Lactoferrin modulation of mycobacterial cord factor trehalose 6-6'-dimycolate induced granulomatous response

Abstract

The immune system responds to tuberculosis (TB) infection by the formation of granulomas. However, subsequent immune-mediated destruction of lung tissue is a cause of significant morbidity and contributes to disease transmission. Lactoferrin, an iron-binding glycoprotein, has demonstrated immunomodulatory properties which decrease tissue destruction and promote T H 1 immune responses, both of which are essential for controlling TB infection. The cord factor trehalose 6,6'-dimycolate (TDM) model of granuloma formation mimics many aspects of TB infection, with similar histopathology accompanied by proinflammatory cytokine production. C57BL/6 mice were intravenously injected with TDM. A subset of mice was given 1 mg bovine lactoferrin 24 hours post-TDM challenge. Lung tissue was analyzed for histological response and production of proinflammatory mediators. C57BL/6 mice demonstrated granuloma formation that correlated with increased production of IL-1β, IL-6, TNF-α, IL-12p40, IFN-γ, and IL-10 protein. Mice treated with lactoferrin post-challenge had significantly fewer and smaller granulomas compared to those given TDM alone. Proinflammatory and T H 1 cytokines essential to the control of mycobacterial infections, such as TNF-α and IFN-γ, were not significantly different in mice treated with lactoferrin. Furthermore, the anti-inflammatory cytokines IL-10 and TGF-β were increased. A potential mechanism for decreased tissue damage seen in the lactoferrin treated mice is proposed. Because of its influence to modulate immune responses, lactoferrin may be a useful adjunct in the treatment of granulomatous inflammation occurring during mycobacterial infection.

Influence of oral lactoferrin on Mycobacterium tuberculosis induced immunopathology

“…For example, mice treated with lactoferrin had increased survival and decreased gut tissue destruction after LPS injection 22 . This also holds true for damage elicited by mycobacterial antigen TDM 23 . Additionally, lactoferrin added to the BCG vaccine resulted in increased protection against an aerosol TB challenge, with evidence of decreased lung damage 24 .…”

Lactoferrin-lipopolysaccharide (LPS) binding as key to antibacterial and antiendotoxic effects

“…This bacterium is not usually associated with sepsis but autoimmune potential alerts to the application of Lf as antibacterial agent. Although Lf has shown a down regulation of the establishment of granuloma produced as consequence of the inflammatory response associated with tuberculosis [92,93], it could possibly favor autoimmune reactions by generating anti-Lf antibodies that have cross reactions and recognize the 65 kDa protein of M. tuberculosis [94]. These anti-lactoferrin antibodies together with the iron free form of LF were shown in one study to contribute to extravasation of albumin in different tissues in rats [95].…”

Lactoferrin restrains allergen-induced pleurisy in mice

“…For example, mice treated with BLF had increased survival and decreased gut tissue destruction after LPS injection [27]. This also holds true for damage elicited by mycobacterial antigen trehalose 6,6″-dimycolate [28]. Additionally, LF added together with BCG vaccine resulted in increased protection against an aerosol TB challenge, with evidence of decreased lung damage [29].…”