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Printed in U.S.A. ACTIVATION OF INFLAMMATORY MEDIATORS IN RAT RENAL ISOGRAFTS BY DONOR BRAIN DEATH 1 MAMORU KUSAKA, 2 JOHANN PRATSCHKE, 2 MARKUS J. WILHELM, 2 FARZARD ZIAI, 3 KAMBIZ ZANDI-NEJAD, 3 HARALD S. MACKENZIE, 3 WAYNE W. HANCOCK, 4 AND NICHOLAS L. TILNEY 2,5 Surgical Research Laboratory, Harvard Medical School, Department of Surgery and Medicine Brigham and Women’s Hospital, Boston and LeukoSite, Inc., Cambridge, Massachusetts Background. Brain death (BD) has been thought to influence the early course of transplanted organs by triggering a series of nonspecific inflammatory events that in turn may increase the kinetics and intensity of the immunological host responses. In this study early nonspecific, cellular, and molecular changes occur- ring in kidney isografts from BD donors are compared with those from normal anesthetized, ventilated con- trols. Methods. After induction of brain death, the animals were mechanically ventilated for 6 hr before organ removal. Only rats with stable blood pressure (mean arterial pressure >80 mmHg) were included. Serum creatinines were measured daily. Representative grafts were harvested 6 hr after brain death and be- tween 1 hr and 5 days after engraftment for morphol- ogy, immunohistology, and reverse transcriptase- polymerase chain reaction. The presence of serum cytokines was assessed by enzyme linked immunoab- sorbant assay. Results. Serum creatinine levels rose slightly in re- cipients from BD donors. Serum interleukin-1 levels increased within 6 hr versus controls (P<0.05). mRNA levels of interleukin-1 and macrophage inhibitory protein-1 in the kidneys were up-regulated transiently before engraftment (6 hr after BD) and 1 hr after re- vascularization (P<0.05). By immunohistology, num- bers of infiltrating polymorphonuclear leukocytes peaked at 24 hr in parallel with intragraft induction of P- and E-selectin, complement, and other proinflam- matory chemokines and cytokines. At 5 days, the isografts from BD donors were highly infiltrated by host leukocyte populations associated with intense up-regulation of their products. In contrast, those from control donors remained relatively normal through this initial follow-up period. Conclusions. The intense nonimmune inflammation produced in isografts after donor BD may represent the initial stages of a continuum between an initial nonspecific and later immune reactivity, when placed in the context of allotransplantation. There is growing appreciation that the results of organ allografts from marginal or extended donors are less satis- factory over both the short- and long-term than those from 1 Supported by USPHS grant 5RO1 DK 46190 –24. JP and MJW are recipients of a Research Fellowship award from the Deutsche Forschungsgemeinschaft (DFG) (Pr 578/1–1, Wi 1677/1–1), Ger- many. 2 Surgical Research Laboratory, Harvard Medical School, Depart- ment of Surgery, Brigham and Women’s Hospital. 3 Renal Division, Department of Medicine, Brigham and Women’s Hospital. 4 LeukoSite, Inc. 5 Address correspondence to: Nicholas L. Tilney, MD, Department of Surgery, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. KUSAKA ET AL. February 15, 2000 405