Prophylactic effects of cucurbitacin B in the EAE Model of multiple sclerosis by adjustment of STAT3/IL-23/IL-17 axis and improvement of neuropsychological symptoms

Jahromi, Samaneh Reiszadeh; Haddadi, Mohammad; Mousavi, Pegah; Sanadgol, Nima

doi:10.1007/s11011-022-01083-5

Cited by 4 publications

(1 citation statement)

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“…While IL-10 generation and the antigen-specific T reg /T eff ratio are correlated, here we observe that PPI-7 and PPI-9 (formulations with the highest antigen-specific T reg / T eff ratio), while mildly increasing IL-10, at least did not suppress PD-L1. PD-L1 is commonly studied in cancer immunotherapy, as PD-L1 inhibition improves some cancer therapies and has been shown to be important for tolerating cell phenotypes (27,28). Furthermore, PPI-7 and PPI-9 only moderately influenced CD40 and CD80 markers on DCs but still highly suppressed TNF-α secretion.…”

Section: Discussionmentioning

confidence: 99%

High-throughput screening identification of novel immunomodulatory combinations for the generation of tolerogenic dendritic cells

Jia,

Kim,

Esser-Kahn

et al. 2024

Front. Med.

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IntroductionTolerogenic Dendritic Cells (tolDCs) have an exceptional promise as a potential therapy for autoimmune disease and transplantation rejection. TolDCs are a unique phenotype of antigen presenting cells (APCs) that can influence naïve T cells into antigen specific T regulatory cells (Tregs), which can re-establish tolerance against auto/allo-antigens in the long term. Despite their promise, tolDCs have not found clinical success. Most strategies seek to generate tolDCs ex vivo by differentiating naïve dendritic cells (DCs) with immunosuppressive agents. Recently, we developed a tolDC generation strategy, which we call Push/Pull Immunomodulation (PPI). In PPI, DCs are treated with combinations of toll-like-receptor (TLR) agonists and immunomodulatory agents, which generate more robust, Treg-inducing tolDCs than previous strategies. Here, we seek to identify more potent and clinically viable PPI formulations using data from a high-throughput screening project.MethodsOver 40,000 combinations of pathogen-associated molecular patterns (PAMPs) and immunomodulatory small molecules were screened using a modified murine macrophage line, RAW dual cells, to observe the effect of these combinations on two major immune regulatory transcription factors, NF-κB and IRF. Combinations were further screened for inflammatory cytokine activity using a human monocyte cell line, THP-1, then on murine DCs. Leading candidates were co-cultured with T cells to assess antigen specific T cell responses.ResultsFrom this data, we identified 355 combinations that showed low or moderate IRF activity, low NF-κB activity, low inflammatory cytokine generation and good viability: all hallmarks of tolerogenic potential. We further screened these 355 combinations using bone marrow derived DCs (BMDCs) and identified 10 combinations that demonstrated high IL-10 (tolerogenic) and low TNF-α (inflammatory) secretion. After further optimizing these combinations, we identified two combinations that generate robust tolDCs from BMDCs ex vivo. We further show that these PPI-tolDCs can also generate antigen specific Tregs but do not increase overall Treg populations.DiscussionThese second-generation PPI formulations have significant potential to generate robust tolDCs and strong antigen specific Tregs.

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Section: Discussionmentioning

confidence: 99%