Background Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy for refractory hematologic diseases, but its success is often limited by life-threatening, endothelial injury-related complications such as sinusoidal obstruction syndrome (SOS) and transplant-associated thrombotic microangiopathy (TA-TMA). As early intervention is critical for improving outcomes, the identification of specific predictive biomarkers is urgently needed. Nuclear proteins released from damaged cells, such as high-mobility group box 1 (HMGB1) and histone H3 (H3), are recognized as damage-associated molecular patterns (DAMPs) implicated in endothelial damage and may serve as potential biomarkers. Study design We conducted a prospective study, collecting serial blood samples from 115 patients undergoing allogeneic HSCT from pre-conditioning to day 28 post-transplant. Serum levels of HMGB1 and H3 were measured by ELISA, and their association with the development of SOS and TA-TMA was investigated using ROC curve analysis and logistic regression. Results During the observation period, 10 patients (8.7%) developed SOS and 13 (11.3%) developed TA-TMA. Notably, an increase in serum HMGB1 from baseline to day 14 or day 28, as well as elevated H3 levels at day 21, were significantly associated with the subsequent development of TA-TMA. Also, HMGB1 levels at day 14 were predictive of the development of SOS. Multivariate analysis confirmed that a high HMGB1 level at day 14 was an independent predictor for TA-TMA. Conclusion HMGB1 holds promise as a predictive marker for TA-TMA. However, as this was an exploratory, single-center study with a small sample size, further validation in larger cohorts is required.
Multiple sclerosis (MS) is driven by dysregulated B and T cell interactions. Anti-CD20 B cell depletion with rituximab (RTX) strongly suppresses MS disease activity, yet how it relates to T cell immunity is unclear. We analysed clinically acquired flow cytometry data from 310 people with MS before and six months after RTX initiation, with plasma proteomics and CD4 T cell receptor sequencing in subgroups. Baseline T cell profiles correlated with B cell numbers, age, and HLA-DRB1*15:01 status. To limit confounding from prior therapies, RTX-associated changes were primarily assessed in treatment-naïve participants, in whom effector memory Th17 and Th1.17 CD4 subsets were selectively reduced, while CD8 subsets, the plasma inflammatory proteome, and CD4 clonality were largely unchanged. This observational study cannot establish causality, but identifies distinct memory CD4 subsets, relevant to MS disease activity, that are measurable in routine clinical flow cytometry.
Introduction: Effective biomarkers for monitoring and predicting progression of idiopathic pulmonary fibrosis (IPF), a debilitating scarring lung disease, are currently insufficient. Markers of alternatively activated macrophages, and their soluble (s) forms in serum have been associated with various fibrotic diseases. In this study, we investigated the association of three macrophage biomarkers (sCD163, sCD206 and sSIRPα) with prognosis and clinical severity in patients with IPF.Methods: Serum samples were collected from 149 IPF patients at baseline and after 12 and 36 months. Levels of sCD206, sCD163, and sSIRPα were quantified using enzyme-linked immunosorbent assays.Results: Levels of sCD206, sCD163, and sSIRPα were stable and did not significantly increase over time. Contrary to sCD163 and sSIRPα, sCD206 demonstrated repeated significant correlations to routine biochemical parameters (positive correlation to lactate dehydrogenase, p = 0.010, and C-reactive protein, p = 0.000; negative correlation to albumin, p = 0.003, and haemoglobin, p = 0.014) at baseline. At baseline, higher levels of sCD206 were significantly associated with lower results for forced vital capacity, 6-min walk test distance, and more shortness of breath (p = 0.000, p = 0.018, and p = 0.020, respectively). By both unadjusted and adjusted Cox regression analysis, IPF patients with sCD206 levels >0.2815 mg/L had a significantly increased risk of dying (Hazard ratio (HR): 2.60 (95% CI 1.59–4.24), p < 0.001 and HR: 2.17 (95% CI 1.30–3.62), p = 0.003, respectively).Conclusion: sCD206 is associated with both IPF disease severity and mortality. The role of CD206+ macrophage function in IPF and the potential prognostic value of sCD206 should be further investigated.
Introduction Alemtuzumab is an effective therapy for severe kidney transplant rejection. Yet, not all patients benefit from this treatment, while they are at risk for its toxic effects. A prediction model could help to identify these patients and potentially guide treatment decisions. Methods We developed a prediction model using logistic regression and four prespecified, clinical predictor variables on a clinical dataset of two hundred patients who were treated for glucocorticoid-resistant and/or severe kidney transplant rejection with alemtuzumab. The outcome was a composite of graft loss or having a marginal graft function over the entire six months post-treatment. The model was internally validated using bootstrapping and a pilot external validation was performed with an independent validation cohort (n = 96). To make optimal use of the available data, the model was refitted to the combined datasets. Its potential for clinical utility was subsequently assessed with a decision curve analysis. Results The model included the predictors rejection subtype, timing, donor type, and dialysis dependence. It showed an optimism-corrected c-statistic and calibration slope of 0.75 and 0.81. The pilot external validation demonstrated a c-statistic of 0.71 and calibration slope of 0.86. There was a potential benefit of model-informed treatment decisions over a ‘treat-all’ strategy. Conclusion The model showed moderate discrimination and reasonable calibration for estimating the risk of an unfavorable graft outcome after alemtuzumab treatment and warrants further external validation.
