Altered autoimmune response in NOD-Alox15null mice (99.13)

Abstract

Abstract 12/15-lipoxygenase (12/15-LO) reacts with fatty acids to produce pro-inflammatory lipids, enhance IL-12 production by macrophages (MΦ), and its product 12-(S)-HETE induces pancreatic β-cell apoptosis at nM concentrations. Congenic NOD mice deficient in 12/15-LO (NOD-Alox15null ) show a significant decrease in Type 1 diabetes (T1D) development (2.5 vs. >60% in ♀ by 30 wks). We tested the effects of the deficiency on the immune system in NOD-Alox15null vs. NOD mice. Adoptive transfer of diabetic (diab) or non-diabetic (non-diab) NOD, and non-diab NOD-Alox15null splenocytes (cells) determined ability of T1D disease transfer in NOD.scids. Both diab and non-diab NOD cells conferred T1D in NOD.scid hosts, but non-diab NOD-Alox15null cells did not (>8 wks post-transfer). NOD-Alox15null .scids were also injected with either NOD (diab and non-diab) or NOD-Alox15null (non-diab) cells. NOD cells still transferred disease, but NOD-Alox15null cells did not. As transferred splenocytes were mainly T and B cells, we tested for 12/15-LO mRNA expression in these subsets. 12/15-LO levels were minimally detectable, suggesting that immune effects are likely due to indirect effects on B and T cells. To study the mechanism, we looked at the role of 12/15-LO on APCs. Fewer MΦ infiltrate the pancreas of NOD-Alox15null mice at 4 wks of age compared to NOD controls. Also, MΦ from 10-wko NOD-Alox15null mice show reduced IL-12 expression compared to age-matched NODs. Therefore, 12/15-LO is a key regulator of the autoimmune response leading to T1D.

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