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The therapeutic efficacies of ART-18, ART-65, and OX-39, mouse antibodies of IgG1 isotype recognizing distinct epitopes of the p55 beta chain of the rat IL-2-R molecule, were probed in LEW rat recipients of (LEW X BN)F1 heterotopic cardiac allografts (acute rejection in untreated hosts occurs within 8 d). A 10-d course with ART-18 prolongs graft survival to approximately 21 d (p less than 0.001). Therapy with ART-65, but not with OX-39, was effective (graft survival approximately 16 and 8 d, respectively). Anti-IL-2-R mAb treatment selectively spared T cells with donor-specific suppressor functions; the CD8+ (OX8+ W3/25-) fraction from ART-18-modified recipients, and primarily the CD4+ (W3/25+ OX8-) subset from ART-65-treated hosts conferred unresponsiveness to naive syngeneic rats after adoptive transfer, increasing test graft survival to approximately 16 and 45 d, respectively. Concomitant administration of ART-18 and ART-65 to recipient animals in relatively low doses exerted a strikingly synergistic effect, with 30% of the transplants surviving indefinitely and 50% undergoing late rejection over 50 d. These studies provide evidence that anti-IL-2-R mAbs selectively spare phenotypically distinct T cells with suppressor functions. The data also suggest that in vivo targeting of functionally different IL-2-R epitopes may produce synergistic biological effects.

Objective: To evaluate the interaction of donor and recipient age on transplant outcome and immune response., Summary Background Data: The age of donor and recipient is becoming increasingly important in organ transplantation. We tested the relevance and consequences of recipient and donor age on immunoresponsiveness and transplant outcome in a uni- and multilateral cohort analysis., Methods: We obtained and analyzed data from 108,188 recipients of deceased donor kidneys of the United Network for Organ Sharing database transplanted between 1995 and 2008. Univariate analysis of allograft and patient survival was calculated by Kaplan Meyer. Multivariate analyses were performed using the Cox Proportional Hazards method. Data were assessed and compared by decades of increasing donor and recipient age with and without censoring transplant loss for death with a functioning graft. This approach allowed a detailed analysis of interacting factors., Results: Transplant survival was lowest in elderly recipients. However, when the analysis was censored for patient's death with a functioning kidney transplant, survival improved incrementally with each decade of increasing recipient age. This was even more surprising as older recipients had received less well-matched organs of poorer quality. The frequency of acute rejection decreased dramatically with increasing age, emphasizing the effect of age on the vigor of the recipient's immune responses. In contrast, increasing donor age was associated with more frequent acute rejection rates. The effects of donor and recipient age in combination demonstrated that grafts of older donors fared significantly better in older recipients., Conclusions: Our results show that increasing recipient age is associated with an improved transplant survival, lower rates of rejection, and superior outcome of older donor organs. Physiological and/or immunologic aspects of organ and recipient age seem to determine, at least in part, the success of renal transplantation.

Joseph Murray performed the first successful human kidney transplant on December 23, 1954. Forty-three years later, he along with participants Francis Moore and Leroy Vandam, commissioned a painting of the event from artist Joel Babb (1). To document this unique record of medical history, we identify all those present at the operation and depicted in the portrait, describe how the artist created the work, explain irregularities and inaccuracies in the painting, provide a 50-year follow-up on everyone involved, and comment on any influence this landmark event may have had on their subsequent careers.

Background: We sought to analyze the risk factors and natural history associated with post-cardiac surgery acute pancreatitis., Methods: Retrospective analysis of all patients having undergone cardiac surgery at our hospital between January 1, 1992, and October 1, 2001., Results: A total of 10,249 cardiac operations were performed. Thirty-nine (0.4%) patients developed postoperative pancreatitis. There was a higher incidence during the period spanning 1992 through 1996 than 1997 through 2001 (0.6% versus 0.2%, P< .05). Patients with pancreatitis had longer postoperative length of stay (51+/-5 days versus 10+/-1 days, P<.05) and a greater in-hospital mortality rate (28% versus 4%, P<.05) than patients who did not develop pancreatitis. A history of alcohol abuse, cardiac surgery performed during 1992 to 1996, increased cardiopulmonary bypass time, and increased cross-clamp time were independent risk factors for the development of pancreatitis. Multiple-organ failure was an independent predictor for death among patients with pancreatitis., Conclusions: Although the frequency of post-cardiac surgery pancreatitis is diminishing, it is still associated with significant mortality.

Both antigen-dependent and -independent factors influence long-term organ allograft function and survival. Brain death (BD), a significant antigen-independent, donor-related injury upregulates a variety of inflammatory mediators in peripheral organs. One of the earliest responses to such an insult is the expression of selectins by endothelial cells of the transplanted tissues; these in turn trigger a cascade of nonspecific events, that enhance host alloresponses and which may be worsened by toxic effects of long-term immunosuppression. Using a rat model in which donor BD accentuates subsequent renal allograft injury, we have tested the effects of therapy with recombinant P-selectin glycoprotein ligand (rPSGL-Ig) alone, or in combination with sirolimus (SRL) and cyclosporin A. We found that in contrast to the effects of standard doses of SRL or cyclosporine, rPSGL-Ig decreased inflammation in the early posttransplant period such that lower doses of maintenance immunosuppression were sufficient to maintain long-term graft function.

Background: Marginal donor organs are used increasingly for transplantation. To define the influences of donor hypertension, we compared the behavior of kidney allografts from hypertensive and normotensive donors in an established rat model of chronic rejection., Methods: Donor hypertension was induced by partial occlusion of the right renal artery with a silver clip. After 10 weeks, the left kidney was removed and transplanted. Normotensive animals served as controls. All recipients were treated with a low dose of cyclosporine for 10 days (1.5 mg/kg). Blood pressure and proteinuria were determined weekly four times after transplantation. To examine the effects of donor hypertension on late events, grafts (n=6/time point) were examined morphologically and by quantitative reverse transcriptase-polymerase chain reaction analysis at serial intervals., Results: Recipients of kidneys from hypertensive donors developed systemic hypertension in contrast with normotensive controls (P<0.05). Allografts from hypertensive animals showed accelerated deterioration in structure and function after transplantation. Proteinuria became significantly elevated as early as 6 weeks (P<0.05) compared with controls and increased progressively thereafter (P<0.005). Grafts from hypertensive donors, histologically normal at the time of engraftment, developed significant morphologic deterioration after 12 weeks (P<0.01). Changes in allografts from normotensive donors remained minor. mRNA of proinflammatory mediators in hypertensive donor grafts (P<0.01) was up-regulated before transplantation and increased progressively over time (P<0.01)., Conclusions: Donor hypertension intensifies the chronic injury associated with allogeneic kidney transplantation in the rat model used. This condition also leads to induction of recipient hypertension and may be a more important risk factor for chronic graft dysfunction than previously appreciated.

Background: Systemic hypertension affects many allograft recipients, is an important risk factor for chronic graft dysfunction, and is linked to reduced graft survival. The condition may up-regulate the expression of inflammatory host cells and their products. These, in turn, may significantly injure vascular endothelium and other components of allografted kidneys., Methods: Lewis rats received orthotopic F344 renal allografts, a standard model of chronic rejection. Renovascular hypertension was produced by placing a silver clip (0.25 mm) on the renal artery of the retained contralateral native kidney 4 weeks after transplantation. Sham-clipped rats served as normotensive controls. Four recipient groups (Gp) were studied: Gp 1, rats with an allograft plus a clipped native kidney; Gp 2, those with an allograft and a sham-clipped native kidney; Gp 3, isografted animals with a clipped native kidney; and Gp 4, those bearing an isograft and a sham-clipped native kidney. Systolic blood pressure and proteinuria were measured every 2 weeks for 24 weeks. Grafts were assessed serially for morphologic and immunohistologic changes., Results: Systemic blood pressure rose to hypertensive levels in Gps 1 and 3 within a week of clipping but never increased in Gps 2 and 4. Proteinuria developed in hypertensive animals but remained at baseline in normotensive controls. Intimal thickening of allograft arteries progressed to luminal obliteration with extensive perivascular and interstitial fibrosis by 24 weeks. In contrast, vascular changes in isografts of hypertensive hosts were restricted to medial hypertrophy. Tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, platelet derived growth factor (PDGF), endothelin, Il-6, major histocompatibility complex (MHC) class II, and B7 were up-regulated in allografts in hypertensive hosts. Vascular deposition of immunoglobulin (IgG) was increased. These changes were markedly less pronounced in Gp 3 isografts and minimal in the kidneys of the normotensive animals of Gps 2 and 4., Conclusions: An experimental model is presented that examines the influence of recipient hypertension in the pathogenesis of chronic dysfunction and injury developing in rat renal allografts over time.

Donor brain death has been considered a significant risk factor for both early and late organ allograft dysfunction. This central injury not only evokes an upsurge of catecholamines with resultant peripheral tissue vasoconstriction and ischemia but also promotes release of hormones and inflammatory mediators that may also affect the organs directly. One of the resultant influences of these events is the rapid upregulation of the acute-phase adhesion molecules, the selectins. These initiate leukocyte adhesion to vascular endothelium and trigger subsequent cellular and molecular changes in the compromised tissues. An established F344 --> LEW rat model of chronic rejection was used to examine (1) whether the initial inflammatory events that develop within kidney allografts from brain-dead donors could be normalized using a recombinant soluble form of P-selectin glycoprotein ligand and (2) whether amelioration of these early changes would alter the inexorable progression of chronic allograft rejection. Untreated living donor controls experienced unrelenting chronic rejection over time. This complex process was accelerated in brain-dead donor kidneys. Treatment with P-selectin glycoprotein ligand prevented the early inflammatory changes in the transplanted organs and their subsequent (200 d) functional and morphologic manifestations, particularly when the soluble ligand was administered both to the donor before organ removal and to the recipient after engraftment. This strategy of using a naturally occurring selectin ligand to prevent donor-associated chronic graft dysfunction may be of special clinical interest in cadaver donor transplantation.

Background: The lack of adequate numbers of kidneys for transplantation has stimulated interest in the use of organs from non-heart-beating donors (NHBDs). The short- and long-term effects of this risk factor on kidney isografts and allografts were examined with a rat model., Methods: NHBDs were killed by ether overdose. Kidney isografts (male Lewis rats [LEW]-->LEW) were transplanted orthotopically into bilaterally nephrectomized recipients 15, 30, 45, and 90 min after asystole to determine short-term survival patterns, which were compared to those of rats bearing kidneys from living donors (LDs, 0 min). Isografts and allografts (Fisher 344 rats-->LEW) from 45-min and 105-min NHBDs and from LD controls were placed in additional recipients in which contralateral native nephrectomy was performed on day 10 to allow the injured graft to recover from its ischemic insult. Serum creatinine, proteinuria, and graft morphology were assessed serially over a 24-week follow-up period., Results: Early survival and renal dysfunction of isografted rats correlated with the interval of donor cardiac arrest before transplantation. Long-term survival of recipients of kidneys from LDs and between 45-min and 105-min NHBDs was also significantly different (100% vs. 87% vs. 37% at 24 weeks, respectively, P<0.03). Proteinuria increased progressively over time, proportionate to the period of donor asystole, and was associated with increasing cellular infiltration, tubular atrophy, and glomerulosclerosis in the grafts. The development of important functional and structural changes was intensified in NHBD allografts. LD allografts showed early changes of chronic rejection., Conclusions: The results emphasize the continuum between an initial nonspecific, donor-associated renal injury and late functional and morphologic changes associated with the interval of donor cardiac arrest. These events are accelerated in NHBD allografts that experience the added insult of host alloreactivity.

The effects of a signaling anti-CD28 mAb (JJ319), which interferes with the CD28-B7 T cell costimulation pathway thought to be involved in the development of chronic rejection of organ transplants, was investigated. Functional, morphologic, and molecular changes in rat renal allografts were examined up to 24 wk after placement. Control Lewis rats, recipients of F344 kidneys, received a single dose of a nonspecific mouse mAb intravenously on the day of transplantation (group 1). Group 2 animals were given anti-CD28 mAb in similar fashion. Group 3 animals were treated with a short course of cyclosporin A (CsA), and group 4 received both anti-CD 28 mAb and CsA. The majority (>95%) of animals in groups 2, 3, and 4 survived throughout the follow-up, compared with 28% in group 1 (P < 0.001). Group 2 and 4 recipients produced negligible proteinuria, whereas group 1 controls developed progressively increasing proteinuria after 4 wk and group 3 animals developed proteinuria by 24 wk. Allografts in groups 2 and 4 were morphologically unremarkable at 24 wk. Kidneys of group 1 animals rapidly developed changes of acute rejection, and those that survived long-term showed extensive glomerulosclerosis and interstitial fibrosis. Changes of early chronic rejection were noted in group 3 grafts. By reverse transcriptase-PCR, expression of representative inflammatory factors interferon-gamma and interleukin-10 were significantly elevated at 24 wk only in the surviving group 1 animals. A single dose of a signaling anti-CD28 mAb administered at transplantation or in combination with a short course of CsA significantly prolonged recipient survival, normalized function, and preserved the morphology of renal allografts in an established model of chronic rejection. These data support an important role for T cell costimulation in the evolution of the chronic process.

Objective: To improve the quality of organs from brain-dead donors by assessing the influence of alternative strategies on the early behavior of kidneys after transplantation into unmodified hosts., Summary Background Data: Kidneys transplanted from living donors perform consistently better than those from cadaver sources. The authors have recently shown that donor brain death produces inflammatory changes in peripheral organs within hours, amplifies coincident ischemia-reperfusion injury, and accelerates acute and chronic rejection. Normalization of the graft by donor hormone treatment has hitherto been unsuccessful., Methods: A standardized rat model of brain death was used. Experimental groups included recipients of allogeneic grafts from living and brain-dead donors (F344-->LEW). Donors were treated immediately after induction of brain death either with intravenous steroids, which block inflammatory cytokine release, or a soluble P-selectin glycoprotein ligand (sPSGL), which blocks initial selectin-mediated cellular adhesion. Kidney grafts were examined serially up to 10 days by morphology, immmunohistology, and reverse transcriptase-polymerase chain reaction., Results: Overall survival of ummodified recipients of kidneys from brain-dead donors was significantly reduced versus living donors. Animals with organs from brain-dead donors that had received steroids or sPSGL survived significantly longer than those from untreated brain-dead donors. The intensity of ischemia-reperfusion injury and of acute rejection was reduced. Cellular infiltration and transcription of mRNA of representative proinflammatory mediators were diminished., Conclusions: Treatment of organ donors at the time of brain death markedly improves organ quality after kidney transplantation, upgrading it to that from a living donor.

The clinical observation that the results of kidney grafts from living donors (LD), regardless of relationship with the host, are consistently superior to those of cadavers suggests an effect of brain death (BD) on organ quality and function. This condition triggers a series of nonspecific inflammatory events that increase the intensity of the acute immunologic host responses after transplantation (Tx). Herein are examined the influences of this central injury on late changes in renal transplants in rats. A standardized model of BD was used. Groups included both allografts and isografts from normotensive brain dead donors and anesthetized LD. Renal function was determined every 4 wk after Tx, at which time representative grafts were examined by morphology and by reverse transcriptase-PCR. Long-term survival of brain-dead donor transplants was significantly less than LD grafts. Proteinuria was significantly elevated in recipients of grafts from BD donors versus LD controls as early as 6 wk postoperatively and increased progressively through the 52-wk follow up. These kidneys also showed consistently more intense and progressive deterioration in renal morphology. Changes in isografts from brain-dead donors were less marked and developed at a slower tempo than in allografts but were always greater than those in controls. The transcription of cytokines was significantly increased in all brain-dead donor grafts. Donor BD accelerates the progression of long-term changes associated with kidney Tx and is an important risk factor for chronic rejection. These results explain in part the clinically noted difference in long-term function between organs from cadaver and living sources.

Background: Donor brain death upregulates expression of inflammatory mediators in the heart. It is hypothesized that these nonspecific changes trigger and amplify acute rejection in unmodified recipients compared with hearts from normal living donors. We examined the inflammatory and immunological consequences of gradual-onset donor brain death on cardiac allografts after transplantation., Methods and Results: Functioning hearts were engrafted from normotensive donors after 6 hours of ventilatory support. Hearts from brain-dead rats (Fisher, F344) were rejected significantly earlier (mean+/-SD, 9. 3+/-0.6 days) by their (Lewis) recipients than hearts from living donor controls (11.6+/-0.7 days, P=0.03). The inflammatory response of such organs was accelerated, with rapid expression of cytokines, chemokines, and adhesion molecules and brisk infiltration of associated leukocyte populations. Upregulation of major histocompatibility class II antigens increased organ immunogenicity. Acute rejection evolved in hearts from brain-dead donors more intensely and at a significantly faster rate than in controls., Conclusions: Donor brain death is deleterious to transplanted hearts. The resultant upregulation of inflammatory factors provokes host immune mechanisms and accelerates the acute rejection process in unmodified hosts.

The replacement of diseased organs and tissues by the healthy ones of others has been a unique milestone in modern medicine. For centuries, transplantation remained a theme of fantasy in literature and the arts. Within the past five decades, however, it has developed from a few isolated attempts to salvage occasional individuals with end-stage organ failure to a routine treatment for many patients. In parallel with the progressive improvements in clinical results has come an explosion in immunology, transplantation biology, immunogenetics, cell and molecular biology, pharmacology, and other relevant biosciences, with knowledge burgeoning at a rate not dreamed of by the original pioneers. Indeed, there have been few other instances in modern medicine in which so many scientific disciplines have contributed in concert toward understanding and treating such a complex clinical problem as the failure of vital organs. The field has been a dramatic example of evolution from an imagined process to an accepted form of therapy.

Chronic rejection remains the major obstacle to long-term allograft survival. Detailed understanding of putative etiologic risk factors, both antigen-dependent and -independent, is important for designing effective therapeutic strategies to ameliorate this process. Cell senescence may be an important factor in chronic rejection.

Objective: To define the potential influences of donor brain death on organs used for transplantation., Summary Background Data: Donor brain death causes prompt upregulation of inflammatory mediators on peripheral organs. It is hypothesized that this antigen-independent insult may influence the rate and intensity of host alloresponsiveness after engraftment., Methods: The rates of survival of unmodified Lew recipients sustained by kidney allografts from brain-dead, normal anesthetized, and anesthetized ventilated F344 donors were compared. Brain death was induced by gradually increasing intracranial pressure under electroencephalographic control. Tracheotomized brain-dead animals and anesthetized controls were mechanically ventilated for 6 hours before transplant nephrectomy. The rate and intensity of the acute rejection event were examined by histology, immunohistology, and reverse transcriptase-polymerase chain reaction., Results: Animals bearing kidneys from brain-dead donors died of renal failure secondary to acute rejection at a significantly faster rate than those from anesthetized living controls or anesthetized animals ventilated for 6 hours. Within 3 hours after placement and reperfusion of brain-dead donor grafts, significant neutrophil infiltration was observed, followed by increasing numbers of macrophages and T cells. mRNA of proinflammatory mediators detected in kidneys within 6 hours of brain death and upregulated even before transplantation increased thereafter and appeared to accelerate and amplify host alloresponsiveness, as manifested by the rapid expression of chemokines, cytokines, adhesion molecules, and major histocompatibility complex class II antigens in the engrafted organ. The process evolved in the controls less intensely and at a slower rate., Conclusions: Donor brain death is a significant risk factor for peripheral organs used for transplantation. The activated state of such organs appears to trigger host immune mechanisms that accelerate the process of acute rejection. The effects of this central injury may explain in part the less satisfactory performance of cadaver organs in human transplantation compared with those from living sources.

Background: We sought to assess the effects of angiotensin receptor blockade on glomerular hypertension, macrophage recruitment, and cytokine expression, all of which contribute to the development of chronic graft injury in this model., Methods: The effects of treatment with the specific angiotensin II type 1 (AT1) receptor antagonist, losartan, were assessed over 24 weeks in F344-->LEW rats (LOS, N = 9) versus vehicle-treated F344-->LEW controls (CON, N = 9)., Results: UprotV rose progressively in CON (from 7.0 +/- 2.9 to 41 +/- 17 mg/day at 24 wk) but remained at baseline in LOS (4.2 +/- 0.6 to 9.4 +/- 1.3 mg/day, P < 0.05 vs. CON). Glomerular capillary pressure (PGC) was increased in CON (71 +/- 1 mm Hg at week 20), but remained within the normal range in LOS rats (54 +/- 2 mm Hg, P < 0.05). Glomerulosclerosis averaged 0.3 +/- 0.2% in LOS versus 4 +/- 2% in CON rats (P < 0.05). Tubulointerstitial injury was minimal in both LOS and CON rats (+). The overexpression of renal cortical cytokine mRNA levels for the monocyte chemoattractants, monocyte chemoattractant protein-1 (MCP-1) and RANTES, as well as interleukin-1, inducible nitric oxide synthase, and transforming growth factor-beta, assessed by competitive reverse transcription-polymerase chain reaction, was suppressed in LOS versus CON rats at 20 weeks. Macrophage and T-cell numbers were decreased, and MCP-1, RANTES, and intercellular adhesion molecule-1 staining in the graft, identified by immunohistochemistry, were attenuated in LOS versus CON rats., Conclusions: The renoprotective effects of losartan in F344-->LEW rats were associated with lowered PGC, inhibition of macrophage chemoattractants and recruitment, and suppression of macrophage-associated cytokines at 20 weeks. These findings suggest that chronic allograft injury in F344-->LEW rats is, to a large extent, mediated by angiotensin II-dependent mechanisms and that these involve glomerular hemodynamics, macrophages, and macrophage-associated cytokines.

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 occurring in kidney isografts from BD donors are compared with those from normal anesthetized, ventilated controls., 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 between 1 hr and 5 days after engraftment for morphology, immunohistology, and reverse transcriptase-polymerase chain reaction. The presence of serum cytokines was assessed by enzyme linked immunoabsorbant assay., Results: Serum creatinine levels rose slightly in recipients from BD donors. Serum interleukin-1beta levels increased within 6 hr versus controls (P<0.05). mRNA levels of interleukin-1beta and macrophage inhibitory protein-1 in the kidneys were up-regulated transiently before engraftment (6 hr after BD) and 1 hr after revascularization (P<0.05). By immunohistology, numbers of infiltrating polymorphonuclear leukocytes peaked at 24 hr in parallel with intragraft induction of P- and E-selectin, complement, and other proinflammatory 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.

Background: The relatively few studies that have examined the systemic events after brain death have primarily involved large animals. For more precise definition of the physiology of this central catastrophe and its influence on peripheral organs, we have established a reproduceable model of gradual onset brain death in rats., Methods: The central injury is induced by graded inflation of a Fogarty catheter placed intracranially under EEG and blood pressure monitoring. The rats were mechanically ventilated for 6 hr before removal of their kidneys. Complications and mortality are discussed., Results: The majority (83%) of the 100 experimental animals could be used as organ donors. After a transient period of autonomic storm, the mean arterial blood pressure remained consistently between 80-100 mmHg, not appreciably different from controls. Despite normotension, the transplanted kidneys from brain dead donors showed a significantly longer interval to regain uniform cortical color and turgor than kidneys from control animals., Conclusions: We describe a controlled model of gradual onset brain death in the rat in which normotension can be sustained for several hours before the kidneys are removed for transplantation. Despite stable donor blood pressure, ischemia of peripheral organs may explain in part the increased incidence of delayed graft function of cadaver kidneys compared with those from living donors. This model is suitable for transplant-related studies involving organs from donors with irreversible central injury.

Long-term survival rates of solid organ allografts have improved relatively little during the transplant experience despite more effective immunosuppression, better organ preservation techniques and advances in perioperative management. Because grafts of potentially diminished quality are increasingly accepted to reduce the severe shortage of organs, it has become apparent that a variety of donor-associated risk factors may influence adversely their short and long-term outcome. Recent interest has focused particularly on systemic changes occurring after donor brain death (BD). Numbers of experimental and clinical studies have elucidated the complexities of the hemodynamic, metabolic, neurohormonal, and other physiological alterations following this devastating central injury. This article will address the potential derangements in peripheral organs which may influence their behavior after transplantation.

I/R is an important non-specific, antigen independent event, which significantly influences the outcome of transplanted organs. Increasing graft immunogenicity and host alloresponsiveness inflicts additional deleterious effects. Ischemia has also been associated with donor conditions such as brain death and the non-heart-beating donor. As an event surrounding organ procurement, preservation and revascularization occurring early in the transplant process, it initiates a cascade of molecular and cellular events which trigger the release of proinflammatory mediators and attraction of various cell types infiltrating the tissues. This inflammatory event influences both acute functional and structural changes in the organ which contributes to reduced graft survival. Eventually, attenuation of I/R by strategies targeting various mediators and cell populations at different levels of the inflammatory cascade may constitute a means to improve both short and long-term success of solid organ grafts.