Immunomodulatory properties of human recombinant lactoferrin in mice: Implications for therapeutic use in humans

Background. Trauma and major surgery cause extensive immune hyporeactivity in patients. Thus, the preventive, preoperative application of immunoregulatory therapeutics may normalize this immune reactivity and decrease morbidity and mortality in these subjects. Objectives. The aim of this study was to investigate the immunomodulatory actions of recombinant human lactoferrin (rhLF) in mice, and to relate these effects to in vitro actions of rhLF on tumor necrosis factor alpha (TNF-alpha) production in lipopolysaccharide-stimulated whole blood cell cultures (LPS-stimulated WBCC) from patients admitted to intensive care units. Material and methods. BALB/c and CBA mice were used. rhLF was tested for allergic response to ovalbumin (OVA), delayed-type hypersensitivity (DTH) to OVA, and carrageenan-induced inflammation in an air pouch. Blood samples from 30 patients diagnosed with severe sepsis/septic shock (Apache II 21 +/- 1, mortality rate 40%) were collected on days 1, 3 and 5 of observation. The effects of rhLF on LPS-induced TNF-alpha production were measured in WBCCs. Results. Recombinant human lactoferrin reduced the parameters of OVA-induced inflammation and inhibited the elicitation phase of DTH and carrageenan-induced inflammation in mice. The majority of patients from whom whole blood cell cultures (WBCC) were established showed a strong hyporeactivity to LPS upon admission. rhLF exerted differential effects on the production of LPS-induced TNF-alpha in those cultures on days 1, 3 and 5 of observation. Cytokine production was upregulated only in patients with sustained anergy to LPS, and inhibited or unchanged in moderately reactive patients. Conclusions. Evidence for the potential preventive or therapeutic utility of rhLF in patients with impaired immune reactivity has been demonstrated.