LEW-to-F344 carotid artery allografts: analysis of a rat model of posttransplant vascular injury involving cell-mediated and humoral responses.
A key manifestation of chronic rejection is an obliterative arteriosclerosis. Myointimal thickening in the vessel is preceded by an endothelialitis involving accumulation of host mononuclear cells in the perivascular and intimal spaces. We report a paratopic LEW-to-F344 rat carotid artery transplantation model developed to study the cells, cytokines, and inflammatory response associated with this early phase of vascular immune injury. Compared with contralateral control arteries and isografts, LEW-to-F344 carotid allografts develop intimal thickening with mononuclear cell infiltration that persists (days 20, 45, 75, 90, and 120). Allografted vessels had dense collections of intimal and adventitial leukocytes (CD45+) consisting of equal numbers of T cells and macrophages. There were small but variable numbers of intimal smooth muscle cells. Intimal cells showed dense staining for tumor necrosis factor-alpha, interleukin-8, platelet-derived growth factor, iNOS, and ICAM and weaker labeling for interleukin-1 beta and interleukin-6. There was also prominent staining for interleukin-4 and interleukin-7 with no detectable interferon-gamma or interleukin-2 staining and high titer labeling for IgG1 (but not IgG2). The predominance of the T cell infiltrate coupled with interleukin-4 and IgG1 expression in carotid allografts is consistent with a TH2 response. This contrasts with balloon-injured rat carotids, which evoke a macrophage-dependent proliferative response. These findings demonstrate that there are distinct as well as common activation pathways in various forms of vascular injury and the LEW-to-F344 carotid model provides the opportunity to gain insight into molecular mechanisms regulating alloimmune injury in the vessel.
New England Deaconess Hospital, Harvard Medical School, Harvard School of Public Health, Massachusetts General Hospital, Boston, USA.
W W
WW
Hancock
C
C
Shi
M H
MH
Picard
C
C
Bianchi
M E
ME
Russell
D000818:Animals; D002339:Carotid Arteries / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis*; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D008264:Macrophages / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000473:pathology; D014184:Transplantation, Homologous; D017539:Tunica Intima / Q000276:immunology / Q000473:pathology
D016207:Cytokines; D018799:Intercellular Adhesion Molecule-1