S1775 Development of a New Class of Thiopurine-Based Immunosuppressive Agents: Improved Ratio Between High Immunosuppressive Effects and Low Associated Toxicity

Atreya, Imke; Diall, Alexandra; Fritz, Gerhard; Henninger, Christian; Dvorský, Radovan; Gruen, Mathias; Hofmann, Ute; Schaeffeler, Elke; Schwab, Matthias; Daehn, Ilse; Karran, Peter; Neurath, Markus F.

doi:10.1016/s0016-5085(10)61246-2

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“…[ 4 , 5 ] Unfortunately, clinical implementations often suffer from limited therapeutic efficacies and systemic side effects, [ 6 , 7 ] due to the rapid clearance and lack of specificity that are associated with the characteristics of small molecules. [ 8 , 9 ] Though the use of biologics that can inhibit cytokines has been some success, clinical outcomes manifest that inhibition of a single target is often insufficient, yet the toxicity of off‐target inhibition remains unpredictable. [ 10 ] Engineering cell‐based vehicles and innovating cell derived nanoparticles have emerged as alternatives to directly interact with immune cells [ 11 , 12 , 13 , 14 , 15 ] and demonstrated instrumental in treating inflammations, such as arthritis and inflammatory bowel disease (IBD).…”

Section: Introductionmentioning

confidence: 99%

Polydopamine Nanoparticle‐Mediated Dopaminergic Immunoregulation in Colitis

Hou

Lin

et al. 2021

Advanced Science

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Despite immunosuppression is critical for reducing immune overactivation, existing immunosuppressive agents are largely restricted by low inhibition efficiencies and unpredictable off-target toxicities. Here, the use of the dopaminergic system is reported to suppress hyperactive immune responses in local inflamed tissues. A polydopamine nanoparticular immunosuppressant (PDNI) is synthesized to stimulate regulatory T (Treg) cells and directly inhibit T helper 1 (Th1), Th2, and Th17 cells. Moreover, PDNI can inhibit the activation of dendritic cells to upregulate the ratio of Treg/Th17, which assists the reversion of inflammatory responses. The application of dopaminergic immunoregulation is further disclosed by combining with gut microbiota modulation for treating inflammations. The combination is implemented by coating living beneficial bacteria with PDNI. Following oral delivery, coated bacteria not only suppress the hyperactive immune responses but also positively modulate the gut microbiome in mice characterized with colitis. Strikingly, the combination demonstrates enhanced treatment efficacies in comparison with clinical aminosalicylic acid in two murine models of colitis. The use of the dopaminergic system opens a window to intervene immune responses and provides a versatile platform for the development of new therapeutics for treating inflammatory diseases.

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