BACKGROUND:Several lines of evidence suggest that cellular immune mechanisms contribute to glomerulonephritis.METHODS:The roles of alphabeta and gammadelta T cells in the pathogenesis of glomerulonephritis were investigated in a model of nephrotoxic nephritis in mice deficient in either T-cell population [T-cell receptor (TCR)beta and TCRdelta knockout mice]. The model, induced by the injection of rabbit anti-mouse glomerular basement membrane antibody, is characterized by the development of proteinuria and glomerular damage over a 21-day observation period in wild-type mice.RESULTS:Mice deficient in either alphabeta or gammadelta T cells developed minimal proteinuria and glomerular lesions and had a significant reduction in macrophage accumulation compared with wild-type mice. In gammadelta T-cell-deficient mice, circulating levels and glomerular deposition of autologous IgG were comparable to wild-type levels, while alphabeta T-cell-deficient mice had no autologous IgG production. Autologous antibody production was not required for the development of glomerulonephritis since mice that lack IgG and B cells (micro-chain-/-) developed similar proteinuria to that observed in wild-type mice.CONCLUSIONS:These studies suggest a proinflammatory role for both alphabeta and gammadelta T cells in glomerular injury, independent of the humoral response. This is the first demonstration, to our knowledge, that both T-cell subsets contribute to the progression of a disease, and it suggests that complex regulatory interactions between alphabeta and gammadelta T cells play a role in glomerular injury.

P-selectin is a leukocyte adhesion receptor present in endothelial cells and platelets. We examined the role of P-selectin in the autologous phase of an accelerated model of anti-glomerular basement membrane (GBM) glomerulonephritis using P-selectin-deficient mice and chimeric mice expressing P-selectin only in platelets or endothelial cells. P-selectin-deficient mice exhibited more severe glomerular damage with increased interstitial mononuclear leukocytic infiltrates, and had significantly increased proteinuria and mortality when compared to wild-type mice. P-selectin on the endothelium was predominantly responsible for protection from the exacerbated disease, because chimeric mice with endothelial P-selectin, and not mice with platelet P-selectin, showed glomerular injury similar to that in wild-type animals. Levels of soluble circulating P-selectin were increased in nephritic wild-type mice and in chimeric mice with endothelial P-selectin, but not platelet P-selectin. Levels of soluble P-selectin, which has been shown to be anti-inflammatory in vitro, were inversely associated with the severity of disease. P-selectin was not expressed in the endothelium of the glomerulus or interstitium. Thus, the protective effect in wild-type mice may be accounted for, in part by soluble P-selectin shed by non-renal endothelial cells, although other endothelial P-selectin-dependent mechanisms cannot be ruled out.

One of the most important events in the reaction to all forms of injury is adhesion of leukocytes to endothelium, a prelude to their emigration into tissues. This process is central to inflammation, atherosclerosis, and immune reactions. Endothelial-leukocyte adhesion is governed largely by the interaction of complementary adhesion molecules on endothelia and leukocytes. The synthesis, surface expression, and avidity of these molecules, are regulated by chemical mediators, particularly chemokines. The most important adhesion molecule pairs are the selectins (E, L and P), the immunoglobulins ICAM-1 and VCAM-1, and the beta 2 and beta 1 integrins (e.g., LFA-1 and VLA-4). In vivo studies in experimental animals and humans have confirmed a role for these molecules in a number of pathological processes, including transplant rejection, septic shock, atherosclerosis, late phase hypersensitivity reactions, immunologically-mediated lung and kidney disease, and reperfusion injury. Besides their importance in understanding pathogenesis, work on adhesion molecules has direct clinical implications in diagnosis and therapy. Current studies suggest that the expression of these adhesion molecules may be a useful marker for active inflammation under certain conditions, and that abrogation of endothelial adhesion by interfering with such molecules may inhibit tissue injury. Mice genetically deficient in adhesion molecules (knock out) have been particularly useful in the study of the role of these molecules in vivo. This lecture will first summarize the state-of the-art on the structure, localization, and distribution of the major adhesion molecules, examine their roles in vivo, in humans and knock-out mice, and point to possible use of the information derived from these studies in diagnosis and therapy.

In this review we discuss (1) the role of the endothelial cell in the initiation of acute and chronic rejection; (2) studies that demonstrate that endothelial cells have the ability to selectively costimulate T cell activation: and (3) the bi-directionality of T cell-endothelial cell interactions in rejection.

We conducted a prospective longitudinal study to determine the clinical significance of endothelial adhesion molecule expression in endomyocardial biopsies from human cardiac allografts, Ten to 18 (mean 13) consecutive allograft biopsies were obtained from 20 serial human transplant recipients over a one-year period, A total of 267 biopsies was examined, The expression of endothelial adhesion molecules intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, as well as the presence of CD3(+) T cell infiltrates was assessed by immunocytochemical staining of frozen sections, Separate specimens taken at the same time were analyzed histologically for ischemic injury or rejection, ICAM-1 - and, to a lesser extent VCAM-1 - was expressed at low levels in normal biopsies, E-selectin was only expressed in 15% of histologically normal biopsy specimens, Ischemic injury noted in the immediate posttransplant period was associated with increased expression of all three adhesion molecules, VCAM-1 expression increased both with the degree of CD3(+) T cell infiltrates (P < 0.001) and with the degree of rejection (P < 0.05). ICAM-1 increased over constitutive levels in association with diffuse CD3(+) infiltrates (P < 0.001) and with rejection (P < 0.05), E-selectin was increased on occasional vessels in association with CD3(+) infiltrates (P < 0.001), but was not associated with active rejection, Increases in E-selectin were most likely to occur in biopsies just prior to rejection episodes (odds ratio 3.3), and were least likely to occur in biopsies following rejection (odds ratio 0.3). ICAM-1, but not VCAM-1, was also elevated in prerejection specimens, VCAM-1 and ICAM-1 declined in postrejection specimens. These data suggest a dynamic pattern in the expression of endothelial cell adhesion molecules during the course of cardiac allograft rejection, This study also suggests that endothelial E-selectin expression may be a useful clinical marker of impending rejection, Finally, inducible VCAM-1 expression may be a helpful adjunct in the diagnosis of ongoing acute rejection, and decreases in its expression may be indicative of successful antirejection therapy.

An increasing body of evidence suggests that endothelial cells as well as parenchymal cells within the kidney express multiple cytokine-inducible leukocyte adhesion molecules. This paper reviews evidence from our own laboratory as well as others on the in vitro induction and function of adhesion molecules in the kidney. We review current data from the literature on the possible role of endothelial cell adhesion molecules in mediating leukocyte infiltration and renal injury in experimental and human transplant rejection and glomerulonephritis. These early studies suggest that leukocyte-endothelial adhesive interactions result in a complex cascade of biological and pathological processes leading to renal injury. Further analysis of such interactions in the kidney will elucidate their specific roles.

The expression of vascular cell adhesion molecule-1 (VCAM-1) in 11 human renal allograft biopsies and 3 normal kidney specimens was investigated by immunocytochemistry. VCAM-1 expression was correlated with the degree of CD3+ T cell infiltration and the clinicopathologic diagnosis of acute rejection. CD3+ infiltrates were seen in all biopsies with rejection, but not in normal biopsies or one with acute tubular necrosis, and were accompanied by CD68+ monocyte/macrophage infiltrates. In normal biopsies, VCAM-1 was present on occasional tubules, where its expression was patchy and restricted to the basolateral surface of cells with slight cytoplasmic staining. The total number of tubules expressing VCAM-1 significantly increased in specimens infiltrated with CD3+ T cells. Moreover, in these infiltrated biopsy specimens, VCAM-1 was present throughout the cytoplasm of tubular cells concentrated on the basolateral surface. VCAM-1 was also observed on vascular endothelial cells where its expression correlated with the degree of CD3+ infiltrate. Mean scores (0 to 3+) for endothelial VCAM-1 expression increased from 0 (CD3+ score, 0) to a mean score of 2.25 in association with CD3+ T cell infiltrates (CD3+ score, 3). Endothelial VCAM-1 was predominantly on vessels in areas of infiltrate, including peritubular capillaries, venules, and arterioles, but was notably absent on glomerular endothelium. VCAM-1 also stained mesangial cells in an occasional CD3+ infiltrated specimen. It was concluded that the expression of VCAM-1 is increased on renal tubules and renovascular endothelium in rejecting renal allografts in association with CD3+ infiltrates.(ABSTRACT TRUNCATED AT 250 WORDS)

We have injected human TNF, LPS, and IL-4 into the skin of baboons to examine regulation of endothelial leukocyte adhesion molecules (ELAM) in vivo and to determine which endothelial adhesion molecules correlate temporally and spatially with cytokine-induced T cell infiltration. The expression of adhesion molecules ELAM-1 (E-selectin), VCAM-1, and ICAM-1 (CD54) were quantified by immunocytochemical staining of frozen sections obtained from skin biopsies; T cell infiltration was measured by immunocytochemical staining of CD3+ T cells in serial sections. We found that injection of TNF causes late (24 to 48 h) T cell infiltration whereas injection of LPS, in doses that do not cause tissue necrosis, does not. The ability of TNF (but not LPS) to recruit T cells correlates with the ability of TNF to cause sustained endothelial cell adhesion molecule expression. Expression of VCAM-1 on post-capillary venules showed the highest degree of spatial localization with infiltrates. IL-4, although not proinflammatory by itself, can cause T cell infiltration in combination with an ineffective dose of TNF. The ability of IL-4 to augment TNF-induced inflammation best correlates with the ability of the combination of IL-4 and TNF to increase endothelial VCAM-1 expression. In contrast, IL-4 does not promote T cell infiltration or endothelial VCAM-1 expression in combination with LPS. In cytokine-injected tissues, VCAM-1 is also expressed on connective tissue cells other than endothelium, including smooth muscle and perineural cells, where it is induced by cytokines in parallel with endothelial VCAM-1. Overall, our data support the hypothesis that endothelial VCAM-1 expression contributes to T cell extravasation at sites of inflammation. Furthermore, we find that IL-4, a product a Ag-activated T cells, can interact with TNF to selectively promote VCAM-1 expression and the development of T cell-rich infiltrates, characteristic of Ag-induced inflammatory reactions.

Endothelium is central to the cellular infiltration that develops during inflammation, and a prominent feature of its involvement is the expression of adhesion molecules for circulating leukocytes. In the present study, we assessed the kinetics of endothelial adhesion molecule expression during the cutaneous endotoxin response in baboons. Immunostained cryostat sections and hematoxylin and eosin-stained paraffin sections of skin biopsies were examined using set scoring systems to provide semiquantitative data on the changes in endothelial phenotype and induced polymorphonuclear leucocyte (PMN) accumulation. Endothelium in control skin did not express endothelial leukocyte adhesion molecule (ELAM)-1 but did show a relatively weak expression of intercellular adhesion molecule (ICAM)-1. By 2 hours after injection of endotoxin (500 mcg of Escherichia coli-derived lipopolysaccharide), a marked expression of ELAM-1 developed that was associated with concurrent extensive adhesion and extravasation of PMN. The ELAM-1 expression subsequently decreased and was virtually absent by 9 hours. Mean scores for endothelial expression of ICAM-1 changed comparatively little over this time course, and mononuclear cell accumulation was minimal. The response to endotoxin differs from that to tumor necrosis factor injection; the latter causes sustained ELAM-1 expression, and delayed but pronounced increases in ICAM-1, with accompanying mononuclear cell extravasation. Thus, local endotoxin administration provides a model of acute inflammation in which PMN accumulation is associated with striking endothelial expression of ELAM-1. In this model, appreciable elevations in ICAM-1 expression are unnecessary for PMN infiltration.

To better understand the events involved in the local migration of inflammatory cells into sites of allergic reactions, we studied expression of the cytokine inducible endothelial cell (EC) neutrophil adhesion molecule, endothelial-leukocyte adhesion molecule (ELAM-1), in sequential skin biopsies from patients with respiratory allergy during the late phase reaction (LPR) between 20 min and until 24 h after intradermal allergen (ragweed or dust mites) injection. In 7 of 7 atopic patients but in only 1 of 4 apparently normal controls, allergen induced appearance of ELAM-1 on EC. ELAM-1 expression occurred concurrently with the development of inflammatory cell infiltrates by 3-4 h after intradermal injection. Saline injected sites in all subjects were negative. Skin organ cultures demonstrated that allergen could produce the same EC changes in vitro whether allergen was injected in vivo 20 min before culture or added during skin culture. These EC changes in organ culture were inhibited by the presence of combined anti-sera to both TNF-alpha and IL-1, but not by antisera to either cytokine alone. We conclude that EC activation occurs in elicited LPR and suggest that cytokine-induced EC activation may play a role in the migration of inflammatory cells into allergic skin reactions. Furthermore, resident cells in the skin rather than infiltrating leukocytes appear to be the source of the cytokines that mediate endothelial activation.

Baboons were subjected to septic or traumatic/hypovolemic shock and their tissues were examined for the de novo expression of endothelial leukocyte adhesion molecule 1 (ELAM-1), using immunohistochemical techniques. In animals with septic shock induced with live Escherichia coli, there was widespread expression of ELAM-1, recognized by monoclonal antibodies H4/18 or ENA-1 in most tissues examined with strong staining in the lung, liver, and kidneys. Endothelial leukocyte adhesion molecule 1 expression was evident in capillaries, venules, small veins, arterioles, and arteries. In contrast, baboons with traumatic/hypovolemic shock had minimal levels of focal ELAM expression in all organs studied. Similarly evidence of neutrophil activation, measured by granulocyte elastase levels in the plasma was much more pronounced in animals with septic shock. The study documents that lipopolysaccharide (LPS)- and cytokine-induced endothelial activation occurs in vivo in septic shock. Much higher levels of ELAM-1 expression and plasma granulocyte-elastase titer in septic shock, as contrasted with traumatic/hypovolemic shock, are consistent with the higher levels of circulating tumor necrosis factor, other cytokines, and LPS in sepsis.

The data presented in this review establish that cultured human endothelial cells have the capacity to present antigens to T cells and to do so in the context of costimulators that lead to effective T cell activation. These activities raise the possibility that venular ECs, at sites of delayed hypersensitivity reactions, could be the primary antigen-presenting cell to circulating memory T cells. This putative role of ECs can explain the rapid rate of initiation of memory responses because ECs are uniquely positioned to have physical access to the pool of circulating memory T cells. Studies also suggest that ECs may present alloantigens to circulating T cells in the context of transplantation, thereby initiating rejection reactions. Nevertheless, we repeat our caveat that these proposed antigen-presenting functions of ECs have not been established in vivo. Cytokine-mediated changes, particularly induction of adhesion molecules and synthesis of lymphocyte-activating cytokines, such as IL-8, provide ECs with the potential to recruit memory T cells to inflammatory sites independent of antigen specificity. Although these functions have also not been rigorously shown to occur in vivo, immunocytochemical studies of experimental and pathological tissues provide significant support for this proposal. Similar adhesive and activating functions of ECs may apply to preferential homing of pre-T cells to thymus and naive T cells to lymph node. We conclude by noting that the weight of evidence reviewed here supports the proposal that the vascular endothelium be considered an integral part of the in vivo immune system.

Cell-mediated immune reactions are initiated and regulated by antigen specific CD4+ helper T cells. However, T cells cannot function independently. In order for a CD4+ T cell to recognize antigen, it must be presented in association with a class II major histocompatibility complex molecule by another cell type and, in order to lead to functional T-cell activation, the antigen presenting cell must also provide costimulatory signals. Once activated, CD4+ T cells function in vivo by secreting cytokines that elicit an inflammatory infiltrate of other cell types that serves to eliminate the source of foreign antigen. In vivo, the development of inflammation requires vascular responses as well as contributions of blood-derived leukocytes. Although several cell types in vitro can present antigen, provide costimulation, and perform actions that contribute to inflammation, vascular endothelial cells may be uniquely important immune accessory cells because they are anatomically uniquely positioned to function in vivo during cell-mediated immune reactions. In this report, we shall review recent data from our laboratories which further characterize the immune accessory functions of endothelial cells.

articleCytokines and endothelial cell biologyJ. S. Pober, and R. S. CotranJ. S. PoberDepartment of Pathology, Brigham and Women's Hospital, Boston,Massachusetts., and R. S. CotranDepartment of Pathology, Brigham and Women's Hospital, Boston,Massachusetts.Published Online:01 Apr 1990https://doi.org/10.1152/physrev.1990.70.2.427MoreSectionsPDF (7 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByRole of metaplasia during gastric regenerationEmma Teal, Martha Dua-Awereh, Sabrina T. 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This paper reviews the evidence that cytokines induce a variety of functional and structural alterations in endothelium and that cytokine-endothelial interactions play important roles in the evolution of inflammatory and immune responses. The effect of cytokines, particularly interleukin-1 and tumor necrosis factor, on leukocyte-endothelial adhesion has led to the discovery of several endothelial adhesion molecules, and the molecular and biological characteristics of these are described. Finally, the review discusses the possible contribution of cytokine-induced activation to vascular injury in such pathological processes as septic shock, the Shwartzman reaction, delayed hypersensitivity, and immune-mediated vasculitis.