Adjunctive TNF Inhibition with Standard Treatment Enhances Bacterial Clearance in a Murine Model of Necrotic TB GranulomasReportar como inadecuado




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Background

It has been hypothesized that early host-responses during TB treatment may paradoxically promote survival of persistent bacteria. We therefore evaluated whether adjunctive inhibition of tumor necrosis factor alpha TNF-α–a key cytokine in host responses against TB–could hasten bacterial clearance in a mouse strain that develops necrotic lesions in response to Mycobacterium tuberculosis infection.

Methodology-Principal Findings

Six weeks after an aerosol infection, C3HeB-FeJ mice received standard TB treatment with or without adjunctive TNF inhibition etanercept for the initial six weeks. Functional TNF-α levels and lung pathology were found to be reduced in the mice receiving etanercept. Compared to standard TB treatment, the addition of etanercept resulted in a significantly lower pulmonary bacterial burden, corresponding to the phase when a significant proportion of bacteria are multiplying slowly p<0.0233. Finally, only 10.5% of mice receiving adjunctive etanercept versus 27.8% receiving standard TB treatment alone relapsed.

Conclusion

This study provides proof-of-principle that modulation of TNF-α activity can hasten bacterial clearance during standard multi-drug TB treatment. Oral agents that modulate TNF-α should therefore be considered as adjunct therapies for shortening TB treatments. However, due to concerns of reactivation disease, additional studies need to be performed before TNF-α inhibitors are used for TB treatment in humans.



Autor: Ciaran Skerry, Jamie Harper, Mariah Klunk, William R. Bishai, Sanjay K. Jain

Fuente: http://plos.srce.hr/



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