Tapinarof is a natural AhR agonist that resolves skin inflammation in mice and humans

Tapinarof (GSK2894512) is a naturally derived topical treatment with demonstrated efficacy for patients with psoriasis and atopic dermatitis, although the biologic target and mechanism of action had been unknown. We demonstrate that the anti-inflammatory properties of tapinarof are mediated through activation of the aryl hydrocarbon receptor (AhR). We show that tapinarof binds and activates AhR in multiple cell types, including cells of the target tissue-human skin. In addition, tapinarof moderates proinflammatory cytokine expression in stimulated peripheral blood CD4+ T cells and ex vivo human skin, and impacts barrier gene expression in primary human keratinocytes; both of these processes are likely to be downstream of AhR activation based on current evidence. That the anti-inflammatory properties of tapinarof derive from AhR agonism is conclusively demonstrated using the mouse model of imiquimod-induced psoriasiform skin lesions. Topical treatment of AhR-sufficient mice with tapinarof leads to compound-driven reductions in erythema, epidermal thickening, and tissue cytokine levels. In contrast, tapinarof has no impact on imiquimod-induced skin inflammation in AhR-deficient mice. In summary, these studies identify tapinarof as an AhR agonist and confirm that its efficacy is dependent on AhR.status: publishe

The BAFFling effects of rituximab in lupus: danger ahead?

Suboptimal trial design and concurrent therapies are thought to account for the unexpected failure of two clinical trials of rituximab in patients with systemic lupus erythematosus (SLE). However, in this Opinion article we propose an alternative explanation: that rituximab can trigger a sequence of events that exacerbates disease in some patients with SLE. Post-rituximab SLE flares that are characterized by high levels of antibodies to double-stranded DNA are associated with elevated circulating BAFF (B-cell-activating factor, also known as TNF ligand superfamily member 13B or BLyS) levels, and a high proportion of plasmablasts within the B-cell pool. BAFF not only perpetuates autoreactive B cells (including plasmablasts), particularly when B-cell numbers are low, but also stimulates T follicular helper (TFH) cells. Moreover, plasmablasts and TFH cells promote each others' formation. Thus, repeated rituximab infusions can result in a feedback loop characterized by ever-rising BAFF levels, surges in autoantibody production and worsening of disease. We argue that B-cell depletion should be swiftly followed by BAFF inhibition in patients with SLE

BCMA peptide-engineered nanoparticles enhance induction and function of antigen-specific CD8+ cytotoxic T lymphocytes against multiple myeloma: clinical applications

The purpose of these studies was to develop and characterize B-cell maturation antigen (BCMA)-specific peptide-encapsulated nanoparticle formulations to efficiently evoke BCMA-specific CD8+ cytotoxic T lymphocytes (CTL) with poly-functional immune activities against multiple myeloma (MM). Heteroclitic BCMA72-80 [YLMFLLRKI] peptide-encapsulated liposome or poly(lactic-co-glycolic acid) (PLGA) nanoparticles displayed uniform size distribution and increased peptide delivery to human dendritic cells, which enhanced induction of BCMA-specific CTL. Distinct from liposome-based nanoparticles, PLGA-based nanoparticles demonstrated a gradual increase in peptide uptake by antigen-presenting cells, and induced BCMA-specific CTL with higher anti-tumor activities (CD107a degranulation, CTL proliferation, and IFN-γ/IL-2/TNF-α production) against primary CD138+ tumor cells and MM cell lines. The improved functional activities were associated with increased Tetramer+/CD45RO+ memory CTL, CD28 upregulation on Tetramer+ CTL, and longer maintenance of central memory (CCR7+ CD45RO+) CTL, with the highest anti-MM activity and less differentiation into effector memory (CCR7- CD45RO+) CTL. These results provide the framework for therapeutic application of PLGA-based BCMA immunogenic peptide delivery system, rather than free peptide, to enhance the induction of BCMA-specific CTL with poly-functional Th1-specific anti-MM activities. These results demonstrate the potential clinical utility of PLGA nanotechnology-based cancer vaccine to enhance BCMA-targeted immunotherapy against myeloma