediatrics, University of Minnesota
Transplantation Immunology (TRAN)
Lukas Murdych, Felicia Kemp, Christian R Tamar et al.· Journal of Immunology· 0 citations
Chronic inflammatory and autoimmune diseases are among the leading causes of morbidity and mortality worldwide, yet immunosuppressive therapy (IST) often fails to achieve durable remission and induces toxicity. Severe aplastic anemia (SAA) is a lethal bone marrow failure driven by autoreactive T cells. Patients treated with cyclosporine A (CsA) exhibit sustained inflammation, frequent relapse, and secondary complications. Specialized pro-resolving lipid mediators, such as Resolvin E1 (RvE1), promote resolution of inflammation and restore tissue homeostasis. Using a preclinical murine model, we examined how immunosuppressive and resolution-targeted therapies shape disease outcomes, and whether their combination improves recovery.
SAA was induced in sub-lethally irradiated mice via MHC-mismatched splenocyte transfer. Mice were treated with 10 mg/kg CsA and/or 0.0125 mg/kg RvE1 after disease onset. Long-term recovery was assessed 30-90 days post-withdrawal. scRNAseq, ligand-receptor analyses, receptor knockouts, and reciprocal chimeras were used to determine cell-specific mechanisms.
CsA improved survival (75%), but caused persistent T cell activation, Th17 expansion, granulocytic skewing, and renal toxicity. Conversely, RvE1 (50% survival) normalized T cells and restored hematopoietic output without organ injury. Combination therapy achieved 100% survival, restored immune profiles, and prevented systemic toxicity. ChemR23 on immune cells was required for RvE1 protection. scRNAseq revealed CsA-induced transcriptional dysregulation, inflammatory cell-cell crosstalk, and aberrant histone gene expression, consistent with durable immune remodeling. RvE1 co-therapy normalized these transcriptional networks.
CsA impairs inflammation resolution and long-term organ function. Co-treatment with RvE1 restores immune and hematopoietic homeostasis, supporting integration of pro-resolving therapy with IST for safer, durable remission for autoimmune and inflammatory diseases.
CDMRP Bone Marrow Failure Research Program-IDA (BM190079 and BM220031) and NHLBI R01HL159411
Therapeutic Approaches to Autoimmunity (THER)
Rachel Grazda, Amber Bahr, Lily Nti-kyeremeh et al.· Journal of Immunology· 0 citations
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