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Liver and Pancreatic-Targeted Interleukin-22 as a Therapeutic for Metabolic Dysfunction-Associated Steatohepatitis

ABSTRACT: Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutics. Previous research has shown that interleukin-22 (IL-22) can suppress beta-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. 10-fold lower doses of these bispecific biologics exceeded the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restored glycemic control, markedly reduced hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Sumaira Zia Hasnain

PROVIDER: MSV000094483 | MassIVE | Sun Apr 07 22:59:00 BST 2024

SECONDARY ACCESSION(S): PXD051262

REPOSITORIES: MassIVE

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Project description:The beneficial effects of mesenchymal stem cell administration have been reported in numerous preclinical studies. Briefly, decreased levels of Th2-related cytokines, namely IL-4, IL-5, and IL-13, impaired eosinophils infiltration, and mucus secretion within the lung have been recognized as hallmarks of MSC-mediated immunosuppression in OVA-Alumn- induced experimental model. However, to date, the effects of MSCs transfer on mixed airway inflammation remain elusive. Therefore, here we aimed to investigate the influence of internasal adipose tissue-derived MSCs on mixed inflammation in a house dust mite (HDM) extract-induced experimental asthma model. To induce mixed airway inflammation, mice were challenged with 10 g of HDM extract for 5 days each week. Additionally, to investigate the short- and long-term effects, adipose tissue-derived MSCs were administrated at two-time points. To analyze MSC-mediated changes, we assessed lung morphology, frequencies of T cells effectors, epithelial barrier integrity, lung transcriptomic profiles, and the levels of cytokines and chemokine in bronchoalveolar lavage (BAL). We observed the limitation of cellular infiltration and mucus production after MSCs administration. Moreover, we noted a trend to decrease in the frequencies of T cells producing IL-4 and IFNy as a long-term effect of MSCs administration. Additionally, the expression of ZO-1 was increased in both analyzed time-points of MSCs transfer. Notably, we found the changes in the transcriptomic profiles reflecting, the inflammation of the respiratory system, the proliferation of lymphocytes, migration of leukocytes, and recruitment of neutrophils and eosinophils. Finally, we also noted the differences in the levels of CXCL and CCL chemokines in BAL between short- and long-term models, while the changes in Th2-related cytokines levels were limited. Overall, here we confirmed the therapeutic potential of adipose tissue-derived MSCs administration in a novel HDM extract-induced experimental model of mixed airway inflammation.

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Liver and Pancreatic-Targeted Interleukin-22 as a Therapeutic for Metabolic Dysfunction-Associated Steatohepatitis

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