Lactoferrin effects on immune response in critically ill

We have studied in vitro the effect of lactoferrin on the proliferative response of peripheral blood mononuclear cells and their ability to produce IL-6 and TNF-alpha in three groups of patients - septic survivors, septic non-survivors and patients after multiple organ injury. Lactoferrin is an iron-binding glycoprotein with a wide spectrum of biological activities (Ann Rev Nutr 1995, 15:93). It may contribute to the protection against pathogens and their metabolites by enhancing phagocytosis, cell adherence, and controlling release of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha.

Material

We investigated 53 adult patients (40 men and 13 women, aged 15-73 years) meeting the ACCP/SCCM criteria of sepsis or sepsis shock (Crit Care Med 1992, 20:864) who were treated in our intensive therapy unit for peritonitis, pancreatitis. ARDS, or major trauma. The mean APACHE II score on admission was 21.85 and 18.5 in septic and post-traumatic patients, respectively. The patients were divided into three groups: multiple trauma (T, n = 10), septic survivors (SS, n = 14), septic non-survivors (SN, n = 19). The control group consisted of 13 healthy volunteers.

Methods

The proliferative response of PBMC in vitro was tested using 3-day culture with mitogens (PHA, LPS). The cell proliferation was measured using MTT colorimetric method. The activity of TNF-alpha and IL-6 was measured with bioassary using indicator cell lines WEHI-164.13. and 7TDI. respectively.

Results

Lactoferrin significantly inhibited PHA-induced proliferation in three groups of patients during the whole monitoring period (P < 0.05). Lactoferrin alone appeared to be a very good inducer of IL-6. The effect of lactoferrin on LPS-induced IL-6 production by leukocytes was also stimulatory. The influence of lactoferrin on IL-6 production was very significant especially in the group of septic survivor patients. Lactoferrin appeared to be a very good inducer of TNF-alpha, however, its action varied considerably among particular groups of patients. In trauma patients lactoferrin exhibited a moderate up-regulatory activity. Most significant stimulatory effects of lactoferrin were seen in septic survivor group, which resulted in a permanently high TNF-alpha production during the whole monitoring period. Quite different response pattern was observed in the group of septic non-survivor patients; their cells ability to produce TNF-alpha was low and the effect of lactoferrin was not so significant as in the survivor group.

Conclusions

(i) Lactoferrin seems to exert a beneficial action on the immune response. It slightly decreases the PHA-induced lymphocyte proliferation, (ii) Lactoferrin is a good inducer of IL-6 and TNF-alpha production. It cannot, however, break through lymphocyte anergy, as measured in LPS-induced cytokine secretion test.