Endothelial cells as antigen-presenting cells: role in human transplant rejection

The immunological properties of human endothelial cells suggest they perform a pivotal role in acute and chronic rejection following solid organ transplantation. In this review the basic features of acute and chronic rejection are described as are the cellular and molecular requirements for antigen presentation. Traditionally, antigen-presenting cells are considered to be bone marrow-derived cells. However, these conclusions have been derived from rodent models of allograft rejection where bone marrow-derived passenger leukocytes are the only source of donor major histocompatibility complex (MHC) class II in the grafted organ. In contrast, in humans, virtually all the microvascular and small vessel endothelial cells are ‘constitutively’ positive for MHC class II antigens. The phenotypic properties of human endothelial cells, their response to cytokines and their ability to stimulate resting T cells are described. Unlike bone marrow-derived antigen presenting cells (APCs), which utilise B7/CD28 interactions, human endothelial cells utilise lymphocyte function antigen 3 (LFA3)/CD2 pathways to stimulate T cells. They activate a CD45RO + B7-independent subpopulation of T cells. Their effect on allogeneic T cells is compared with other non-bone marrow-derived cells such as fibroblasts, epithelial cells and smooth muscle cells, which are unable to stimulate resting T cells. Evidence is presented suggesting that release of MHC and non-human leukocyte antigens (HLA) from endothelial cells stimulates an alloantibody and autoimmune response leading to chronic rejection. Received 30 March 1998; received after revision 4 May 1998; accepted 4 May 1998     

The earliest record of human activity in northern Europe

The colonization of Eurasia by early humans is a key event after their spread out of Africa, but the nature, timing and ecological context of the earliest human occupation of northwest Europe is uncertain and has been the subject of intense debate. The southern Caucasus was occupied about 1.8 million years (Myr) ago, whereas human remains from Atapuerca-TD6, Spain (more than 780 kyr ago) and Ceprano, Italy (about 800 kyr ago) show that early Homo had dispersed to the Mediterranean hinterland before the Brunhes-Matuyama magnetic polarity reversal (780 kyr ago). Until now, the earliest uncontested artefacts from northern Europe were much younger, suggesting that humans were unable to colonize northern latitudes until about 500 kyr ago. Here we report flint artefacts from the Cromer Forest-bed Formation at Pakefield (52 degrees N), Suffolk, UK, from an interglacial sequence yielding a diverse range of plant and animal fossils. Event and lithostratigraphy, palaeomagnetism, amino acid geochronology and biostratigraphy indicate that the artefacts date to the early part of the Brunhes Chron (about 700 kyr ago) and thus represent the earliest unequivocal evidence for human presence north of the Alps.     

Uptake of Pneumocystis carinii mediated by the macrophage mannose receptor

Human exposure to Pneumocystis carinii is common but, in the absence of acquired or genetic dysfunction of either cellular or humoral immunity, exposure rarely leads to illness. Although alveolar macrophages can degrade P. carinii, macrophage receptors involved in P. carinii recognition have not been clearly defined. Characterization of a predominant surface glycoprotein of the high mannose type led us to investigate the role of the macrophage mannose receptor in this process. We report here that binding and uptake of cultured rat P. carinii by human and rat alveolar macrophages is reduced by 90% in the presence of competitive inhibitors of mannose receptor activity and by adherence of alveolar macrophages to mannan-coated surfaces. Further, only those COS cells transfected with the human macrophage mannose receptor complementary DNA that express surface mannose receptors bind and ingest P. carinii. These studies establish that the macrophage mannose receptor is sufficient for uptake of P. carinii and emphasize the role of the alveolar macrophage in first-line host defence against P. carinii.     

Glycogenolysis induced by serotonin in brain: identification of a new class of receptor

Serotonin-containing neurones in brain have been proposed to have a role in the control of physiological mechanisms such as sleep, thermoregulation, pain perception and endocrine secretions as well as in the physiopathology of migraine or depressive illness. One difficulty in testing these possibilities lies in the scarcity of pharmacological agents able to interact selectively with the probably multiple classes of serotonin receptors in the central nervous system. Development of such agents would be facilitated by simple in vitro models in which biological responses to serotonin in mammalian brain could be quantified. Thus a serotonin-sensitive adenylate cyclase has been characterized in rat brain, but the response to serotonin is weak in newborn and practically absent in adult animals. In addition, two pharmacologically distinct classes of serotoninergic binding site have been identified using 3H-serotonin and 3H-spiperone as ligands, but their identification as receptors remains to be established. More recently, serotonin has been shown to stimulate phosphorylation of a neuronal protein in slices from the facial motor nucleus, although the receptors mediating this action were not characterized. We now report that serotonin stimulates glycogen hydrolysis in slices of cerebral cortex, that this action is mediated by a novel class of receptors and that tricyclic antidepressants are among the best competitive antagonists of the indolamine.