Adjunct antibody administration with standard treatment reduces relapse rates in a murine tuberculosis model of necrotic granulomas

PloS One
Alvaro A OrdonezSanjay K Jain

Abstract

Matrix metalloproteinase (MMP)-9 is a zinc-dependent protease associated with early immune responses to Mycobacterium tuberculosis infection, macrophage recruitment and granuloma formation. We evaluated whether adjunctive inhibition of MMP-9 could improve the response to standard TB treatment in a mouse model that develops necrotic lesions. Six weeks after an aerosol infection with M. tuberculosis, C3HeB/FeJ mice received standard TB treatment (12 weeks) comprising rifampin, isoniazid and pyrazinamide alone or in combination with either anti-MMP-9 antibody, etanercept (positive control) or isotype antibody (negative control) for 6 weeks. Anti-MMP-9 and the isotype control had comparable high serum exposures and expected terminal half-life. The relapse rate in mice receiving standard TB treatment was 46.6%. Compared to the standard TB treatment, relapse rates in animals that received adjunctive treatments with anti-MMP-9 antibody or etanercept were significantly decreased to 25.9% (P = 0.006) and 29.8% (P = 0.019) respectively, but were not different from the arm that received the isotype control antibody (25.9%). Immunostaining demonstrated localization of MMP-9 primarily in macrophages in both murine and human lung tissues inf...Continue Reading

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Citations

Jun 20, 2018·The Journal of Infectious Diseases·Alvaro A OrdonezSanjay K Jain
Apr 2, 2020·Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging·Alvaro A OrdonezSanjay K Jain
Mar 21, 2019·International Journal of Molecular Sciences·Ursula K RohlwinkKatalin A Wilkinson
Feb 11, 2021·Immunological Reviews·Gül KilinçMariëlle C Haks
May 7, 2021·Frontiers in Immunology·Stefanie KrugWilliam R Bishai

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Datasets Mentioned

BETA
AB0046

Methods Mentioned

BETA
ELISA

Software Mentioned

Prism
GraphPad

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