No abstract

n-3 PUFA influence immune functioning and may affect the cytokine phenotype during development. To examine whether maternal fish oil supplementation during lactation could modify later immune responses in children, 122 lactating Danish mothers with a fish intake below the population median were randomized to groups supplemented for the first 4 mon of lactation with 4.5 g/d of fish oil (equivalent to 1.5 g/d of n-3 long-chain PUFA) or olive oil. Fifty-three mothers with a fish intake in the highest quartile of the population were also included. The FA composition of erythrocyte membranes was measured at 4 mon and at 2 1/2 yr. Plasma immunoglobulin E (IgE) levels and cytokine production in lipopolysaccharide-stimulated whole-blood cultures were determined at 2 1/2 yr. Erythrocyte n-3 PUFA at 4 mon were higher in infants from the fish oil group compared with the olive oil group (P < 0.001) but were no longer different at 2 1/2 yr. The median production of lipopolysaccharide-induced interferon gamma (IFN-gamma) in the fish oil group was fourfold higher than that in the olive oil group (P = 0.034), whereas interleukin-10 (IL-10) production was similar. The IFN-gamma/IL-10 ratio was twofold higher in the fish oil group (P = 0.019) and was positively correlated with 20:5n-3/20:4n-6 in erythrocytes at 4 mon (P = 0.050). The percentages of atopic children and plasma IgE were not different in the two groups, but the study was not designed to look at atopy. Cytokine responses and erythrocyte FA composition in children of mothers with a high fish intake were intermediate in comparison with those in the randomized groups. Fish oil supplementation during lactation resulted in increased in vitro IFN-gamma production in the children 2 yr after the supplementation was given, which may reflect a faster maturation of the immune system.

(n-3) PUFA influence immune function in adults and may also affect immune maturation during development. This randomized trial is, to our knowledge, the first to investigate whether fish oil supplementation in late infancy modifies immune responses. The study was a 2 x 2 intervention in 64 healthy Danish infants, who received cow's milk or infant formula alone or with fish oil (FO) (3.4 +/- 1.1 mL/d) from 9 to 12 mo of age. Before and after the intervention, fatty acid composition of erythrocyte membranes, plasma IgE, C-reactive protein, and soluble IL-2 receptor concentrations were measured. TNF-alpha, INF-gamma, and IL-10 concentrations in whole-blood cultures, stimulated for 22 h with LPS+phytohemaglutinin (PHA) or Lactobacillus paracasei, were also determined. IgA was measured in feces when infants were 10 mo of age. FO supplementation effectively raised erythrocyte (n-3) PUFA (P < 0.001), increased L. paracasei-induced INF-gamma (P = 0.05) and tended to reduce LPS+PHA-induced IL-10 (P = 0.08). The FO intervention did not affect any of the other analyzed immune variables. The erythrocyte content of eicosapentanoic acid was negatively associated with LPS+PHA-induced IL-10 (r = -0.38, P = 0.02). Feeding milk rather than formula did not affect cytokine production, but plasma soluble IL-2 receptor concentration was greater in the formula group than in the cow's milk group (P = 0.03). Since the capacity to produce INF-gamma has been proposed as a maturation marker for the immune system in early life, this study suggests a faster immune maturation with FO supplementation with no apparent reduction in immune activation. The implications for later health need further investigation.

Summary Appropriate activation of CD4+ T cells is fundamental for efficient initiation and progression of acquired immune responses. Here, we showed that CD4+ T‐cell activation is dependent on changes in membrane n‐3 polyunsaturated fatty acids (PUFAs) and is dynamically regulated by the type of signals provided by dendritic cells (DCs). Upon interaction with DCs primed by different concentrations and species of gut bacteria, CD4+ T cells were activated according to the type of DC stimulus. The levels of CD80 were found to correlate to the levels of expression of CD28 and to the proliferation of CD4+ T cells, while the presence of CD40 and CD86 on DCs inversely affected inducible costimulator (ICOS) and cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4) levels in CD4+ T cells. For all DC stimuli, cells high in n‐3 PUFAs showed reduced ability to respond to CD28 stimulation, to proliferate, and to express ICOS and CTLA‐4. Diminished T‐cell receptor (TCR) and CD28 signalling was found to be responsible for n‐3 PUFA effects. Thus, the dietary fatty acid composition influences the overall level of CD4+ T‐cell activation induced by DCs, while the priming effect of the DC stimuli modulates CD80, CD86 and CD40 levels, thereby affecting and shaping activation of acquired immunity by differential regulation of proliferation and costimulatory molecule expression in CD4+ T cells.

Oral administration of antigen induces antigen-specific immunologic tolerance, which is known to be dose-dependent. We studied the influence of continuous oral administration of nanogram and microgram doses of antigen on oral tolerance induction. Mice were continuously exposed to varying doses (1 ngÀ1 mg/day) of ovomucoid (OM) for a minimum of 30 days and a maximum of 100 days. It was possible to induce oral tolerance measured as reduced proliferation and antibody production (immunoglobulin (Ig)G 1 , IgG 2a and total Igs) when mice were fed 1 mg of OM/day for 40 or 50 days. It was not possible to induce oral tolerance with daily doses of antigen of 10 mg or less. Feeding of 100 mg OM/day for 40 and 50 days and 1 mg OM/day for 30 days generated tolerization of Th2-dependent responses, but retained an intact response of Th1-dependent antibodies, whereas feeding of 1 mg OM/day for 40 and 50 days resulted in tolerization of both Th1-and Th2-antibody responses. The results presented here suggest that there is a threshold of microgram-doses below which oral tolerance cannot be induced, and that selective suppression of Th2 responses can be achieved by continuous microdose feeding, while an extension of the feeding dose or feeding period tolerizes both Th1-and Th2-dependent responses.