Immunomodulation and its effector mechanisms in atherosclerosis

Abstract

Atherosclerosis is a disease of the arterial intima, characterized by cholesterol deposition, inflammation and fibrosis. The pathogenesis of atherosclerosis is related to both innate and adaptive immune responses, and modulation of immune reactions in animal models of atherosclerosis affects the progression of the disease. The studies in this thesis have utilized apolipoprotein E deficient (Apoe-/-) mice to unravel immune mechanisms involved in progression and protection of atherosclerosis.

Apoe-/- mice and wild-type mice were compared to clarify the role of apolipoprotein E (apoE) as a modulator of immune responses. Our data show that apoE controls T cell activation by down-regulating the expression of MHC class II and costimulatory molecules on the antigen-presenting cell. We thereby explain how apoE can inhibit T cell proliferation.

To investigate the effect of Interleukin 18 (IL-18) on atherosclerosis in the absence of adaptive immunity, immunodeficient SCID/Apoe-/- mice were treated with IL-18. We demonstrate that IL-18 promotes atherogenesis in the absence of T cells and show that NK cells, macrophages and vascular cells produce IFNγ in response to IL-18 in amounts that are sufficient for disease progression.

Transfer of MDA-LDL specific CD4+ T cells to SCID/Apoe-/- mice was performed to determine whether the proatherogenic effect of CD4+ T cell transfer is antigen specific. The transfer accelerates atherosclerosis and leads to elevated levels of IFNγ, demonstrating that Th1 cellular immunity directed to MDA-LDL promotes atherosclerosis in hypercholesterolemic mice.

To explore the role of dendritic cells in atherosclerosis, we transferred DC loaded with MDA-LDL to Apoe-/- mice. This treatment induced antigen-specific proatherogenic immunity that augmented local inflammation and growth of atherosclerotic lesions, illustrating that DC may take part in the initiation of atherosclerosis-related immunity.

Finally, we studied immunization-induced atheroprotection in the absence of B cells and antibodies in μMT/Apoe-/- mice. Our data demonstrate B cellindependent protection by MDA-LDL immunization, paralleled by induction of regulatory T cells. We thereby confirm that immunization with MDA-LDL inhibits disease development in hypercholesterolemic mice and identify a B cellindependent protective mechanism.

In conclusion, we have studied immunomodulation and effector mechanisms in mouse models of atherosclerosis. In brief, we show that; apoE acts as a dampener on the antigen presenting cell, IL-18 is proatherogenic even in the absence of adaptive immunity, DC presenting MDA-LDL initiate proatherogenic reactions and protective immunization remains in B cell deficient mice.