BRAIN DEATH ENHANCES INJURY OF RAT CARDIAC ALLOGRAFTS BY INDUCTION OF MULTIPLE CHEMOKINES, CHEMOKINE RECEPTORS AND PROINFLAMMATORY MEDIATORS

Abstract

126 The results of renal allografts from living donors are invariably superior to those from cadavers. Brain death (BD), a major difference between the two groups, may be an important antigen-independent risk factor for subsequent graft behavior. We have shown that rat cardiac allografts from BD donors are rejected in a significantly accelerated fashion by unmodified hosts as compared to those from normal animals. The present study investigated the effects of BD on relatively early intragraft events developing in a chronic rat cardiac allograft model. Brain death was induced in LEW rats via inflation of an intracranial 3F-Fogarty balloon. The animals were ventilated for 6 hours thereafter under hemodynamically stable conditions (MAP>80 mm Hg). Hearts were then excised and transplanted into F344 rats; hearts from normal, anesthetized animals served as controls. Recipients were treated with cyclosporine 5 mg/kg/d and well functioning grafts were removed after 15 days and examined by histology and immunohistology (6/group). Control allografts were well preserved with minor mononuclear cell infiltration. In contrast, hearts from BD donors showed multiple small infarcts, areas of ischemic injury and obviously increased cell infiltration (3-4x) as reflected by multifocal interstitial and perivascular mononuclear aggregates. Leukocyte populations were comparable between the groups and consisted of T cells (10-20%) and macrophages (>75%). BD also increased immune activation of the otherwise stable grafts as shown by marked upregulation of IL-2R and iNOS expression, as well as endothelial induction of ICAM-1 and endothelin. In addition, whereas control grafts showed only focal MCP-1 expression and corresponding staining for the chemokine receptor CCR2, BD induced dense endothelial and leukocyte expression of the chemokines IP-10 and Mig and receptor CXCR3, as well as MIP-1β and receptor CCR5. In the early course after transplantation in immunosuppressed recipients, grafts from BD donors experience a more intense cellular rejection than control grafts. The upregulation of chemokines and corresponding receptors in BD vs. control grafts indicates important changes arising as a consequence of donor brain injury. Such changes are amenable to testing using receptor antagonists. Thus, these studies show mechanisms by which BD may compromise long-term graft function and suggest potential pathways for therapeutic intervention in the early post-transplant period.