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Controlling the cytokine storm in severe bacterial diarrhoea with an oral T oll‐like receptor 4 antagonist
Author(s) -
Islam Dilara,
Lombardini Eric,
Ruamsap Nattaya,
Imerbsin Rawiwan,
Khantapura Patchariya,
Teo Ian,
Neesanant Pimmnapar,
Gonwong Siriphan,
Yongvanitchit Kosol,
Swierczewski Brett E.,
Mason Carl J.,
Shaunak Sunil
Publication year - 2016
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/imm.12549
Subject(s) - antagonist , medicine , pharmacology , receptor , immunology , chemistry
Summary Shigella dysenteriae causes the most severe of all infectious diarrhoeas and colitis. We infected rhesus macaques orally and also treated them orally with a small and non‐absorbable polypropyletherimine dendrimer glucosamine that is a Toll‐like receptor‐4 ( TLR 4) antagonist. Antibiotics were not given for this life‐threatening infection. Six days later, the clinical score for diarrhoea, mucus and blood was 54% lower, colon interleukin‐8 and interleukin‐6 were both 77% lower, and colon neutrophil infiltration was 75% less. Strikingly, vasculitis did not occur and tissue fibrin thrombi were reduced by 67%. There was no clinical toxicity or adverse effect of dendrimer glucosamine on systemic immunity. This is the first report in non‐human primates of the therapeutic efficacy of a small and orally bioavailable TLR antagonist in severe infection. Our results show that an oral TLR 4 antagonist can enable controlled resolution of the infection‐related‐inflammatory response and can also prevent neutrophil‐mediated gut wall necrosis in severe infectious diarrhoeas.