No abstract

Primary Mycobacterium tuberculosis (Mtb) infection results in the formation of a densely packed granulomatous response that essentially limits entry and efficacy of immune effector cells. Furthermore, the physical nature of the granuloma does not readily permit entry of therapeutic agents to sites where organisms reside. The Mtb cell wall mycolic acid, trehalose 6,6’-dimycolate (TDM), is a physiologically-relevant molecule to model macrophage mediated events during establishment of the tuberculosis-induced granuloma pathogenesis. No current therapeutic modalities focus to modulate host immune responses to ameliorate tuberculosis disease. Previous studies identified lactoferrin (LF), a natural iron-binding protein proven to modulate inflammation, as able to ameliorate granuloma cohesiveness. Therefore, a series of studies were enabled to further examine the effect of recombinant human LF (rHLF) on histological progression of the TDM-induced pathology. Treatment with rHLF demonstrated significant reduction in size and number of inflammatory foci following TDM injection, with reduced pulmonary pro-inflammatory cytokines TNF-α and IL-1β. LF allowed greater penetration of fluoroquinolone therapeutic to sites of pathology; TDM alone treated mice demonstrated exclusion of ofloxacin to regions of inflammatory response, whereas rHLF treated animals demonstrated increased penetration to responding foci. Finally, recent findings support the hypothesis that this mycobacterial mycolic acid can specifically recruit M1-like polarized macrophages; rHLF treatment was shown to limit the level of this M1-like phenotypic recruitment, corresponding highly with the occurrence of the decreased inflammatory response.

Infection with Mycobacterium tuberculosis ( Mtb ) results in the primary formation of a densely packed inflammatory foci that limits entry of therapeutic agents into pulmonary sites where organisms reside. No current therapeutic regimens exist that modulate host immune responses to permit increased drug penetration to regions of pathological damage during tuberculosis disease. Lactoferrin is a natural iron-binding protein previously demonstrated to modulate inflammation and granuloma cohesiveness, while maintaining control of pathogenic burden. Studies were designed to examine recombinant human lactoferrin (rHLF) to modulate histological progression of Mtb -induced pathology in a non-necrotic model using C57Bl/6 mice. The rHLF was oral administered at times corresponding to initiation of primary granulomatous response, or during granuloma maintenance. Treatment with rHLF demonstrated significant reduction in size of primary inflammatory foci following Mtb challenge, and permitted penetration of ofloxacin fluoroquinolone therapeutic to sites of pathological disruption where activated (foamy) macrophages reside. Increased drug penetration was accompanied by retention of endothelial cell integrity. Immunohistochemistry revealed altered patterns of M1-like and M2-like phenotypic cell localization post infectious challenge, with increased presence of M2-like markers found evenly distributed throughout regions of pulmonary inflammatory foci in rHLF treated mice.