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).