Immunomodulation and its effector mechanisms in atherosclerosis
Year: 2007
Type: dissertation
Abstract: Atherosclerosis is a disease of the arterial intima, characterized by\ncholesterol deposition, inflammation and fibrosis. The pathogenesis of\natherosclerosis is related to both innate and adaptive immune responses,\nand modulation of immune reactions in animal models of atherosclerosis\naffects the progression of the disease. The studies in this thesis have\nutilized apolipoprotein E deficient (Apoe-/-) mice to unravel immune\nmechanisms involved in progression and protection of atherosclerosis.\n\nApoe-/- mice and wild-type mice were compared to clarify the role of\napolipoprotein E (apoE) as a modulator of immune responses. Our data show\nthat apoE controls T cell activation by down-regulating the expression of\nMHC class II and costimulatory molecules on the antigen-presenting cell.\nWe thereby explain how apoE can inhibit T cell proliferation.\n\nTo investigate the effect of Interleukin 18 (IL-18) on atherosclerosis in\nthe absence of adaptive immunity, immunodeficient SCID/Apoe-/- mice were\ntreated with IL-18. We demonstrate that IL-18 promotes atherogenesis in\nthe absence of T cells and show that NK cells, macrophages and vascular\ncells produce IFNγ in response to IL-18 in amounts that are sufficient\nfor disease progression.\n\nTransfer of MDA-LDL specific CD4+ T cells to SCID/Apoe-/- mice was\nperformed to determine whether the proatherogenic effect of CD4+ T cell\ntransfer is antigen specific. The transfer accelerates atherosclerosis\nand leads to elevated levels of IFNγ, demonstrating that Th1 cellular\nimmunity directed to MDA-LDL promotes atherosclerosis in\nhypercholesterolemic mice.\n\nTo explore the role of dendritic cells in atherosclerosis, we transferred\nDC loaded with MDA-LDL to Apoe-/- mice. This treatment induced\nantigen-specific proatherogenic immunity that augmented local\ninflammation and growth of atherosclerotic lesions, illustrating that DC\nmay take part in the initiation of atherosclerosis-related immunity.\n\nFinally, we studied immunization-induced atheroprotection in the absence\nof B cells and antibodies in μMT/Apoe-/- mice. Our data demonstrate B\ncellindependent protection by MDA-LDL immunization, paralleled by\ninduction of regulatory T cells. We thereby confirm that immunization\nwith MDA-LDL inhibits disease development in hypercholesterolemic mice\nand identify a B cellindependent protective mechanism.\n\nIn conclusion, we have studied immunomodulation and effector mechanisms\nin mouse models of atherosclerosis. In brief, we show that; apoE acts as\na dampener on the antigen presenting cell, IL-18 is proatherogenic even\nin the absence of adaptive immunity, DC presenting MDA-LDL initiate\nproatherogenic reactions and protective immunization remains in B cell\ndeficient mice.
Source: Figshare
Author: Charlotta Hjerpe
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W1553291902