Essential Fatty Acid Deficiency Prevents Autoimmune Diabetes in Nonobese Diabetic Mice Through a Positive Impact on Antigen-Presenting Cells and Th2 Lymphocytes

Abstract

Protective effects of essential fatty acid deficiency (EFAD) on autoimmunity were shown in rodents. Our goal was to investigate the mechanisms of EFAD effects on autoimmune diabetes in nonobese diabetic (NOD) mice. Weanling female mice were randomized between a control diet group and an EFAD diet group, and the development of diabetes and immune response was determined over a 6-month period. The cumulative incidence of diabetes was significantly reduced in the EFAD group (20 vs 68.75% in the control group; p < 0.01), without affecting the insulitis process. Splenocyte reactivity to phytohemagglutinin and anti-CD3 antibody was significantly increased in EFAD-fed mice (p < 0.01). The EFAD group also exhibited a dramatic increase in baseline (29-fold) and antigen-presenting cell (APC)-stimulated (10-fold) T cell responses in syngeneic mixed leukocyte reaction. These responses were associated with a marked increase in splenocyte interleukin-4 (IL-4) production, a reduction in interferon-? production, and a down-regulation of CD45RB isoform expression. Macrophages in the EFAD group exerted a reduced suppressive effect on concanavalin A-induced splenocyte proliferation and were found to release increased amounts of tumor necrosis factor-a and IL-1 and reduced amounts of prostaglandin E,. These results clearly demonstrate that EFAD prevents diabetes in NOD mice. The data suggest an enhanced activity of Th2-like cells, as well as an effect on APC activity linked to alteration in eicosanoid metabolism.

Rescuing of deficient killing and phagocytic activities of macrophages derived from non-obese diabetic mice by treatment with geldanamycin or heat shock: potential clinical implications

“…For example, it has been shown that deficient internalization of AC by Mfs derived from diabetic individuals is accompanied by decreased production of IL-10 and increased secretion of pro-inflammatory cytokines, generating an unusual pro-inflammatory environment in response to AC (O'Brien et al 2006;Trudeau et al 2000;Marée et al 2008;Mohammad et al 2006). On the contrary, incubation of DMT1-derived Mfs with pro-inflammatory stimuli has been shown to produce unusually high levels of PGE 2 , which leads to down-regulation of cellular immune activation and therefore a decrease in inflammation (Benhamou et al 1995). Clinically, DMT1 patients are more susceptible to the development of recurrent and more severe infections than non-diabetic individuals (Pozzilli and Leslie 1994).…”

Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulin-dependent diabetes mellitus

“…Some studies suggest that heightened prostaglandin (PG) metabolism by macrophages may contribute to non-MHC-encoded APC dysfunction (20)(21)(22). PGs are lipid molecules derived from arachidonic acid; the ratelimiting step in their production is mediated by the cyclooxygenase PG synthase (PGS) (23,24).…”

“…At first glance, enhanced prostanoid production in the NOD mouse would appear to be beneficial, as PGE 2 promotes Th2 responses in vitro (34,35,37) and suppresses IL-12 production (39), both of which are associated with protection from diabetes in the NOD mouse (40)(41)(42). However, reducing macrophage PGE 2 production in vivo, either by dietary fatty acid manipulation (22) or by treating NOD mice with indomethacin to block cyclooxygenase activity, significantly reduces diabetes incidence in female NOD mice by 70% and 50%, respectively (X.T. Xie, unpublished data).…”

Modulation of adjuvant‐induced arthritis by dietary arachidonic acid in essential fatty acid‐deficient rats

“…Since arthritis starts to escalate near day 14, it was reasoned that 2 wk of feeding prior to the arthritic escalation would be sufficient to reach a steady-state level of AA in plasma and inflammatory cells. During the period of maximal arthritic escalation (days [14][15][16][17][18][19][20][21][22][23][24][25], the AA would then be used as a substrate for the synthesis of proinflammatory eicosanoids. The 1× human daily equivalent of AA was insufficient to restore the plasma level of AA to that of the chow control group (Fig.…”