Classical Flt3L-dependent dendritic cells control immunity to protein vaccine

DCs are critical for initiating immunity. The current paradigm in vaccine biology is that DCs migrating from peripheral tissue and classical lymphoid-resident DCs (cDCs) cooperate in the draining LNs to initiate priming and proliferation of T cells. Here, we observe subcutaneous immunity is Fms-like tyrosine kinase 3 ligand (Flt3L) dependent. Flt3L is rapidly secreted after immunization; Flt3 deletion reduces T cell responses by 50%. Flt3L enhances global T cell and humoral immunity as well as both the numbers and antigen capture capacity of migratory DCs (migDCs) and LN-resident cDCs. Surprisingly, however, we find immunity is controlled by cDCs and actively tempered in vivo by migDCs. Deletion of Langerin+ DC or blockade of DC migration improves immunity. Consistent with an immune-regulatory role, transcriptomic analyses reveals different skin migDC subsets in both mouse and human cluster together, and share immune-suppressing gene expression and regulatory pathways. These data reveal that protective immunity to protein vaccines is controlled by Flt3Ldependent, LN-resident cDCs

Erratum: Flt3L dependence helps define an uncharacterized subset of murine cutaneous dendritic cells

[No abstract available

Flt3L dependence helps define an uncharacterized subset of murine cutaneous dendritic cells

Skin-derived dendritic cells (DCs) are potent antigen-presenting cells with critical roles in both adaptive immunity and tolerance to self. Skin DCs carry antigens and constitutively migrate to the skin-draining lymph nodes (LNs). In mice, Langerin-CD11b- dermal DCs are a low-frequency, heterogeneous, migratory DC subset that traffics to LNs (Langerin-CD11b- migDCs). Here, we build on the observation that Langerin-CD11b- migDCs are Fms-like tyrosine kinase 3 ligand (Flt3L) dependent and strongly Flt3L responsive, which may relate them to classical DCs. Examination of DC capture of FITC from painted skin, DC isolation from skin explant culture, and from the skin of CCR7 knockout mice, which accumulate migDCs, demonstrate these cells are cutaneous residents. Langerin-CD11b- Flt3L-responsive DCs are largely CD24(+) and CX 3 CR1 low and can be depleted from Zbtb46-DTR mice, suggesting classical DC lineage. Langerin-CD11b- migDCs present antigen with equal efficiency to other DC subsets ex vivo, including classical CD8α cDCs and Langerin+CD103+ dermal DCs. Finally, transcriptome analysis suggests a close relationship with other skin DCs, and a lineage relationship with other classical DCs. This work demonstrates that Langerin- CD11b- dermal DCs, a previously overlooked cell subset, may be an important contributor to the cutaneous immune environment

Machine learning-based scoring models to predict hematopoietic stem cell mobilization in allogeneic donors

Mobilized peripheral blood has become the primary source of hematopoietic stem cells for both autologous and allogeneic stem cell transplantation. Granulocyte colony-stimulating factor (G-CSF) is currently the standard agent used in the allogeneic setting. Despite the high mobilization efficacy in most donors, G-CSF requires 4-5 days of daily administration, and a small percentage of the donors fail to mobilize an optimal number of stem cells necessary for a safe allogeneic stem cell transplant. In this study, we retrospectively reviewed 1361 related allogeneic donors who underwent stem cell mobilization at Washington University. We compared the standard mobilization agent G-CSF with five alternative mobilization regimens, including GM-CSF, G-CSF+GM-CSF, GM-CSF + Plerixafor, Plerixafor and BL-8040. Cytokine-based mobilization strategies (G-CSF or in combination with GM-CSF) induce higher CD34 cell yield after 4-5 consecutive days of treatment, while CXCR4 antagonists (plerixafor and BL-8040) induce significantly less but rapid mobilization on the same day. Next, using a large dataset containing the demographic and baseline laboratory data from G-CSF-mobilized donors, we established machine learning (ML)-based scoring models that can be used to predict patients who may have less than optimal stem cell yields after a single leukapheresis session. To our knowledge, this is the first prediction model at the early donor screening stage, which may help identify allogeneic stem cell donors who may benefit from alternative approaches to enhance stem cell yields, thus ensuring safe and effective stem cell transplantation

The Human Studies Database Project: Federating Human Studies Design Data Using the Ontology of Clinical Research

Human studies, encompassing interventional and observational studies, are the most important source of evidence for advancing our understanding of health, disease, and treatment options. To promote discovery, the design and results of these studies should be made machine-readable for large-scale data mining, synthesis, and re-analysis. The Human Studies Database Project aims to define and implement an informatics infrastructure for institutions to share the design of their human studies. We have developed the Ontology of Clinical Research (OCRe) to model study features such as design type, interventions, and outcomes to support scientific query and analysis. We are using OCRe as the reference semantics for federated data sharing of human studies over caGrid, and are piloting this implementation with several Clinical and Translational Science Award (CTSA) institutions

Heparanase blockade as a novel dual-targeting therapy for COVID-19

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused over 5 million deaths worldwide. Pneumonia and systemic inflammation contribute to its high mortality. Many viruses use heparan sulfate proteoglycans as coreceptors for viral entry, and heparanase (HPSE) is a known regulator of both viral entry and inflammatory cytokines. We evaluated the heparanase inhibitor Roneparstat, a modified heparin with minimum anticoagulant activity, in pathophysiology and therapy for COVID-19. We found that Roneparstat significantly decreased the infectivity of SARS-CoV-2, SARS-CoV-1, and retroviruses (human T-lymphotropic virus 1 [HTLV-1] and HIV-1