An IL-23-STAT4 pathway is required for the proinflammatory function of classical dendritic cells during CNS inflammation.

Although many cytokine pathways are important for dendritic cell (DC) development, it is less clear what cytokine signals promote the function of mature dendritic cells. The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of proinflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), mice are resistant to the development of inflammation and paralysis.

Essential role of pre-existing humoral immunity in TLR9-mediated type I IFN response to recombinant AAV vectors in human whole blood.

Recombinant adeno-associated virus (AAV) vectors have emerged as the preferred platform for gene therapy of rare human diseases. Despite the clinical promise, host immune responses to AAV vectors and transgene remain a major barrier to the development of successful AAV-based human gene therapies. Here, we assessed the human innate immune response to AAV9, the preferred serotype for AAV-mediated gene therapy of the CNS.

STAT3 Signaling Heterogeneity Underlies Cytokine-Expressing Fate in Th17 Cultures.

The polarization of naive Th cells into differentiated subsets in vitro was a powerful approach to define the development and function of Th cells in vivo. Th cell cultures identified cytokines that promote polarization and defined the phenotype and stability of differentiated cells. One of the limitations of this approach is the heterogeneity of the differentiated culture, essentially with regard to what proportion of the culture is secreting the hallmark cytokine of interest.

Dendritic Cells as a Nexus for the Development of Multiple Sclerosis and Models of Disease.

Multiple sclerosis (MS) results from an autoimmune attack on the central nervous system (CNS). Dysregulated immune cells invade the CNS, causing demyelination, neuronal and axonal damage, and subsequent neurological disorders. Although antigen-specific T cells mediate the immunopathology of MS, innate myeloid cells have essential contributions to CNS tissue damage.

Peanut allergen inhibition prevents anaphylaxis in a humanized mouse model.

Peanut-induced allergy is an immunoglobulin E (IgE)-mediated type I hypersensitivity reaction that manifests symptoms ranging from local edema to life-threatening anaphylaxis. Although there are treatments for symptoms in patients with allergies resulting from allergen exposure, there are few preventive therapies other than strict dietary avoidance or oral immunotherapy, neither of which are successful in all patients. We have previously designed a covalent heterobivalent inhibitor (cHBI) that binds in an allergen-specific manner as a preventive for allergic reactions.

STAT4 is expressed in neutrophils and promotes antimicrobial immunity.

Signal transducer and activator of transcription 4 (STAT4) is expressed in hematopoietic cells and plays a key role in the differentiation of T helper 1 cells. Although STAT4 is required for immunity to intracellular pathogens, the T cell-independent protective mechanisms of STAT4 are not clearly defined. In this report, we demonstrate that STAT4-deficient mice were acutely sensitive to methicillin-resistant Staphylococcus aureus (MRSA) infection.

Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells.

is an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence of parasitism is increased migratory activity of host cells, which facilitates dissemination. Here, we show that triggers the unfolded protein response (UPR) in host cells through calcium release from the endoplasmic reticulum (ER).

FcγRIIIa-dependent IFN-γ release in whole blood assay is predictive of therapeutic IgG1 antibodies safety.

Immunomodulatory monoclonal IgG1 antibodies developed for cancer and autoimmune disease have an inherent risk of systemic release of pro-inflammatory cytokines. In vitro cytokine release assays are currently used to predict cytokine release syndrome (CRS) risk, but the validation of these preclinical tools suffers from the limited number of characterized CRS-inducing IgG1 antibodies and the poor understanding of the mechanisms regulating cytokine release. Here, we incubated human whole blood from naïve healthy volunteers with four monoclonal IgG1 antibodies with different proven or predicted capacity to elicit CRS in clinic and measured cytokine release using a multiplex assay.