MURINE MODEL OF ACCELERATED TRANSPLANT ARTERIOSCLEROSIS

To define the role of specific gene deletions and mutations in the dev elopment of transplant arteriosclerosis, we generated an accelerated m odel of the disease in mice. Carotid arteries were transplanted betwee n B.10A(2R) (H-2(h2)) donor mice and C57BL/6J (H-2(b)) recipients and compared with arteries isografted between H-2(b) mice. Immunosuppressi ve drugs were not used. Within 7 days, the allografted carotid artery formed a neointima composed of mononuclear leukocytes (CD45+) that wer e predominantly monocytes or macrophages (ie, CD11b+ cells with single -lobed nuclei). CD4+ and CD8+ cells were present as well. By 30 days, the neointima became exuberant, and mononuclear leukocytes were largel y replaced by smooth muscle cells. Cells staining for proliferating-ce ll nuclear antigen were abundantly present in the intima at both early and late time points, indicating the proliferation of mononuclear leu kocytes and smooth muscle cells. The area of the intima increased from day 7 to day 30 (P<.0005), as did the number of nuclei (P=.0005), but the density of the nuclei decreased (P=.02), suggesting the formation of extracellular matrix. Six of the eight isografts formed no neointi ma, and in samples from the remaining two, a single layer of smooth mu scle neointimal cells covered just a portion of the vessel circumferen ce. This model, which reproduces many of the features of human transpl ant arteriosclerosis but at an accelerated pace, should prove useful f or determining the roles in transplant arteriosclerosis of genes that code for components of immunologic and inflammatory responses.