A Novel Fusion of IL-10 Engineered to Traffic across Intestinal Epithelium to Treat Colitis
| Autor: | Radhika C. Desai, Hyo Jin Kim, Julia D. Mackay, Weijun Feng, Randall J. Mrsny, Lisa Song, Linh P. Nyugen, Nicole C. Fay, Mahmood Tahir, Sally Postlethwaite, Apurva Chandalia, Baby Periyanayaki Muthusamy, Keyi Liu, Michael P. Coyle, Olson Charles, Elbert Seto, Tom Hunter, Khushdeep Mangat, Alistair Taverner, Minji Seung, Aatif Alam, Maziyar Saberi |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Colon medicine.medical_treatment Immunology Mice SCID Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine Crohn Disease Intestinal mucosa medicine Animals Humans Immunology and Allergy Intestinal Mucosa Rats Wistar Colitis Cells Cultured Inflammation Mice Inbred BALB C Lamina propria Mucous Membrane business.industry Macrophages Mucosal Immunology medicine.disease Intestinal epithelium Interleukin-10 Rats Mice Inbred C57BL Macaca fascicularis Interleukin 10 medicine.anatomical_structure Cytokine Transcytosis Cytokines Female business 030215 immunology |
| Zdroj: | J Immunol |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.2000848 |
| Popis: | IL-10 is a potent anti-inflammatory cytokine capable of suppressing a number of proinflammatory signals associated with intestinal inflammatory diseases, such as ulcerative colitis and Crohn's disease. Clinical use of human IL-10 (hIL-10) has been limited by anemia and thrombocytopenia following systemic injection, side effects that might be eliminated by a gut-restricted distribution. We have identified a transcytosis pathway used by cholix, an exotoxin secreted by nonpandemic forms of the intestinal pathogen Vibrio cholerae. A nontoxic fragment of the first 386 aa of cholix was genetically fused to hIL-10 to produce recombinant AMT-101. In vitro and in vivo characterization of AMT-101 showed it to efficiently cross healthy human intestinal epithelium (SMI-100) by a vesicular transcytosis process, activate hIL-10 receptors in an engineered U2OS osteosarcoma cell line, and increase cellular phospho-STAT3 levels in J774.2 mouse macrophage cells. AMT-101 was taken up by inflamed intestinal mucosa and activated pSTAT3 in the lamina propria with limited systemic distribution. AMT-101 administered to healthy mice by oral gavage or to cynomolgus monkeys (nonhuman primates) by colonic spray increased circulating levels of IL-1R antagonist (IL-1Ra). Oral gavage of AMT-101 in two mouse models of induced colitis prevented associated pathological events and plasma cytokine changes. Overall, these studies suggest that AMT-101 can efficiently overcome the epithelial barrier to focus biologically active IL-10 to the intestinal lamina propria. |
| Databáze: | OpenAIRE |
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