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(American Journal of Pathology. 2002;160:1077-1087.)
© 2002 American Society for Investigative Pathology

Regular Articles

Cold Ischemia Induces Isograft Arteriopathy, but Does Not Augment Allograft Arteriopathy in Non-Immunosuppressed Hosts

Yutaka Furukawa^*, Peter Libby^*, Jennifer L. Stinn, Gerold Becker and Richard N. Mitchell

From the Vascular Medicine and Atherosclerosis Unit,^*
Cardiovascular Division, and the Department of Medicine and theImmunology Research Division,
Department ofPathology, Brigham and Women’s Hospital, Harvard Medical School,Boston, Massachusetts

Prolonged cold ischemia has been suggested as a factor that will exacerbate later graft arterial disease (GAD), a major limiting factor for long-term transplant survival. We therefore examined the effects of cold ischemia on GAD as well as adhesion molecule and cytokine expression in murine cardiac grafts. Mild GAD developed in isografts undergoing 4-hour cold ischemia. Relative to control isografts, cold ischemia induced transiently enhanced endothelial expression of intercellular adhesion molecule-1 (ICAM-1) at 4 hours post-transplant. There was also transiently-augmented gene expression of interleukin (IL)-1ß, IL-6, and transforming growth factor-ß in these cold-ischemic isografts. By 3 days post-transplantation, however, there were no longer any differences between control and cold ischemic isografts. Cold ischemia did not significantly affect the final grade of either parenchymal rejection or GAD in long-term (4 to 12 weeks) major histocompatibility complex (MHC) I- or MHC II-mismatched allografts molecules transplanted without immunosuppression. At early time points after cold ischemia (4 to 24 hours), allografts mismatched for MHC I and/or MHC II showed enhanced expression of ICAM-1 and cytokines comparable to that seen in isografts. By day 7 post-transplant, both control and cold ischemia allografts showed comparable expression of cytokines and adhesion molecules. Although prolonged cold ischemia can initiate mild GAD in isografts by transiently enhancing antigen non-specific inflammatory responses, it does not significantly augment subsequent alloresponses.

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