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PubMed1996

Histamine augments VCAM-1 expression on IL-4- and TNF-alpha-stimulated human umbilical vein endothelial cells.

Interaction between vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells and CD49d molecules on eosinophils is thought to mediate the selective infiltration of eosinophils into inflamed tissues in allergic disease. IL-4 and TNF-alpha are associated with allergic conditions, and they have been shown to selectively augment VCAM-1 expression on endothelial cells, suggesting that they may be responsible for VCAM-1 expression in allergic disease. We used immunocytochemical staining analysis to examine the effect of chemical mediators, including histamine, leukotrienes and platelet-activating factor (PAF), on VCAM-1 expression in IL-4- and TNF-alpha-stimulated endothelial cells. Histamine, significantly augmented (p < 0.05 to p < 0.01) VCAM-1 expression in both IL-4- and TNF-alpha-stimulated endothelial cells. IL-4 and TNF-alpha were found to have a synergistic effect on endothelial cell VCAM-1 expression, when compared with the effect of stimulation with each of these cytokines separately, and the addition of histamine further increased VCAM-1 expression. This enhancing effect of histamine was inhibited by the presence of mepyramine and thioperamide but not by cimetidine. Another chemical mediator, PAF, failed to induce any increase in VCAM-1 expression, however, leukotrienes augmented it slightly in a narrow range of concentrations. The histamine-induced augmentation of VCAM-1 expression was reflected functionally by many more eosinophils attaching to endothelial cells than to cells stimulated with both cytokines. This attachment of eosinophils was inhibited by the presence of antibody to VCAM-1 and CD49d. Addition of histamine 10 h after stimulation with both cytokines still induced an increase in VCAM-1 expression. In addition, an inhibitor of RNA polymerase, alpha-amanitin, dose-dependently decreased this histamine-induced augmentation of VCAM-1 expression. These findings strongly suggest that histamine upregulates VCAM-1 expression at the transcriptional level through newly generated of mRNA in endothelial cells stimulated with IL-4 and TNF-alpha.

Amanitins↗
PubMed1999

Lipoxygenase products increase monocyte adhesion to human aortic endothelial cells.

The development of atherosclerosis is accelerated in individuals with type 2 diabetes. Adhesion of monocytes to the vascular endothelium is a key initial step in atherogenesis. We have previously shown that monocyte adhesion to human aortic endothelial cells (HAECs) cultured long-term in high-glucose medium (25 mmol/L, 2 passages) is increased compared with cells grown in normal glucose (5 mmol/L). One potential mechanism for increased monocyte adhesion to HAECs under hyperglycemic conditions is via the 12-lipoxygenase (12-LO) pathway. In this study, we demonstrated in HAECs that the major LO metabolite of arachidonic acid was the 12-LO product, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], which was increased severalfold in HAECs cultured under high-glucose conditions. Furthermore, treatment of HAECs with 12(S)-HETE induced monocyte, but not neutrophil, adhesion an average of 3-fold (range of 1.5- to 5-fold) compared with untreated cells (75+/-5 versus 26+/-1 monocytes per field, respectively, P<0.001). Expression of the adhesion molecules vascular cell adhesion molecule-1, E-selectin, and intercellular adhesion molecule-1 was not significantly increased. However, both glucose and 12(S)-HETE induced a 60% increase in HAEC surface expression of connecting segment-1 (ie, CS-1) fibronectin, a ligand for very late-acting antigen-4 (VLA-4). The antibodies used to block monocyte integrin VLA-4 and leukocyte function-related antigen-1, a monocytic counterreceptor for intercellular adhesion molecule-1, inhibited the ability of both 12-LO products and high glucose to induce monocyte adhesion. These results definitively demonstrate for the first time in HAECs that the 12-LO pathway can induce monocyte-endothelial cell interaction and that the effects of glucose may be mediated, at least in part, through this pathway. Thus, these results suggest that the 12-LO pathway may play a role in the increased susceptibility of diabetics to atherosclerosis.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1997

Emigrated rat neutrophils adhere to cardiac myocytes via alpha 4 integrin.

Previous work has shown that neutrophils isolated from whole blood adhere to cardiac-myocytes via CD18 (beta 2 integrin) to cause injury to the heart cells. In vitro, we have found that upon endothelial transmigration, neutrophils can also express alpha 4 beta 1; however, whether this contributes to neutrophil adhesion to parenchymal cells remains entirely unknown. Unstimulated and tumor necrosis factor-alpha-stimulated rat cardiac myocytes adherent to gelatin-coated coverslips supported N-formyl-Met-Leu-Phe (fMLP)-induced neutrophil (isolated from whole blood) adhesion entirely via CD18 (blocked with monoclonal antibody [mAb] WT-3). Emigrated neutrophils spontaneously adhered to cardiac myocytes also entirely via CD18. However, if fMLP was used to restimulate emigrated neutrophils, the adhesion to cardiac myocytes was entirely independent of CD18. Although an anti-alpha 4 integrin antibody (mAb TA-2) alone did not reduce the emigrated neutrophil-myocyte interaction, dual administration of TA-2 and WT-3 reduced adhesion by 81%. alpha 4 integrin was expressed in small amounts on the surface of circulating neutrophils, increased following transmigration, and then increased > 5-fold after restimulation of these emigrated neutrophils. In the presence of the anti-CD18 antibody, a fibronectin fragment (FN-40) but not a vascular cell adhesion molecule-1 antibody (mAb 5F10) inhibitied neutrophil-myocyte interactions by 80%. Similar results were seen when the rat chemokine CINC-gro was used instead of fMLP, suggesting that the alpha 4-dependent adhesion was not specific to fMLP. These data demonstrate that alpha 4 integrin can be physiologically induced to increase in number and avidity after neutrophil emigration and that this adhesion molecule can cause firm adhesion to fibronectin on parenchymal cells, including rat cardiac myocytes.

Animals↗
PubMed2000

Direct observations in vivo on the role of endothelial selectins and alpha(4) integrin in cytokine-induced leukocyte-endothelium interactions in the mouse aorta.

The molecular mechanisms underlying leukocyte recruitment in large arteries have been extensively studied using histological techniques on fixed tissues. However, there are no reports that address the dynamics of leukocyte recruitment in large arteries in vivo. We developed an intravital microscopy technique for direct observation of leukocyte-endothelium interactions in the mouse aorta. Circulating leukocytes were labeled intravasally with rhodamine 6G and microscopically visualized within the aorta, allowing direct analysis of leukocyte rolling and adhesion. In untreated vessels, leukocyte-endothelium interactions were virtually absent. However, local pretreatment with cytokines interleukin-1beta and tumor necrosis factor-alpha induced clear-cut leukocyte rolling and adhesion, compatible with normal blood flow and wall shear rate. High shear decreased rolling leukocyte flux and increased leukocyte rolling velocity, thus decreasing the tendency for firm adhesion. Leukocyte rolling was almost abolished by an antibody blocking the function of P-selectin, whereas function-blocking antibodies against E-selectin and the alpha(4)-integrin subunit decreased rolling leukocyte flux to 51+/-34% (mean +/- SD) and 59+/-11% of the value before antibody treatment, respectively. In addition, inhibition of E-selectin function, but not of alpha(4) integrin, resulted in increased leukocyte rolling velocity (from 48+/-32 to 71+/-32 microm per second). Taken together, we introduce the first model for direct studies of leukocyte-endothelium interactions in a large artery in vivo and demonstrate cytokine-induced shear-sensitive leukocyte rolling that is critically dependent on P-selectin and modulated by E-selectin and alpha(4) integrin.

Animals↗
PubMed2002

Activation of leukocytes during the uteroplacental passage in preeclampsia.

Endothelial dysfunction and inflammation appear to play a major role in the pathogenesis of preeclampsia. We hypothesize that a chronic inflammation in the decidua and placenta during preeclampsia may lead to a local leukocyte activation in this compartment. Venous blood was sampled simultaneously from antecubital and uterine veins during cesarean sections in 30 women with preeclampsia, 29 with uncomplicated pregnancies, and from 17 nonpregnant women. The expression of adhesion molecules and complement-related markers on neutrophils and monocytes was analyzed by flow cytometry. In patients with preeclampsia, neutrophil expression of the integrins CD11a, CD11b, and CD11c and of the complement related markers CD35 and CD59 was significantly higher in samples from uterine than from antecubital veins. No differences were found in nonpregnant women. On monocytes the expression of the Sialyl Lewis(x) antigen, the integrins CD11a, CD11c, and CD49d, and the complement-related markers CD46 and CD59 was higher in samples from uterine than from antecubital veins during preeclampsia, but not in uncomplicated pregnancies, whereas in nonpregnant women CD31 was decreased. Our findings suggest activation of neutrophils and monocytes taking place during the uteroplacental passage in preeclamptic, but not in normal pregnancies. Such a local inflammatory response involving enhanced leukocyte/endothelial interaction may contribute to the pathogenesis of this disorder.

Adult↗
PubMed1998

Granulocyte macrophage colony-stimulating factor augments ICAM-1 and VCAM-1 activation of eosinophil function.

Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are members of the immunoglobulin superfamily adhesion molecules on vascular endothelium and important in the development of eosinophil (EOS) accumulation in allergic inflammation. To define the role of these adhesion proteins in EOS inflammation, peripheral blood EOS from allergic donors were incubated in either buffer (control)-, recombinant human (rh)-VCAM-1-, or rh-ICAM-1-coated plates, and the effects of these adhesion proteins on EOS effector functions were determined. VCAM-1 induced spontaneous EOS adhesion whereas EOS adhesion to ICAM-1 required a second signal, such as granulocyte macrophage colony-stimulating factor (GM-CSF). Although only VCAM-1 stimulated EOS superoxide anion (O2-) generation, the addition of GM-CSF (100 pM) to the reactions resulted in a greater and equivalent production of O2- with VCAM-1 and ICAM-1. In the presence of GM-CSF, ICAM-1 and VCAM-1 caused significant release of EOS-derived neurotoxin (EDN). Moreover, only ICAM-1 (no GM-CSF) promoted calcium ionophore A23187 (0.2 microM)-induced EOS leukotriene C4 (LTC4). Enhanced O2- generation, EDN release, and LTC4 generation observed with ICAM-1 and VCAM-1 were significantly inhibited by anti-beta2-integrin antibody. These results suggest that ICAM-1 and VCAM-1 are important in determining the eventual function of airway EOS.

Adult↗
PubMed2000

Glucocorticoid receptor activation reduces CD11b and CD49d levels on murine eosinophils: characterization and functional relevance.

In vitro incubation of mouse blood eosinophils with dexamethasone (DEX) resulted in concentration- and time-dependent reduction in CD11b and CD49d cell-surface expression as detected by flow cytometry. This inhibitory effect ranged between 20 and 40% for both integrins, and it was not related to alteration of cell survival. DEX was maximally effective at 1 microM, and it was prevented by coaddition of the glucocorticoid receptor antagonist RU486 (mifepristone; 10 microM). Budesonide, hydrocortisone, and prednisolone, but not the sex steroids testosterone and progesterone, reduced CD11b and CD49d cell-surface expression to a similar extent. Subchronic treatment of mice with 1 mg/kg DEX again reduced both CD11b and CD49d expression on circulating eosinophils, without alterations in CD11b messenger RNA expression as assessed by polymerase chain reaction analysis. In contrast, membrane but not intracellular protein expression of either CD11b or CD49d was inhibited by eosinophil incubation with DEX in vitro; thus, an interference with exportation of these adhesion molecules to the cell surface is proposed as the mechanism of action of the glucocorticoid. Finally, steroid effects on integrin expression were linked to a reduced eosinophil function as indicated by a lower degree of cell chemotaxis after incubation with DEX, an effect which was again prevented by 10 microM RU486. These observations may explain part of the therapeutic efficacy displayed by glucocorticoid hormones in the clinical control of tissue eosinophilia in allergic disease conditions.

Animals↗
PubMed2003

Interleukin-3, -5, and granulocyte macrophage colony-stimulating factor-induced adhesion molecule expression on eosinophils by p38 mitogen-activated protein kinase and nuclear factor-[kappa] B.

We investigated the intracellular signaling mechanisms for cytokine interleukin (IL)-3, IL-5, or granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced expression of adhesion molecules including very late antigen 4 (CD49 d), macrophage antigen-1 (CD11b), leukocyte function-associated antigen-1 (CD11a/CD18), intercellular adhesion molecule (ICAM)-1, and ICAM-3 on eosinophils. The expression of adhesion molecules and nuclear factor (NF)-kappaB pathway was measured by flow cytometry and cDNA expression array, respectively. The phosphorylation of inhibitor kappaB-alpha and p38 mitogen-activated protein kinase (MAPK) was detected by Western blot, whereas NF-kappaB activity was measured by electrophoretic mobility shift assay. IL-3, IL-5, and GM-CSF could enhance p38 MAPK and NF-kappaB activity and induce ICAM-1, CD11b, and CD18 expressions on eosinophils. They could suppress ICAM-3 expression, but had no effect on CD49 d expression. Either SB 203580 or MG-132 was able to offset the cytokine-induced expression of ICAM-1. Only SB 203580 could reverse the effect on CD11b, CD18, and ICAM-3 expressions. Therefore, the expression of ICAM-1 might involve both p38 MAPK and NF-kappaB activities, whereas the regulation of CD11b, CD18, and ICAM-3 expressions might be mediated through p38 MAPK but not NF-kappaB. These cytokines therefore play a crucial role, via the p38 MAPK and NF-kappaB pathways, in the expression of important adhesion molecules on eosinophils in allergic inflammation.

CD11b Antigen↗
PubMed2006

Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect.

The regulation of HSC proliferation and engraftment of the BM is an important but poorly understood process, particularly during ontogeny. Here we show that in mice, all HSCs are cycling until 3 weeks after birth. Then, within 1 week, most became quiescent. Prior to 4 weeks of age, the proliferating HSCs with long-term multilineage repopulating activity displayed an engraftment defect when transiting S/G2/M. During these cell cycle phases, their expression of CXC chemokine ligand 12 (CXCL12; also referred to as stromal cell-derived factor 1 [SDF-1]) transiently increased. The defective engrafting activity of HSCs in S/G2/M was reversed when cells were allowed to progress into G1 prior to injection or when the hosts (but not the cells) were pretreated with a CXCL12 antagonist. Interestingly, the enhancing effect of CXCL12 antagonist pretreatment was exclusive to transplants of long-term multilineage repopulating HSCs in S/G2/M. These results demonstrate what we believe to be a new HSC regulatory checkpoint during development. They also suggest an ability of HSCs to express CXCL12 in a fashion that changes with cell cycle progression and is associated with a defective engraftment that can be overcome by in vivo administration of a CXCL12 antagonist.

Animals↗
PubMed2003

Rapid recruitment of inflammatory monocytes is independent of neutrophil migration.

Early neutrophil entry into an inflammatory site is thought to mediate a chemokine switch, inducing subsequent monocyte recruitment through the regulation of monocyte chemoattractant protein-1 (MCP-1) release. As the murine monocyte is poorly characterized and difficult to identify, there has been little examination of either its early recruitment in inflammatory models or of the factors that influence its early migration. The phenotyping of rapidly recruited inflammatory leukocytes with 7/4 and Gr-1 monoclonal antibodies (mAbs) identifies 2 distinct populations, which we characterize as murine monocytes and neutrophils. Monocytes migrate in the first 2 hours of inflammation making use of alpha4beta1 but not of Mac-1 or lymphocyte function-associated antigen-1 (LFA-1) integrins. Early migration is dependent on MCP-1, but neither MCP-1 release nor monocyte recruitment is affected by the reduced neutrophil migration seen in LFA-1-/- mice. Endogenous peritoneal macrophages and mesothelial cells lining the peritoneum contain MCP-1, which is released following thioglycollate stimulation. The murine monocyte therefore responds rapidly to chemokines produced in situ by tissue cells at the site of inflammation with no requirement for prior influx of neutrophils.

Animals↗
PubMed2004

Direct evidence of leukocyte adhesion in arterioles by angiotensin II.

Although leukocytes adhere in arteries in various vascular diseases, to date no endogenous proinflammatory molecule has been identified to initiate leukocyte adhesion in the arterial vasculature. This study was undertaken to assess angiotensin II (Ang II)-induced leukocyte adhesion in arterioles in vivo. Rats received intraperitoneal injections of Ang II; 4 hours later, leukocyte recruitment in mesenteric microcirculation was examined using intravital microscopy. Ang II (1 nM) produced significant arteriolar leukocyte adhesion of mononuclear cells. Using function-blocking monoclonal antibodies (mAbs) against different rat cell adhesion molecules (CAMs), we discovered that this effect was dependent on P-selectin and beta(2)-integrin. In postcapillary venules, Ang II also induced leukocyte infiltration, which was reduced by P-selectin and by beta(2)- and alpha(4)-integrin blockade. Interestingly, neutrophils were the primary cells recruited in venules. Although beta(2)-integrin expression in peripheral leukocytes of Ang II-treated animals was not altered, it was increased in peritoneal cells. Immunohistochemical studies revealed increased P-selectin, E-selectin, intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) expression in response to Ang II in arterioles and venules. These findings provide the first evidence that Ang II causes leukocyte adhesion to the arterial endothelium in vivo at physiologically relevant doses. Therefore, Ang II may be a key molecule in cardiovascular diseases in which leukocyte adhesion to the arteries is a characteristic feature.

Angiotensin II↗
PubMed2004

The CXC chemokine MIP-2 stimulates neutrophil mobilization from the rat bone marrow in a CD49d-dependent manner.

The acute release of neutrophils from the bone marrow is a critical step in their trafficking to sites of inflammation. This process is stimulated by systemically acting inflammatory mediators, such as the CXC chemokines. In this study we have used a novel in situ perfusion system of the rat femoral bone marrow to directly investigate the role of specific adhesion molecules in chemokine-stimulated neutrophil mobilization. We show here that neutrophils mobilized in response to rat macrophage inflammatory protein-2 (MIP-2) shed L-selectin and expressed significantly higher levels of CD11b and CD49d. However, inhibition of L-selectin sheddase activity with KD-IX-73-4 had no effect on the number of neutrophils mobilized in response to rat MIP-2. Blockade of CD18, using a neutralizing monoclonal antibody (mAb), did not inhibit neutrophil mobilization but unexpectedly increased the rate and number of neutrophils released from the bone marrow in response to chemokine, suggesting that CD18 could play a role in neutrophil retention within the bone marrow. Blockade of CD49d using either a selective mAb or a specific antagonist resulted in a dramatic inhibition (> 75%) of the chemokine-stimulated neutrophil mobilization from the bone marrow. These data reveal contrasting roles for CD18 and CD49d in the retention and release of neutrophils from the bone marrow.

Animals↗
PubMed2005

Identification of cutaneous lymphocyte-associated antigen as sialyl 6-sulfo Lewis X, a selectin ligand expressed on a subset of skin-homing helper memory T cells.

We previously identified the carbohydrate determinant sialyl 6-sulfo Lewis X (Le(x)) as the major L-selectin ligand on high endothelial venules of peripheral lymph nodes. In this study, we examined the distribution of the sialyl 6-sulfo Le(x) determinant among peripheral lymphocytes. The determinant was expressed on a subset of helper memory T and NK cells. The helper memory T cells expressing sialyl 6-sulfo Le(x) were CD45RO(bright+) PSGL-1(high+) CCR4+ L-selectin+ CCR7+ but did not express alpha4beta7 integrin or CCR9, indicating that they were the skin-homing population of central memory T cells. The T-cell subset significantly expressed mRNA for 6-sulfotransferase HEC-GlcNAc6ST and fucosyltransferase Fuc-T VII, responsible for the synthesis of sialyl 6-sulfo Le(x). Characteristics of the T-cell population were similar to those previously described for cutaneous lymphocyte-associated antigen (CLA)-positive T cells defined by the HECA-452 or 2F3 antibody. The binding of the T-cell subset with the specific anti-sialyl 6-sulfo Le(x) antibody G152 was almost completely abrogated by HECA-452 or 2F3. Binding of recombinant E-, P-, and L-selectins to the T-cell subset was significantly inhibited by G152 and by HECA-452 antibodies. We propose that CLA, which is expressed without any activation stimuli on peripheral skin-homing helper memory T cells in healthy persons, is at least partly the sialyl 6-sulfo Le(x) determinant.

Antibodies, Monoclonal↗
PubMed2002

Early inflammatory markers in elicitation of allergic contact dermatitis.

BACKGROUND: Allergic Contact Dermatitis (ACD) is regarded as a T-cell-mediated delayed-type hypersensitivity reaction. We studied the kinetics of the expression of CS-1 fibronectin, thymus and activation-regulated chemokine (CCL17/ TARC) and different chemokine receptors (CR) in skin biopsies from individuals suffering from back problems, with the antigen responsible of their contact dermatitis and an irrelevant antigen. METHODS: Samples were taken at 2, 10, and 48 hours for histological and immunohistochemical studies using monoclonal antibodies against human CS-1 fibronectin, CCL17, CD3, CD68, CD49d, CXCR3, CCR5, and CCR3. RESULTS: At positive antigen stimulated sites there was an early expression of CS-1 fibronectin (2 hours), followed by CCL17 and a later accumulation of alplha4/beta1+ (CD49d), CD3+, CD68+, CXCR3+ and CCR5+ mononuclear cells. At 48 hours, approximately 59 % of infiltrating cells were CXCR3+, 42% CCR5+, and only 14 % CCR3+. CONCLUSIONS: These results showed for the first time a very early expression of CS-1 fibronectin which preceded production of CCL17 in blood endothelial cells (BCEs) from patients' skin with ACD. The role of these molecules in recruitment of monocytes and effector T cells in ACD is discussed.

Adult↗
PubMed2003

P-selectin mediates IL-13-induced eosinophil transmigration but not eotaxin generation in vivo: a comparative study with IL-4-elicited responses.

The study investigated the role of P-selectin in the responses of eosinophil transmigration and eotaxin generation in vivo elicited by interleukin (IL)-13, as compared with IL-4. Two murine models of leukocyte transmigration were used, migration into cytokine-stimulated peritoneal cavities and through stimulated cremasteric venules, as observed by intravital microscopy. In mice lacking P-selectin, eosinophil infiltration elicited by the cytokines in the peritonitis model was totally inhibited. In the cremaster muscle, however, although spontaneous leukocyte-rolling flux and stimulated leukocyte firm adhesion were inhibited by approximately 97% and approximately 48%, respectively, stimulated transmigration was unaffected. However, IL-13-induced leukocyte transmigration was totally blocked in P-selectin-deficient mice treated with an anti-alpha(4) integrin monoclonal antibody (mAb; PS/2). In comparison, treatment of wild-type mice with the anti-alpha(4) integrin mAb resulted in only partial suppression of IL-13-induced leukocyte transmigration. Significant levels of eotaxin were detected in response to IL-13/IL-4 in both tissues in P-selectin-deficient animals. In conclusion, the regulatory role of P-selectin in leukocyte transmigration elicited by IL-13 appears to be tissue-specific, a phenomenon that is independent of the ability of the cytokine to stimulate eotaxin generation.

Animals↗
PubMed2005

Cellular and molecular mechanisms of coronary vessel development.

Development of coronary vessels is a complex process in developmental biology and it may have clinical implications. Although coronary vessels develop as a form of vasculogenesis followed by angiogenesis, the cells of the entire coronary system do not arise from the developing heart. The key events of the coronary system formation include the generation of primordium and proepicardial organ; formation of epicardium; generation of subepicardial mesenchymal cells, and the formation, remodeling and maturation of the final vascular plexus. These events represent a complex regulation of the cell fate determination, cellular migration, epicardial/ mesenchymal transformation, and patterning of vasculatures. Recent studies suggest that several transcription factors, adhesion molecules, growth factors and signaling molecules play essential roles in these events. This article reviews the literature on the development of coronary vessels, and discusses current advances and controversies of molecular and cellular mechanisms, thereby directing future investigations.

Acetyltransferases↗
PubMed1999

A safety and pharmacokinetic study of intravenous natalizumab in patients with MS.

A phase 1, randomized, placebo-controlled, five-level dose escalation safety and tolerability and pharmacokinetic study of a single IV dose of natalizumab was performed. Doses of 0.03 to 3.0 mg/kg natalizumab or placebo were studied in 28 stable relapsing-remitting or secondary-progressive MS. All doses were safe and well tolerated in MS. Serum concentrations of natalizumab are detectable for 3 to 8 weeks after a single 1- or 3-mg/kg IV dose and justify controlled efficacy studies.

Adult↗
PubMed1995

Defective development of the embryonic and extraembryonic circulatory systems in vascular cell adhesion molecule (VCAM-1) deficient mice.

VCAM-1 is a cytokine-inducible cell surface protein capable of mediating adhesion to leukocytes expressing alpha 4 integrins. Mice deficient in VCAM-1 expression were produced by targeted homologous recombination in ES cells. VCAM-1-deficient embryos were not viable and exhibited either of two distinct phenotypes. Approximately half of the embryos died before embryonic day 11.5 and exhibited a severe defect in placental development in which the allantois failed to fuse with the chorion. The remaining VCAM-1-deficient embryos survived to embryonic day 11.5-12.5 and displayed several abnormalities in their developing hearts including a reduction of the compact layer of the ventricular myocardium and intraventricular septum. The hearts also contained significant amounts of blood in the pericardial space and lacked an epicardium. alpha 4 and VCAM-1 were found to be expressed in wild-type embryos in a reciprocal fashion in the chorion and allantois and in the epicardium and the underlying myocardium, although VCAM-1 was expressed in the intraventricular septum in the absence of adjacent alpha 4-expressing cells. These data suggest important roles for VCAM-1 and alpha 4 in the development of the placenta and the heart.

Allantois↗