Title

Tnfα Inhibitors Exacerbate Mycobacterium Paratuberculosis Infection In Tissue Culture: A Rationale For Poor Response Of Patients With Crohn'S Disease To Current Approved Therapy

Keywords

Crohn's disease; cytokines; inflammatory bowel disease; mycobacterium paratuberculosis; TNF-Alpha

Abstract

Background The role of Mycobacteriumavium subspecies paratuberculosis (MAP) in Crohn's disease (CD) is increasingly accepted as evident by detection of the bacteria in the blood and intestinal tissue from patients with CD, and by supporting data from several open-label anti-MAP treatment studies. Tumour necrosis factor alpha (TNFα) monoclonal antibodies (anti-TNFα) have been widely used for CD treatment. Despite the short-term benefit of anti-TNFα in controlling CD symptoms, most patients suffer from detrimental adverse effects, including higher susceptibility to mycobacterial infections. Methods We investigated the effect of recombinant cytokines and anti-TNFα therapeutics on macrophages infected with clinical MAP strain isolated from CD patient blood. MAP viability was measured in macrophages pulsed with PEGylated and non-PEGylated anti-TNFα monoclonal antibodies at concentrations 0 to 50 μg/mL and with rTNFα, rIL-6, rIL-12, rIL-23 and IFN'3 at a final concentration of 1000 U/mL. Expression of proinflammatory cytokines was measured by RT-PCR following MAP infection. Results Both PEGylated and non-PEGylated forms of anti-TNFα increased MAP viability by nearly 1.5 logs. rIL-6 and rIL-12 induced MAP viability at 5.42±0.25 and 4.79±0.14 log CFU/mL, respectively. In contrast, rTNFα reduced MAP survival in infected macrophages by 2.63 logs. Expression of TNFα, IL-6 and IL-12 was upregulated threefold following MAP or M. tuberculosis infection compared with other bacterial strains (p<0.05), while expression of IL-23 and IFN'3 was not significant after MAP infection. Conclusion The data indicate MAP-positive patients with CD receiving anti-TNFα treatment could result in favourable conditions for MAP infection, which explains the poor response of many patients with CD to anti-TNFα therapy.

Publication Date

1-1-2018

Publication Title

BMJ Open Gastroenterology

Volume

5

Issue

1

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1136/bmjgast-2018-000216

Socpus ID

85055824996 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85055824996

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