© 1997 American Heart Association, Inc.
Articles |
Sustained Anti-CD4/CD8 Treatment Blocks Inflammatory Activation and Intimal Thickening in Mouse Heart Allografts
From the Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Mass.
Correspondence to Mary E. Russell, MD, Cardiovascular Biology Laboratory, Harvard School of Public Health, 677 Huntington Ave, Bldg 2, Boston, MA 02115.
Abstract We evaluated inflammatory activation and vascular
thickening in a heterotopic murine heart transplant model. C57BL/6J
recipient mice received anti-CD4 therapy (days 1 to 4 after
transplantation) or sustained, combined anti-CD4/CD8 therapy (days 1 to
4, weekly thereafter). Morphometric analysis of grafts (>95
days) found the mean percentage of vessel occlusion to be 51.7% in
allografts treated with anti-CD4, 8.3% in allografts treated with
sustained anti-CD4/CD8, and 6.7% in isografts. Mean transcript levels
of the adhesion molecules P-selectin, intercellular adhesion molecule 1
(ICAM-1), and leukocyte function-associated antigen 1 (LFA-1) and the
cytokines interleukin 4 (IL-4), interferon-
(IFN-),
inducible nitric oxide synthase (iNOS), allograft inflammatory factor 1
(AIF-1), and monocyte chemoattractant protein 1 (MCP-1) were measured
with reverse transcription–polymerase chain reaction [RT-PCR] assays
using deoxycytidine triphosphate radiolabeled with phosphorus 32
[32P-dCTP]. The assays were normalized against
glyceraldehyde-3-phosphate dehydrogenase [G3PDH]
Levels were found to be significantly higher in the anti-CD4 group than
in the anti-CD4/CD8 group. A strong correlation was also found between
the percentage of luminal occlusion and the expression of these markers
of inflammation (r=.92-.99, P<.0001). Sustained
therapy involving proximal blockade of CD4 and CD8 interrupts pathways
leading to inflammation and vascular thickening. However, long-term
heart allografts in mice treated with a short course of anti-CD4
display an ongoing inflammatory cell activation that culminates in
arteriosclerosis. This model may help examine the
role of targeted immune factors using knockout mice to identify those
causally involved in vessel thickening.
Key Words: arteriosclerosis • transplant vasculopathy • mouse cardiac allograft • cytokines • adhesion molecules
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