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Th2-predominant inflammation and blockade of IFN-γ signaling induce aneurysms in allografted aortas
Koichi Shimizu, … , Richard T. Lee, Richard N. Mitchell
Koichi Shimizu, … , Richard T. Lee, Richard N. Mitchell
Published July 15, 2004
Citation Information: J Clin Invest. 2004;114(2):300-308. https://doi.org/10.1172/JCI19855.
View: Text | PDF | Corrigendum
Article Cardiology

Th2-predominant inflammation and blockade of IFN-γ signaling induce aneurysms in allografted aortas

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Abstract

Abdominal aortic aneurysms (AAAs) cause death due to complications related to expansion and rupture. The underlying mechanisms that drive AAA development remain largely unknown. We recently described evidence for a shift toward T helper type 2 (Th2) cell responses in human AAAs compared with stenotic atheromas. To evaluate putative pathways in AAA formation, we induced Th1- or Th2-predominant cytokine environments in an inflammatory aortic lesion using murine aortic transplantation into WT hosts or those lacking the receptors for the hallmark Th1 cytokine IFN-γ, respectively. Allografts in WT recipients developed intimal hyperplasia, whereas allografts in IFN-γ receptor–deficient (GRKO) hosts developed severe AAA formation associated with markedly increased levels of MMP-9 and MMP-12. Allografts in GRKO recipients treated with anti–IL-4 antibody to block the characteristic IL-4 Th2 cytokine or allografts in GRKO hosts also congenitally deficient in IL-4 did not develop AAA and likewise exhibited attenuated collagenolytic and elastolytic activities. These observations demonstrate an important dichotomy between cellular immune responses that induce IFN-γ– or IL-4–dominated cytokine environments. The findings establish important regulatory roles for a Th1/Th2 cytokine balance in modulating matrix remodeling and have important implications for the pathophysiology of AAAs and arteriosclerosis.

Authors

Koichi Shimizu, Masayoshi Shichiri, Peter Libby, Richard T. Lee, Richard N. Mitchell

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Figure 6

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Representative immunohistochemistry of CD4+ (A and C) and CD11b+ (B and ...
Representative immunohistochemistry of CD4+ (A and C) and CD11b+ (B and D) cells in allografts from GRKO recipients harvested 4 weeks after transplantation (n = 6). Boxed area in A or B (original magnification, ×100) is enlarged in C or D (original magnification, ×400), respectively. The majority of the graft infiltrating cells, especially adjacent to degraded elastic lamellae, consisted of CD11b+ macrophages. Expression of MMP-12 (F and H) colocalized with CD11b+ cells (E and G) in allografts from GRKO recipients harvested 4 weeks after transplantation (n = 6).

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