Biology subjects

Hermann, D.

Publications and source records attributed to Hermann, D..

3 recordsLinked to original sources

bioRxiv2026

Comprehensive preclinical reevaluation of PaBQU and DBQU regimens identifies lesional liability in hard-to-treat forms of tuberculosis

Murine efficacy models inform advancement of preclinical tuberculosis treatment regimens to human clinical testing. A recent human Phase 2 trial was terminated early because investigational regimens (4-months of PaBQU or DBQU) did not meet the treatment shortening criteria outlined in the Target Regimen Profile ([≤] 3 months). We queried whether a factor leading to this early termination may have been lesional liability, meaning slow or diminished onset of effect in the caseum of complex lung lesions. We conducted a translational study, comparing the easy-to-treat BALB/c mouse, lacking complex lesions, to the hard-to-treat C3HeB/FeJ mouse that develops complex human-like lesions. We evaluated traditional and novel pharmacodynamic markers (colony forming units and RS ratio), relapse outcomes and ex vivo caseum pharmacokinetics. PaBQU and DBQU were slower to elicit bactericidal activity, RS ratio activity and prevent relapse in the C3HeB/FeJ mouse than the BALB/c mouse. A reference regimen (BPaMZ) had less lesional liability than PaBQU and DBQU. Fewer drugs in PaBQU were projected to achieve target attainment in caseum compared to BPaMZ, particularly early in treatment due to slow accumulation of bedaquiline in caseum. Here, we demonstrated application of a multi-modality pharmacokinetic-pharmacodynamic analysis that compared regimen activity in the hard-to-treat C3HeB/FeJ and easy-to-treat BALB/c mouse models, identifying lesional liability of PaBQU and DBQU. Systematic interrogation of additional diverse regimens is needed to determine the value of preclinical lesional liability as a means of predicting clinical treatment shortening activity.

microbiology↗

bioRxiv2026

Monocytes shape the neuroprotective and immunomodulatory effects of mesenchymal stromal cell-derived extracellular vesicles

BACKGROUNDMesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) exert neuroprotective effects in ischemic stroke largely through immunomodulatory mechanisms. Monocytes are first-line responders to MSC-EVs. Their contribution to MSC-EV-induced neuroprotection remains poorly understood. This study investigated the role of monocytes in shaping neuroprotective responses to MSC-EVs after ischemic stroke. METHODSMale C57BL/6J mice were exposed to transient middle cerebral artery occlusion (MCAO). Monocytes were depleted using pharmacological (clodronate liposomes), immunological (anti-CCR2), or genetic (Mrp8-Cre+/- Nr4a1fl/fl) approaches removing total, CCR2+, or Ly6Clow monocytes, respectively. In additional cohorts, neutrophils and T cells were simultaneously depleted by anti-Ly6G or anti-CD4/CD8 antibodies. Small EVs from clonally expanded immortalized MSCs were administered intravenously. Neurological deficits, ischemic injury, and immune responses were analyzed up to 72 hours post-MCAO. Complementary ex vivo studies were performed, in which MSC-EVs were administered to monocyte-depleted or non-depleted peripheral blood mononuclear cells (PBMCs) obtained from acute ischemic stroke patients. RESULTSIn ischemic mice with intact monocyte compartment, MSC-EVs reduced neurological deficits, infarct volume, neuronal injury, and brain leukocyte infiltrates. These protective effects were abolished in monocyte-depleted mice, particularly following CCR2+ monocyte depletion. Under these conditions, MSC-EV treatment exacerbated neurological deficits, ischemic injury, and leukocyte infiltration, accompanied by neutrophil and T cell expansion and overactivation. Depletion of neutrophils or T cells prevented the EV-induced worsening of stroke outcome in monocyte-deficient mice. Ly6Clow monocytes played a crucial role in orchestrating immune responses to MSC-EVs. Their depletion abolished EV-induced neuroprotection. In stroke patient PBMCs, MSC-EVs induced phenotypic reprogramming of monocytes, whereas they promoted CD4+ and CD8+ T cell activation in the absence of monocytes. CONCLUSIONSMonocytes shape the immunomodulatory actions of MSC-EVs. In their absence, MSC-EVs trigger neutrophil and T cell overactivation that worsens stroke outcome. These findings highlight the importance of monocyte- and T cell-related potency assays for the clinical translation of MSC-EV therapies.

neuroscience↗

bioRxiv2021

Model-Based Meta-Analysis of Relapsing Mouse Model Studies from the Critical Path to Tuberculosis Drug Regimens Initiative Database

Tuberculosis (TB), the disease caused by Mycobacterium tuberculosis (Mtb), remains a leading infectious disease-related cause of death worldwide, necessitating the development of new and improved treatment regimens. Non-clinical evaluation of candidate drug combinations via the relapsing mouse model (RMM) is an important step in regimen development, through which candidate regimens that provide the greatest decrease in probability of relapse following treatment in mice may be identified for further development. Although RMM studies are a critical tool to evaluate regimen efficacy, making comprehensive "apples to apples" comparisons of regimen performance in the RMM has been a challenge, in large part due to the need to evaluate and adjust for variability across studies arising from differences in design and execution. To address this knowledge gap, we performed a model-based meta-analysis on data for 17 unique regimens obtained from a total of 1592 mice across 28 RMM studies. Specifically, a mixed-effects logistic regression model was developed that described the treatment duration-dependent probability of relapse for each regimen and identified relevant covariates contributing to inter-study variability. Using the model, covariate-normalized metrics of interest, namely treatment duration required to reach 50% and 10% relapse probability, were derived and used to compare relative regimen performance. Overall, the model-based meta-analysis approach presented herein enables cross-study comparison of efficacy in the RMM, and provides a framework whereby data from emerging studies may be analyzed in the context of historical data to aid in selecting candidate drug combinations for clinical evaluation as TB drug regimens.

pharmacology and toxicology↗