Alive and kicking: endothelium at the geographic nexus of vascular rejection.

Transplantation of vascularized cardiac grafts across an alloimmune barrier has revolutionized the treatment of organ failure, including heart failure. With current immunosuppressive therapy, acute vascular rejection is an uncommon complication of allograft transplantation. However, the shortage of donor organs continues to limit the benefit of organ replacement therapy. The United Network of Organ Sharing (UNOS) registry data indicate that although 2202 heart transplants were performed in 2001, approximately 4000 patients remained on the waiting list and 622 patients died before receiving an organ. Many times this number died without even being listed for transplant at all. Xenotransplantation, transplantation of organs between different species, could theoretically provide an unlimited source of organs. However, a number of barriers remain to the clinical implementation of xenotransplantation. One of the most important of these barriers, acute vascular rejection, develops in the continuum of delayed xenograft rejection (DXR). DXR occurs shortly after implantation of a vascularized xenograft and remains a major impediment to clinical application of xenotransplantation of vascularized organs. Acute vascular rejection occurs within a time frame of one to several days after transplantation, as a consequence of immune activation. Histologically, it is characterized by platelet aggregation, fibrin deposition, and cellular infiltration by host natural killer cells and monocytes.1 Small vessels are typically involved in DXR, and eventually, focal infarcts and interstitial hemorrhage develop in the transplanted organ. As a tissue, the endothelium sits at the geographic nexus of blood and tissue. It regulates homeostasis (nutrient delivery and waste removal) and modulates pathophysiology (inflammation, thrombosis, fibrinolysis, and platelet aggregation). In solid-organ transplantation, the development of diffuse, concentric narrowing of small blood vessels (called transplant vasculopathy), provides evidence that the vascular endothelium is indeed an alloimmune target organ. In DXR, inciting events remain unclear, particularly the relevance and timing of endothelial cell apoptosis and activation. Apoptotic endothelial cell death would cripple critical endothelial homeostatic functions, such as inhibition of thrombosis and suppression of cellular activation cascades, and theoretically could result in DXR.2 Furthermore, processed antigens from apoptotic endothelial cells could amplify the host versus graft immune reaction. Endothelial cell activation is an equally plausible mechanism for initiating DXR. In this scenario, not only are endothelial cells alive during the development of DXR, but their metabolic machinery is revved up for maximal disruption of basal vascular homeostasis. In this state, endothelial cells are capable of expressing glycoprotein adhesion receptors, synthesizing cytokines, enhancing immune costimulation, altering the thrombotic/antithrombotic balance, and permitting unchecked platelet aggregation. Which of these two mutually exclusive mechanisms, endothelial apoptosis or endothelial activation, dominates the vascular milieu during DXR? In this issue of Circulation Research, Holzknecht et al3 deliver a clear answer to this question, providing an overdue description of the inciting events in the pathogenesis of DXR after heart transplantation. Using a pig to baboon model of heart transplantation, these authors show that vascular fibrin deposition precedes the appearance of apoptotic endothelial cells by TUNEL staining. In addition, they demonstrate that markers of necrosis (membrane attack complex and human C4 immunoreactivity) precede TUNEL positivity by at least 4 days. Focal areas of necrosis can also be seen by gross histological examination to precede evidence of apoptosis. In the same model system, mRNA levels for potential proand antiapoptotic genes increase, but lag significantly behind the histological development of DXR. An active role for endothelial cells in DXR is supported by high levels of immune staining for the metabolic marker ribosomal P-antigen in endothelium on the first day after cardiac xenotransplantation. A supporting electron micrograph shows a nonapoptotic endothelial cell with expanded rough endoplasmic reticulum, indicative of cellular activation. These data show clearly that the endothelium is nonapoptotic during early critical stages of DXR. Taken together, this would suggest that active endothelial cell processes rather than apoptotic death underlie DXR at the earliest stages.4 These data do not exclude the possibility that endothelial cells undergo apoptosis during DXR at later stages; in fact, the data would suggest just the opposite. The salient message is that endothelial apoptosis does not initiate DXR. Instead, DXR is probably the outcome of a complex process that begins at the molecular level in the moments after vascular anastomosis and reperfusion of the xenograft. Immune and nonimmune factors present in these first moments critically influence the development of delayed organ The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From Columbia University, College of Physicians and Surgeons, New York, NY. Dr Pinsky has received project support in the past from Immunex and has in the past served as a consultant to Biogen and APT Therapeutics. Correspondence to David J. Pinsky, MD, Division of Cardiology and Circulatory Physiology, Dept of Medicine, Columbia University, College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032. E-mail [email protected] (Circ Res. 2002;91:1085-1088.) © 2002 American Heart Association, Inc.