Search Results (46)

Background: Post-transplant cyclophosphamide (PTCy) is a standard graft-versus-host disease (GVHD) prophylaxis in allogeneic hematopoietic cell transplantation (allo-HCT). While effective, concerns remain about cyclophosphamide-related cardiotoxicity, especially in patients with pre-existing cardiac morbidity, a population often underrepresented in clinical trials. Objectives: To assess the incidence and outcomes of early (ECE, ≤100 days) and late (LCE, >100 days) cardiac events in acute myeloid leukemia (AML) patients with and without baseline cardiac morbidity undergoing allo-HCT with PTCy. Study Design: Retrospective multicenter study by the Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH-TC) including 461 AML patients (62 with cardiac morbidity) transplanted between 2012 and 2022. Cardiac morbidity was defined by documented cardiac disease or left ventricular ejection fraction < 45%. Cumulative incidence, overall survival (OS), and non-relapse mortality (NRM) were analyzed using competing risks models and adjusted with propensity score matching (PSM) and inverse probability weighting (IPW). Results: Cardiac events occurred in 13.2% of patients: 11% vs. 7% ECE (p = 0.93) and 8% vs. 5.3% LCE (p = 0.85) in those with vs. without cardiac morbidity. Most ECEs were arrhythmias or heart failure. Adjusted analyses confirmed no significant differences in CE incidence, OS, or NRM between groups. Two-year OS was 69% vs. 70% (p = 0.50); NRM was 18% vs. 17% (p = 0.20). ECE was associated with higher mortality in both groups. Conclusions: PTCy is feasible in AML patients with pre-existing cardiac morbidity when combined with comprehensive cardiovascular evaluation and cardio-oncology follow-up, supporting its safe use in broader patient populations with appropriate cardiologic support. Full article

Background/Objectives: Human leukocyte antigens (HLAs) are major determinants of successful allogeneic hematopoietic stem cell transplantation (allo-HSCT). Their alleles are closely linked to outcomes, even in HLA-identical sibling donor (ISD) HSCT. This retrospective study analyzed the impact of HLA alleles on HLA-ISD HSCT outcomes in Omani patients. Methods: Data were collected for a heterogenous cohort of patients registered at the Sultan Qaboos University Hospital (SQUH), who underwent HLA-ISD HSCT from 2012 to 2022 (n = 153). HSCT outcomes, namely acute GVHD (aGVHD), chronic GVHD (cGVHD), chimerism status (complete or mixed) at 6 to 12 months after HSCT, neutrophil and platelet engraftment time, and patient five-year overall survival, were included. Low-resolution HLA-typing records were collected for five HLA loci: HLA-A, B, C, DRB1 and DQB1. GVHD and chimerism were analyzed by logistic regression analysis. Platelet and neutrophil engraftment times were assessed by Mann–Whitney tests. Patient overall survival was evaluated by the Kaplan–Meier model and Log-rank testing. At a 95% confidence interval, the p-value threshold was corrected using Bonferroni correction. Results: The incidence rates of aGVHD and cGVHD from all grades were 16% and 15%, respectively. Although no association between HLA alleles or any of the investigated outcomes was identified, survival curve analyses indicated a significant protective effect of HLA-DQB1*05 (p = 0.01). Patients carrying this allele had a better-estimated 5-year overall survival (90%) than did DQB1*05 negative patients (68%). Conclusions: This study suggests that HLA-DQB1*05 in the Omani population could have an impact on overall survival and might be a predictive biomarker. Further studies on a larger scale in other regional populations are needed to validate our findings and explore the underlying mechanism. Full article

Background: Donor lymphocyte infusion (DLI) is employed to enhance the graft-versus-leukemia (GvL) effect and improve remission rates following allogeneic hematopoietic cell transplantation (alloHCT). However, graft-versus-host disease (GvHD) remains a significant complication of both alloHCT and DLI. Regular exercise has been shown to reduce cancer risk, enhance treatment responses, and mitigate therapy-related toxicities. This study investigated the effects of voluntary wheel running on GvL and GvHD following DLI in a xenogeneic mouse model. Methods: Immunodeficient NSG-IL15 mice were challenged with a luciferase-expressing chronic myelogenous leukemia cell line (K562), and then they received DLI with peripheral blood mononuclear cells (PBMCs) from healthy volunteers (GvL model). Non-tumor bearing mice received DLI to model GvHD. Half of the mice in each group were then given free access to a running wheel. Tumor growth (bioluminescence), GvHD, and body weight were monitored biweekly for ~40 days. Results: In the GvHD model, exercise extended overall survival by 60% and reduced GvHD severity. In the GvL model, exercise significantly lowered tumor burden and extended tumor-free survival in both DLI and vehicle control groups by 44.5% and 37.5%, respectively, suggesting both immune-dependent and immune-independent mechanisms. RNA sequencing of bone marrow from saline-injected mice revealed that genes associated with mitochondrial function, protein synthesis, and metabolic processes were downregulated in tumors from exercised mice. Conclusions: In summary, voluntary wheel running improved DLI outcomes by enhancing GvL and reducing GvHD. These benefits may be mediated, in part, through exercise-induced metabolic reprogramming of leukemia cells. Full article

Background/Objectives: Organ transplantation is a life-saving intervention for patients with terminal organ failure, but long-term success is hindered by graft rejection and dependence on lifelong immunosuppressants. These drugs pose risks such as opportunistic infections and malignancies. Chimeric antigen receptor (CAR) technology, originally developed for cancer immunotherapy, has been adapted to regulatory T cells (Tregs) to enhance their antigen-specific immunosuppressive function. This systematic review evaluates the preclinical development of CAR-Tregs in promoting graft tolerance and suppressing graft-versus-host disease (GvHD). Methods: A systematic review following PROSPERO guidelines (CRD420251073207) was conducted across PubMed, Scopus, and Web of Science for studies published from 2015 to 2024. After screening 105 articles, 17 studies involving CAR-Tregs in preclinical or in vivo transplant or GvHD models were included. Results: CAR-Tregs exhibited superior graft-protective properties compared to unmodified or polyclonal Tregs. HLA-A2-specific CAR-Tregs consistently improved graft survival, reduced inflammatory cytokines, and suppressed immune cell infiltration across skin, heart, and pancreatic islet transplant models. The inclusion of CD28 as a co-stimulatory domain enhanced Treg function and FOXP3 expression. However, challenges such as Treg exhaustion, tonic signaling, and reduced in vivo persistence were noted. Some studies reported synergistic effects when CAR-Tregs were combined with immunosuppressants like rapamycin or tacrolimus. Conclusions: CAR-Tregs offer a promising strategy for inducing targeted immunosuppression in allogeneic transplantation. While preclinical findings are encouraging, further work is needed to optimize CAR design, ensure in vivo stability, and establish clinical-scale manufacturing before translation to human trials. Full article

Precision probiotics have shown great promise as novel therapies but have not been fully realized. One major obstacle is that different strains of the same gut microbiota species can induce markedly variable phenotypic outcomes. Here, we aimed to optimize and validate in a preclinical model, a six-species precision probiotic therapy for graft-versus-host disease (GVHD), an autoimmune complication following allogeneic stem cell transplantation. We had identified these six species as associated with protection against GVHD in a prior clinical study. We isolated strains of three of the targeted taxa (B. longum, C. bolteae, and Blautia spp.) from human stem cell transplant patients and characterized their SCFA production in vitro. We observed significant strain-to-strain variability among these gut microbiota taxa in their capacity to produce short-chain fatty acids, a microbiota-derived metabolite shown to be important for mitigating gut GVHD and inflammatory bowel disease, in vitro. We found that B. longum was able to augment butyrate production by C. bolteae and Blautia when co-cultured in vitro. “Optimized” precision probiotics mitigated GVHD and significantly increased survival (p = 0.013, log-rank test) in mice compared to a “standard” probiotic consortium of the same bacterial species obtained from a commercial repository. Importantly, the optimized probiotics resulted in significant increases in intestinal short-chain fatty acid concentrations compared to standard probiotics (p < 0.001, Mann–Whitney test). Our findings highlight the promising potential of utilizing an optimized precision probiotic approach to maximize therapeutic efficacy. Full article

Hematopoietic stem cell transplantation (HSCT) is a life-saving therapy for hematologic malignancies, such as leukemia and lymphoma and other severe conditions but is associated with significant risks, including graft versus host disease (GVHD), relapse, and treatment-related mortality. The increasing complexity of clinical, genomic, and biomarker data has spurred interest in machine learning (ML), which has emerged as a transformative tool to enhance decision-making and optimize outcomes in HSCT. This review examines the applications of ML in HSCT, focusing on donor selection, conditioning regimen, and prediction of post-transplant outcomes. Machine learning approaches, including decision trees, random forests, and neural networks, have demonstrated potential in improving donor compatibility algorithms, mortality and relapse prediction, and GVHD risk stratification. Integrating “omics” data with ML models has enabled the identification of novel biomarkers and the development of highly accurate predictive tools, supporting personalized treatment strategies. Despite promising advancements, challenges persist, including data standardization, algorithm interpretability, and ethical considerations regarding patient privacy. While ML holds promise for revolutionizing HSCT management, addressing these barriers through multicenter collaborations and regulatory frameworks remains essential for broader clinical adoption. In addition, the potential of ML can cope with some challenges such as data harmonization, patients’ data protection, and availability of adequate infrastructure. Future research should prioritize larger datasets, multimodal data integration, and robust validation methods to fully realize ML’s transformative potential in HSCT. Full article

Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease which can present with mixed organ involvement. Kidney involvement in lupus nephritis (LN) is a severe complication and major cause of mortality in SLE patients, second only to cardiovascular disease. While mouse models have helped uncover some molecular pathways involved in SLE/LN, we need a better understanding of the connection of these pathways and the immune cells involved in disease pathogenesis to develop new and effective therapies. Furthermore, models used for studying SLE/LN in mice have a heterogeneous immune response and may not always represent disease manifestations observed in patients. Identifying models that have shared pathways with human disease would allow for better translation for developing effective SLE/LN therapies. The molecular pathways of five different SLE/LN models (MRL/lpr, poly (I:C)-induced, interferon-α-induced, bm12 GvHD, and spontaneous NZB/W F1) were compared to characterize the immune response in mouse kidneys. These models demonstrated varied magnitudes in immune responses and proportions of innate vs. adaptive cell involvement. These findings were compared to human molecular pathways and cell types from public databases, including the Accelerating Medicine Partnership–Systemic Lupus Erythematosus Program (AMP-SLE), to help corelate mechanisms involved in mouse models to human disease. Full article

Allogeneic hematopoietic cell transplantation (allo-HCT) is a highly effective, well-established treatment for patients with various hematologic malignancies and non-malignant diseases. The therapeutic benefits of allo-HCT are mediated by alloreactive T cells in donor grafts. However, there is a significant risk of graft-versus-host disease (GvHD), in which the donor T cells recognize recipient cells as foreign and attack healthy organs in addition to malignancies. We previously demonstrated that targeting JAK1/JAK2, mediators of interferon-gamma receptor (IFNGR) and IL-6 receptor signaling, in donor T cells using baricitinib and ruxolitinib results in a significant reduction in GvHD after allo-HCT. Furthermore, we showed that balanced inhibition of JAK1/JAK2 while sparing JAK3 is important for the optimal prevention of GvHD. Thus, we have generated novel JAK1/JAK2 inhibitors, termed WU derivatives, by modifying baricitinib. Our results show that WU derivatives have the potential to mitigate GvHD by upregulating regulatory T cells and immune reconstitution while reducing the frequencies of antigen-presenting cells (APCs) and CD80 expression on these APCs in our preclinical mouse model of allo-HCT. In addition, WU derivatives effectively downregulated CXCR3 and T-bet in primary murine T cells. In summary, we have generated novel JAK inhibitors that could serve as alternatives to baricitinib or ruxolitinib. Full article

Background: Although acute kidney injury (AKI) is a common complication in patients undergoing hematopoietic stem cell transplantation (HSCT), its prophylaxis remains a clinical challenge. Attempts at prevention or early diagnosis focus on various methods for the identification of factors influencing the incidence of AKI. Our aim was to test the artificial intelligence (AI) potential in the construction of a model defining parameters predicting AKI development. Methods: The analysis covered the clinical data of children followed up for 6 months after HSCT. Kidney function was assessed before conditioning therapy, 24 h after HSCT, 1, 2, 3, 4, and 8 weeks after transplantation, and, finally, 3 and 6 months post-transplant. The type of donor, conditioning protocol, and complications were incorporated into the model. Results: A random forest classifier (RFC) labeled the 93 patients according to presence or absence of AKI. The RFC model revealed that the values of the estimated glomerular filtration rate (eGFR) before and just after HSCT, as well as methotrexate use, acute graft versus host disease (GvHD), and viral infection occurrence, were the major determinants of AKI incidence within the 6-month post-transplant observation period. Conclusions: Artificial intelligence seems a promising tool in predicting the potential risk of developing AKI, even before HSCT or just after the procedure. Full article

This systematic review and meta-analysis aims to identify the outcomes of stem cell transplant (SCT) patients during the COVID-19 era. Pooled event rates (PER) were calculated, and meta-regression was performed. A random effects model was utilized. In total, 36 eligible studies were included out of 290. The PER of COVID-19-related deaths and COVID-19-related hospital admissions were 21.1% and 55.2%, respectively. The PER of the use of hydroxychloroquine was 53.27%, of the receipt of immunosuppression it was 39.4%, and of the use of antivirals, antibiotics, and steroids it was 71.61%, 37.94%, and 18.46%, respectively. The PER of the time elapsed until COVID-19 infection after SCT of more than 6 months was 85.3%. The PER of fever, respiratory symptoms, and gastrointestinal symptoms were 70.9, 76.1, and 19.3%, respectively. The PER of acute and chronic GvHD were 40.2% and 60.9%, respectively. SCT patients are at a higher risk of severe COVID-19 infection and mortality. The use of dexamethasone improves the survival of hospitalized SCT patients with moderate to severe COVID-19 requiring supplemental oxygen or ventilation. The SCT patient group is a heterogeneous group with varying characteristics. The quality of reporting on these patients when infected with COVID-19 is not uniform and further prospective or registry studies are needed to better guide clinical care in this unique setting. Full article

Severe combined immunodeficient (SCID) mice serve as a critical model for human xenotransplantation studies, yet they often suffer from low engraftment rates and susceptibility to graft-versus-host disease (GVHD). Moreover, certain SCID strains demonstrate ‘immune leakage’, underscoring the need for novel model development. Here, we introduce an SCID mouse model with a targeted disruption of the dclre1c gene, encoding Artemis, which is essential for V(D)J recombination and DNA repair during T cell receptor (TCR) and B cell receptor (BCR) assembly. Artemis deficiency precipitates a profound immunodeficiency syndrome, marked by radiosensitivity and compromised T and B lymphocyte functionality. Utilizing CRISPR/Cas9-mediated gene editing, we generated dclre1c-deficient mice with an NOD genetic background. These mice exhibited a radiosensitive SCID phenotype, with pronounced DNA damage and defective thymic, splenic and lymph node development, culminating in reduced T and B lymphocyte populations. Notably, both cell lines and patient-derived tumor xenografts were successfully engrafted into these mice. Furthermore, the human immune system was effectively rebuilt following peripheral blood mononuclear cells (PBMCs) transplantation. The dclre1c-knockout NOD mice described herein represent a promising addition to the armamentarium of models for xenotransplantation, offering a valuable platform for advancing human immunobiological research. Full article

Allogeneic haematopoietic stem cell transplantation (HSCT) leads to the establishment of graft-versus-leukaemia (GVL) immunity, but in many cases also results in the development of graft-versus-host disease (GVHD). This study aimed to determine if P2X7 antagonism using Brilliant Blue G (BBG) could improve the beneficial effects of post-transplant cyclophosphamide (PTCy) in a humanised mouse model of GVHD, without comprising GVL immunity. NOD.Cg-Prkdc^scid Il2rg^tm1Wjl (NSG) mice were injected with human peripheral blood mononuclear cells (PBMCs) (Day 0), then with cyclophosphamide (33 mg/kg) on Days 3 and 4, and with BBG (50 mg/kg) (or saline) on Days 0–10. PTCy with BBG reduced clinical GVHD development like that of PTCy alone. However, histological analysis revealed that the combined treatment reduced liver GVHD to a greater extent than PTCy alone. Flow cytometric analyses revealed that this reduction in liver GVHD by PTCy with BBG corresponded to an increase in human splenic CD39⁺ Tregs and a decrease in human serum interferon-γ concentrations. In additional experiments, humanised NSG mice, following combined treatment, were injected with human THP-1 acute myeloid leukaemia cells on Day 14. Flow cytometric analyses of liver CD33⁺ THP-1 cells showed that PTCy with BBG did not mitigate GVL immunity. In summary, PTCy combined with BBG can reduce GVHD without compromising GVL immunity. Future studies investigating P2X7 antagonism in combination with PTCy may lead to the development of novel treatments that more effectively reduce GVHD in allogeneic HSCT patients without promoting leukaemia relapse. Full article

Mycophenolate mofetil (MMF) is commonly used for acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). However, limited population pharmacokinetic (PPK) data are available for pediatric HSCT patients. This study aimed to develop a PPK model and recommend optimal oral MMF dosage in pediatric HSCT patients. This prospective study involved pediatric HSCT patients at a tertiary academic institution. Patients received oral MMF 15–20 mg/kg twice daily for aGVHD prophylaxis and treatment. The PPK analysis was conducted using a nonlinear mixed-effects modeling method. Simulation was performed considering different body surface areas (BSAs) (0.5 m², 1.0 m², 1.5 m²) and dosing (400 mg/m², 600 mg/m², 900 mg/m² twice daily). Based on the simulation, an optimal dosage of oral MMF was suggested. A total of 20 patients and 80 samples were included in the PPK model development. A one-compartment model with first-order absorption adequately described the pharmacokinetics of mycophenolic acid (MPA). BSA was a statistically significant covariate on V_d/F. Simulation suggested the optimal dosage of oral MMF as 900 mg/m² twice daily, respectively. A reliable PPK model was developed with good predictive performance. This model-informed optimal MMF dosage in pediatric HSCT patients can provide valuable dosing guidance in real-world clinical practice. Full article

Graft-versus-host disease (GvHD) is a common and severe complication following allogeneic hematopoietic stem cell transplantation (HSCT). Its prevention and treatment is a major challenge. Ferulic acid (FA) has anti-inflammatory and antioxidant properties that could be attractive in this setting. Our aim was to evaluate a bioactive ingredient derived from wheat bran (WB), selected for its high concentration of FA, in a murine model of GvHD. The ingredient was obtained via a bioprocess involving hydrolysis and spray-drying. GvHD was induced via HSCT between MHC-mismatched mouse strains. FA treatment was administered orally. Survival and disease scores (weight loss, hunching, activity, fur texture, and skin integrity, each scored between 0 and 2 depending on disease severity) were recorded daily, histological evaluation was performed at the end of the experiment, and serum inflammatory cytokines were analyzed on days 9 and 28. Treatment with FA did not protect GvHD mice from death, nor did it diminish GvHD scores. However, histological analysis showed that ulcers with large areas of inflammatory cells, vessels, and keratin were less common in skin samples from FA-treated mice. Areas of intense inflammatory response were also seen in fewer small intestine samples from treated mice. In addition, a slight decrease in INF-γ and TNF-α expression was observed in the serum of treated mice on day 28. The results showed some local effect of the ingredient intervention, but that the dose used may not be sufficient to control or reduce the inflammatory response at the systemic level in mice with GvHD. Higher dosages of FA may have an impact when evaluating the immunomodulatory capabilities of the hydrolyzed WB ingredient. Thus, further experiments and the use of technological strategies that enrich the ingredients in soluble ferulic acid to improve its efficacy in this setting are warranted. Full article

Graft-versus-host disease (GVHD) is a T cell-mediated inflammatory disorder that arises from allogeneic haematopoietic stem cell transplantation and is often fatal. The P2X7 receptor is an extracellular adenosine 5′-triphosphate-gated cation channel expressed on immune cells. Blockade of this receptor with small molecule inhibitors impairs GVHD in a humanised mouse model. A species-specific blocking monoclonal antibody (mAb) (clone L4) for human P2X7 is available, affording the opportunity to determine whether donor (human) P2X7 contributes to the development of GVHD in humanised mice. Using flow cytometric assays of human RPMI 8266 and murine J774 cells, this study confirmed that this mAb bound and impaired human P2X7. Furthermore, this mAb prevented the loss of human regulatory T cells (hTregs) and natural killer (hNK) T cells in vitro. NOD-scid IL2Rγ^null mice were injected with 10 × 10⁶ human peripheral blood mononuclear cells (Day 0) and an anti-hP2X7 or control mAb (100 μg i.p. per mouse, Days 0, 2, 4, 6, and 8). The anti-hP2X7 mAb increased hTregs and hNK cells at Day 21. Moreover, anti-hP2X7 mAb-treatment reduced clinical and histological GVHD in the liver and lung compared to the control treatment at disease endpoint. hTregs, hNK, and hNK T cell proportions were increased, and human T helper 17 cell proportions were decreased at endpoint. These studies indicate that blockade of human (donor) P2X7 reduces GVHD development in humanised mice, providing the first direct evidence of a role for donor P2X7 in GVHD. Full article