2.2 Lf as an immunomodulatory and anti-inflammatory agent
Lf is a unique multifunctional moiety which is not only a broad-spectrum
antiviral, but has immunomodulatory (Siqueiros-Cendón et al., 2014) and
anti-inflammatory (Baveye et al., 1999) actions that may play a role in
the pathophysiology of severe infections. The key immunomodulatory role
of this protein stems from its unique potential to maintain immune and
physiological homeostasis and limit tissue damage by modulation of
cytokines, chemokines, and cell surface receptors involved in cascades
of signaling pathways (Actor et al., 2009). The myriad of biological
pathways of control and feedback interactions with Lf has been
extensively reviewed (Kruzel et al., 2017). Specific examples of Lf’s
balancing and restorative role is perhaps illustrated in the context of
systemic inflammatory response syndrome (SIRS) which describes the
complex physiologic response to severe insults such as sepsis as defined
by a consensus conference in 1991 (Bone et al., 1992). An updated and
overlapping concept of ’cytokine storm’ similarly reflects
hyper-induction of inflammatory responses resulting from unchecked
immune activation (Behrens & Koretzky, 2017), which Kruzel’s group and
others have proposed Lf might treat (Actor et al., 2009).
Injection of lipopolysaccharide (LPS) into animals reproduces the
pathophysiologic changes induced by bacteria, and it is considered a
standard model for sepsis. Using this model, it was demonstrated that Lf
treatment reduced or eliminated many biological reactions normally seen
upon LPS administration in a dose dependent manner (Kruzel et al.,
2010), and in an earlier study, a single dose of lactoferrin before LPS
injection reduced the mortality of mice to 16.7% from 83.3% in
controls (Kruzel et al., 2000).
Given promising laboratory and animal studies, Lf has been investigated
in a number of clinical settings against sepsis. Recently, a
meta-analysis of 10 randomized controlled trials involving 3,679 infants
concluded that Lf reduces late onset sepsis in pre-term infants (Razak
& Hussain, 2019). Separately, a human recombinant Lf talactoferrin was
studied in a phase 2 clinical trial to assess outcome in severe sepsis
and found a 12.5% reduction in all cause mortality in those treated
(Guntupalli et al., 2013), but the results were regrettably not
replicated in a follow-up phase 2/3 trial (Vincent et al., 2015).