Abstract 495: High-Density Lipoprotein-Mediated Modulation of Autoimmunity in Normolipidemic Lupus-Prone Mice

Abstract

The notion that quantitative and/or qualitative modulation of High-Density Lipoprotein (HDL) can protect against autoimmunity and the development of Systemic Lupus Erythematosus (SLE) is supported by demonstration of its anti-inflammatory and immunosuppressive properties in hypercholesterolemic rodent models lacking Apolipoprotein A-I (Apo A-I) or treated with 4F Apo A-I mimetic peptide. However, it is not known whether similar effects of Apo A-I (HDL) deficiency or 4F treatment are manifested in the absence of hypercholesterolemia, or whether raising HDL elicits opposite effects to those caused by Apo A-I deficiency. It also remains to be determined whether beneficial effects of 4F also include mitigation of SLE-associated HDL dysfunction (depressed HDL levels and PON-1 activity) that we previously showed was also inherent in normolipidemic SLE-prone gld mice. We transferred SLE from SLE-prone Sle123 mice into congenic wild-type, Apo A-I knockout or Apo A-I transgenic mice by bone marrow transplantation. Transgenic Apo A-I overexpression resulted in significant improvement in several Lupus phenotypes, including lower anti-DNA auto-antibodies, reduced in situ T lymphocyte proliferation, decreased activated CD4 + T lymphocytes and CD4 + effector/memory cells, and improved kidney pathology. Surprisingly, Apo A-I deficiency had no significant influence on the above Lupus phenotypes and, as with Apo A-I overexpression, did not affect CD4 + FoxP3 + regulatory T cell numbers. Feeding gld mice diet supplemented with 4F peptide (∼6mg/Kg body weight: synthesized from D-amino acids to make it orally bio-available) did not reduce auto-antibodies or modify any of the Lupus phenotypes above other than kidney pathology, which was significantly improved. Interestingly, this beneficial effect of 4F was mediated in the absence of any significant improvement in HDL levels or PON-1 activity. Considering that HDL deficiency did not modulate major Lupus phenotypes in the absence of hypercholesterolemia, we conclude that supra-physiologically high levels of Apo A-I (HDL) may be required to have broad therapeutic benefit, while Apo A-I mimetic peptide treatment may be a more clinically viable strategy to treat glomerulonephritis in SLE.