John Owen - Apolipoprotein A-I modulates regulatory T cells in autoimmune LDLr-/-, ApoA-I-/- mice.

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      Publication Details (including relevant citation   information):

        J Biol Chem   285:36158-36169, 2010

      Abstract:

      The immune system is complex, with multiple layers of regulation   that serve to prevent the production of self-antigens. One layer   of regulation involves regulatory T cells (Tregs) that play an   essential role in maintaining peripheral self-tolerance. Patients   with autoimmune diseases such as systemic lupus erythematosus and   rheumatoid arthritis have decreased levels of HDL, suggesting   that apoA-I concentrations may be important in preventing   autoimmunity and the loss of self-tolerance. In published   studies, hypercholesterolemic mice lacking HDL apoA-I or   LDLr(-/-), apoA-I(-/-) (DKO), exhibit characteristics of   autoimmunity in response to an atherogenic diet. This phenotype   is characterized by enlarged cholesterol-enriched lymph nodes   (LNs), as well as increased T cell activation, proliferation, and   the production of autoantibodies in plasma. In this study, we   investigated whether treatment of mice with lipid-free apoA-I   could attenuate the autoimmune phenotype. To do this, DKO mice   were first fed an atherogenic diet containing 0.1% cholesterol,   10% fat for 6 weeks, after which treatment with apoA-I was begun.   Subcutaneous injections of 500 μg of lipid-free apoA-I was   administered every 48 h during the treatment phase. These and   control mice were maintained for an additional 6 weeks on the   diet. At the end of the 12-week study, DKO mice showed decreased   numbers of LN immune cells, whereas Tregs were proportionately   increased. Accompanying this increase in Tregs was a decrease in   the percentage of effector/effector memory T cells. Furthermore,   lipid accumulation in LN and skin was reduced. These results   suggest that treatment with apoA-I reduces inflammation in DKO   mice by augmenting the effectiveness of the LN Treg response.

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