PubMed Health⌕ Search

Biomedical subjects

R S Cotran

Publications and source records attributed to R S Cotran.

At least 19 recordsLinked to original sources
PubMed1992

Effects of tumor necrosis factor, lipopolysaccharide, and IL-4 on the expression of vascular cell adhesion molecule-1 in vivo. Correlation with CD3+ T cell infiltration.

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.

Animals↗
PubMed1992

Expression of vascular cell adhesion molecule-1 in human renal allografts.

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)

Acute Disease↗
PubMed1991

Immunologic interactions of T lymphocytes with vascular endothelium.

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.

Antigen-Presenting Cells↗
PubMed1991

Expression of endothelial-leukocyte adhesion molecule-1 in elicited late phase allergic reactions.

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.

Cell Adhesion↗
PubMed1991

Recruitment of neutrophils in the local endotoxin response: association with de novo endothelial expression of endothelial leukocyte adhesion molecule-1.

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.

Animals↗
PubMed1991

Expression of endothelial leukocyte adhesion molecule-1 in septic but not traumatic/hypovolemic shock in the baboon.

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.

Animals↗
PubMed1990

The potential roles of vascular endothelium in immune reactions.

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.

Antigen-Presenting Cells↗
PubMed1990

Cytokine-endothelial interactions in inflammation, immunity, and vascular injury.

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.

Animals↗
PubMed1989

Endothelial cell activation and high interleukin-1 secretion in the pathogenesis of acute Kawasaki disease.

To investigate the pathogenesis of Kawasaki disease, the effects of intravenous gammaglobulin treatment on circulating cytotoxic antibodies against endothelial cells, in-situ endothelial cell activation, and cytokine production and action were examined. Gammaglobulin treatment did not reduce cytotoxic antibody activity against endothelial cells in six patients tested. Expression of endothelial cell activation antigens (endothelial-leucocyte adhesion molecule-1 [ELAM-1] and intercellular adhesion molecule-1) was detected by means of immunoperoxidase staining in skin biopsy samples from five patients before treatment. Samples were obtained immediately after treatment from six patients; there was no endothelial cell activation in four and the two with persistent activation had persistent fever and mucocutaneous symptoms. Peripheral blood mononuclear cells from ten of sixteen acute Kawasaki disease patients spontaneously secreted high levels of interleukin-1 (IL-1). IL-1 secretion remained high in four gammaglobulin-treated patients in whom coronary artery abnormalities developed but fell to normal in six treated patients who had no coronary artery abnormalities. In cell culture, gamma globulin did not inhibit endothelial cell expression of ELAM-1 in response to IL-1 or tumour necrosis factor. The association between improvement of clinical symptoms and the reduction of cytokine secretion and reversal of endothelial cell activation supports a role for immune-mediated injury to cytokine-induced endothelial cell antigens in the pathogenesis of this disorder.

Antigens, Surface↗
PubMed1989

Tumor necrosis factor and interferon-gamma induce distinct patterns of endothelial activation and associated leukocyte accumulation in skin of Papio anubis.

Recombinant human interferon (IFN)-gamma (2 X 10(4) or 2 X 10(5) U), tumor necrosis factor (TNF, 10(4) or 10(5) U), or both were injected intracutaneously into baboons (Papio anubis), and biopsies were examined at various intervals for evidence of altered endothelial cell antigen expression, endothelial morphology, and leukocyte infiltration. IFN-gamma induced increased binding of anti-HLA-DP mAb by 24 hours and a mild-to-moderate accumulation of mononuclear cells. TNF induced increased binding of anti-endothelial leukocyte adhesion molecule (ELAM)-1 mAb by 2 hours that was associated with polymorphonuclear leukocyte accumulation, and increased binding of anti-intercellular adhesion molecule (ICAM)-1 mAb by 9 hours that was associated with the onset of progressive mononuclear leukocyte accumulation. TNF also caused endothelial cell hypertrophy and increased vascular permeability. The combination of IFN-gamma and TNF induced a set of changes that qualitatively resemble those of a delayed hypersensitivity reaction to simian agent 8 envelope antigen. These findings are consistent with the concept that cytokine-activated endothelium plays an important role in the adhesion and subsequent extravasation of leukocytes during immune inflammation.

Animals↗
PubMed1988

Endothelial activation during interleukin 2 immunotherapy. A possible mechanism for the vascular leak syndrome.

A major sequela of immunotherapy with interleukin 2 (IL-2) is development of a vascular leak syndrome. The pathogenesis of this toxic effect is not known. We have examined pre- and post-treatment skin biopsies from 14 patients undergoing systemic administration of IL-2 for evidence of endothelial cell activation. Specifically, we have used the immunoperoxidase technique to detect the expression of three different activation antigens: endothelial-leukocyte adhesion molecule 1, detected with monoclonal antibody H4/18; intercellular adhesion molecule 1, detected with antibody RR1/1; and histocompatibility leukocyte antigen-DQ, detected with antibody Leu 10. Each of these antigens may be induced on cultured endothelial cells by various cytokines (although not by IL-2) and is expressed during endothelial cell activation in vivo at sites of delayed hypersensitivity and other immune responses. Pretreatment biopsies from each patient showed no endothelial expression of endothelial-leukocyte adhesion molecule 1 and only weak to moderate expression of intercellular adhesion molecule 1 and histocompatibility leukocyte antigen-DQ (except for one specimen unreactive with Leu 10). After 5 days of treatment, every patient showed marked endothelial expression of all three antigens (except for the same patient who remained unreactive with Leu 10). Endothelial-leukocyte adhesion molecule-1 expression was confined to postcapillary venular endothelium whereas intercellular adhesion molecule-1 and Leu 10 also were expressed on stromal cells and mononuclear cells. Thus, we conclude that i.v. administration of IL-2 leads to endothelial cell activation. Because IL-2 fails to induce the same antigens on cultured endothelial cells, we infer that IL-2 acts in vivo by inducing the production of other cytokines (e.g., interleukin 1, tumor necrosis factor, lymphotoxin, and interferon-gamma). Finally, since endothelial cell activation at sites of cell-mediated immune responses is well known to result in vascular leakiness to macromolecules, we propose that the vascular leak syndrome accompanying IL-2 therapy may arise from widespread inappropriate endothelial cell activation.

Antigens, Surface↗
PubMed1988

Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation.

Cachexia is a potentially lethal syndrome of unknown etiology characterized by anorexia, weight loss, and protein wasting that frequently complicates the treatment of chronic inflammation and cancer. Cachectin/TNF was isolated during the search for a humoral mediator of cachexia and found to stimulate the breakdown of energy stores from adipocytes and myocytes in vitro, but the chronic effects of the monokine in vivo are not known. Sublethal doses of recombinant human cachectin administered twice daily for 7-10 d caused cachexia in rats, as evidenced by reduced food intake, weight loss, and depletion of whole-body lipid and protein stores. Significant anemia is also observed and found to be the result of decreased red blood cell mass, not expanded plasma volume. Leukocytosis and histopathological evidence of tissue injury and inflammation are observed in several organs, including omentum, liver, spleen, and heart. These data suggests that the exposure of the normal host to cachectin is capable of inducing a pathophysiological syndrome of cachexia, anemia, and inflammation similar to that observed during inflammatory states or malignancy.

Anemia↗