Controlling the cytokine storm in severe bacterial diarrhoea with an oral Toll-like receptor 4 antagonist
File(s)
Author(s)
Type
Journal Article
Abstract
Shigella dysenteriae causes the most severe of all infectious diarrheas and colitis. We infected rhesus macaques orally and also treated them orally with a small and non-absorbable polypropyletherimine dendrimer glucosamine (DG) that is a Toll Like Receptor-4 antagonist. Antibiotics were not given for this life threatening infection. Six days later, the clinical score for diarrhea, mucus and blood was 54% lower, colon IL-8 and IL-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 DG on systemic immunity. This is the first report in nonhuman primates of the therapeutic efficacy of a small and orally bioavailable TLR antagonist in severe infection. Our results show that an oral TLR4 antagonist can enable controlled resolution of the infection-related-inflammatory response and can also prevent neutrophil-mediated gut wall necrosis in severe infectious diarrheas.
Date Issued
2015-10-23
Date Acceptance
2015-10-13
Citation
Immunology, 2015, 147 (2), pp.178-189
ISSN
0019-2805
Publisher
Wiley
Start Page
178
End Page
189
Journal / Book Title
Immunology
Volume
147
Issue
2
Copyright Statement
This is the peer reviewed version of the following article: Islam, D., Lombardini, E., Ruamsap, N., Imerbsin, R., Khantapura, P., Teo, I., Neesanant, P., Gonwong, S., Yongvanitchit, K., Swierczewski, B. E., Mason, C. J. and Shaunak, S. (2016), Controlling the cytokine storm in severe bacterial diarrhoea with an oral Toll-like receptor 4 antagonist. Immunology, 147: 178–189, which has been published in final form at https://dx.doi.org/10.1111/imm.12549. This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
Sponsor
The Williams Trust Fund
Grant Number
N/A
Subjects
Toll-like receptor-4
bacterial diarrhoea
cytokines
inflammation
Immunology
1107 Immunology
1114 Paediatrics And Reproductive Medicine
Publication Status
Published