Linked Life Data

8225375

Source:http://linkedlifedata.com/resource/pubmed/id/8225375

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PredicateObject
rdf:type
lifeskim:mentions
pubmed:dateCreated
1993-12-21
pubmed:abstractText
Despite recognition of chronic vascular injection by numerous investigators since the beginning of experimental and solid organ transplantation, the pathogenesis of graft arteriosclerosis remains poorly understood. We have defined a reproducible model of this disease by transplanting heterotopic cardiac grafts across minor histocompatibility barriers using inbred strains of rat. We found that long-term surviving Lewis grafts in untreated F344 recipients are subjected to a chronic rejection process which results in the development of diffuse graft arteriosclerotic lesions, indistinguishable in appearance from those seen in human cardiac grafts. Immunohistochemical studies confirm that end-stage lesions are similar in composition to human lesions, made up predominantly of vascular smooth muscle cells with occasional monocytes and T cells. Analysis of serial rejecting allografts demonstrates that a distinct inflammatory stage precedes smooth muscle cell accumulation in areas of intimal thickening, suggesting that mononuclear cells play a role in the developing lesion. Endothelial expression of class II and ICAM-1 appears to lead to early mononuclear cell adherence to the endothelium. Analysis using quantitative RT-PCR confirms that MCP-1 is expressed by ED1-positive monocyte/macrophages in rejecting cardiac grafts, suggesting that this chemoattractant may help drive mononuclear cell accumulation in the expanding intima. Immunohistochemical labelling of PDGF, TNF, and IL-1 in vascular lesions suggests that these growth factors may trigger intimal vascular smooth muscle cell proliferation in chronically rejecting allografts. Hypercholesterolemia did not enhance the severity of lesion development in long-term surviving allografts, suggesting that lipid levels are not a major etiologic factor in graft arteriosclerotic lesion formation in the Lewis-F344 model. Finally, the dietary manipulation of EFAD reduced graft infiltration by mononuclear cells and markedly diminished arterial lesion development in chronically rejecting grafts. Heparin anologues have previously been shown to inhibit proliferative vascular smooth muscle cell lesions in rats following endothelial injury (Clowes & Karnovsky 1977), and we are currently assessing the role of heparin in the therapy of graft arteriosclerosis in the Lewis-F344 model. We are also investigating the role of CD4-positive mononuclear cells in the pathogenesis of lesion development, using the anti-CD4 monoclonal antibody BWH-4 to deplete recipients of CD4-positive cells (Sayegh et al. 1991). In summary, our studies in the Lewis-F344 model suggest that monocyte/macrophages play an important role in the pathogenesis of cardiac graft arteriosclerosis. Future studies utilizing this model should help further elucidate the mechanisms resulting in--and help define potential therapies for--chronic rejection in cardiac transplantation.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0105-2896
pubmed:author
pubmed:issnType
Print
pubmed:volume
134
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5-19
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
1993
pubmed:articleTitle
Chronic rejection in experimental cardiac transplantation: studies in the Lewis-F344 model.
pubmed:affiliation
Harvard Medical School, Harvard School of Public Health, Boston, MA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Review