Immunomodulation and its effector mechanisms in atherosclerosis
Author: Hjerpe, Charlotta
Date: 2007-06-01
Location: Welandersalen, Karolinska Universitetssjukhuset, Solna
Time: 09.00
Department: Institutionen för medicin / Department of Medicine
View/ Open:
thesis.pdf (559.5Kb)
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.
List of papers:
I. Tenger C, Zhou X. (2003). "Apolipoprotein E modulates immune activation by acting on the antigen-presenting cell." Immunology 109(3): 392-7
Pubmed
II. Tenger C, Sundborger A, Jawien J, Zhou X. (2005). "IL-18 accelerates atherosclerosis accompanied by elevation of IFN-gamma and CXCL16 expression independently of T cells." Arterioscler Thromb Vasc Biol 25(4): 791-6
Pubmed
III. Zhou X, Robertson AK, Hjerpe C, Hansson GK. (2006). "Adoptive transfer of CD4+ T cells reactive to modified low-density lipoprotein aggravates atherosclerosis." Arterioscler Thromb Vasc Biol 26(4): 864-70
Pubmed
IV. Hjerpe C, Johansson D, Hansson GK, Zhou X. (1970). "Transfer of dendritic cells pulsed with modified low-density lipoprotein aggravates atherosclerosis." (Submitted)
VI. Hjerpe C, Johansson D, Robertson AK, Hansson GK, Zhou X (1970). "Atheroprotection by immunization remains in B cell deficient mice." (Submitted)
I. Tenger C, Zhou X. (2003). "Apolipoprotein E modulates immune activation by acting on the antigen-presenting cell." Immunology 109(3): 392-7
Pubmed
II. Tenger C, Sundborger A, Jawien J, Zhou X. (2005). "IL-18 accelerates atherosclerosis accompanied by elevation of IFN-gamma and CXCL16 expression independently of T cells." Arterioscler Thromb Vasc Biol 25(4): 791-6
Pubmed
III. Zhou X, Robertson AK, Hjerpe C, Hansson GK. (2006). "Adoptive transfer of CD4+ T cells reactive to modified low-density lipoprotein aggravates atherosclerosis." Arterioscler Thromb Vasc Biol 26(4): 864-70
Pubmed
IV. Hjerpe C, Johansson D, Hansson GK, Zhou X. (1970). "Transfer of dendritic cells pulsed with modified low-density lipoprotein aggravates atherosclerosis." (Submitted)
VI. Hjerpe C, Johansson D, Robertson AK, Hansson GK, Zhou X (1970). "Atheroprotection by immunization remains in B cell deficient mice." (Submitted)
Issue date: 2007-05-11
Rights:
Publication year: 2007
ISBN: 978-91-7357-177-7
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