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PubMed2004

Growth hormone stimulates the selective trafficking of thymic CD4+CD8- emigrants to peripheral lymphoid organs.

Growth hormone (GH) has been shown to stimulate T cell development. However, its mechanisms of action on the peripheral T cell pool remain unknown. To address this question, intrathymic injection of GH in combination with fluorescein isothiocyanate (FITC) was used to assess the effects of GH on T cell trafficking from the thymus to the periphery. GH promoted a significant increase in the percentage and differential distribution of thymic CD4+CD8-FITC+ cells in secondary lymphoid organs. A significantly higher percentage of CD4+CD8-FITC+ cells was observed in the lymph nodes, while a relative decrease of these cells was found in the spleen. Moreover, we verified that GH treatment resulted in increased numbers of CD62L+CD4+CD8-FITC+ T cells in the lymph nodes, while the same treatment resulted in a decline in the percentage of VLA-6+CD4+CD8-FITC+ T cells in the spleen. Together, these findings suggest that GH is a potent immunoregulatory molecule which selectively stimulates the preferential homing of CD4+CD8- thymic emigrants to the subcutaneous lymph nodes possibly via the differential expression of CD62L and VLA-6.

Animals↗
PubMed2003

Recruitment of Chlamydia pneumoniae-infected macrophages to the carotid artery wall in noninfected, nonatherosclerotic mice.

OBJECTIVE: Monocyte recruitment into the subendothelium is a crucial step in atherogenesis. Chlamydia pneumoniae resides in circulating monocytes and in the atherosclerotic vascular wall. However, the role of C pneumoniae for monocyte recruitment is unknown. The aim of this study was to examine the impact of C pneumoniae on monocyte adhesion and migration. METHODS AND RESULTS: C pneumoniae-infected, fluorescence-labeled mouse macrophages (ANA-1) were injected intravenously into noninfected, healthy mice. In vivo videomicroscopy showed increased rolling and firm adhesion to the carotid artery compared with noninfected macrophages. In vitro, C pneumoniae infection (yielding 25% to 35% infected monocytes) increased adhesion of human monocytes or MonoMac6 cells to human umbilical vein endothelial cells and improved cell migration through endothelial-like ECV604 cells. Cell adhesion was inhibited by antibody blockade of very late antigen-4, lymphocyte function-associated antigen-1, macrophage antigen-1, or urokinase receptor, which were found upregulated or activated on C pneumoniae infection (flow cytometry). In contrast, C trachomatis did not induce monocyte adhesion at comparable infection rates (25% to 35%), indicating a unique activation pathway for C pneumoniae. Polymyxin B did not affect C pneumoniae-induced adhesion, excluding a relevant role of lipopolysaccharide in this process. CONCLUSIONS: These data indicate that C pneumoniae can direct monocytes to predilection sites of nonatherosclerotic vessel walls in vivo by activation of the integrin adhesion receptor system.

Animals↗
PubMed2003

Upregulation of SR-PSOX/CXCL16 and recruitment of CD8+ T cells in cardiac valves during inflammatory valvular heart disease.

OBJECTIVE: SR-PSOX/CXCL16 is a transmembrane chemokine and is implicated in activated CD8+ T cell trafficking. In the present study, we examined the expression pattern of SR-PSOX/CXCL16 in the heart and investigated a potential role of SR-PSOX/CXCL16 in inflammatory valvular heart disease. METHODS AND RESULTS: Initial expression of SR-PSOX/CXCL16 in murine embryos was detected in endothelial cells lining endocardial cushions in the forming heart at E11.5. From mid-gestation to adult, expression of this gene in the heart was exclusively observed in valvular endothelial cells. Examination of SR-PSOX/CXCL16 expression in human cardiac valves demonstrated that SR-PSOX/CXCL16 was strongly expressed in valvular and neocapillary endothelial cells in patients with infective endocarditis. SR-PSOX/CXCL16 expression in neocapillary endothelial cells was also observed in patients with rheumatic and atherosclerotic valvular disease. Moreover, CD8+ T cells were distributed closely to endothelial cells expressing SR-PSOX/CXCL16. In vitro adhesion assays showed that SR-PSOX/CXCL16 induced adhesion of activated CD8+ T cells to vascular cell adhesion molecule-1 (VCAM-1) through very late antigen-4 (VLA-4) activation. Furthermore, SR-PSOX/CXCL16 stimulated interferon-gamma (IFN-gamma) production by CD8+ T cells. CONCLUSIONS: SR-PSOX/CXCL16 may be involved in CD8+ T cell recruitment through VLA-4 activation and stimulation of IFN-gamma production by CD8+ T cells during inflammatory valvular heart disease.

Animals↗
PubMed2004

Intracellular labile iron modulates adhesion of human monocytes to human endothelial cells.

OBJECTIVE: Elevated iron stores and high plasma iron concentration have been linked to an increased risk of atherosclerosis. Iron may thereby affect the interaction of monocytes to endothelium, an initial event in the formation of atherosclerotic plaques. METHODS AND RESULTS: Addition of 10 mumol/L non-transferrin-bound iron to the incubation medium caused a 2-fold increase in monocyte adhesion to human umbilical vein endothelial cells (HUVECs). A concordant increase in the expression of the following adhesion molecules was observed: vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and endothelial selectin on HUVECs as well as very late antigen-4, and lymphocyte function-associated antigen-1 on monocytes. The inclusion of either deferiprone or salicylaldehyde isonicotinoylhydrazone counteracted these effects. Intracellular iron chelation by deferoxamine was completed only after 10 hours of incubation, shown by reversal of iron-quenched intracellular calcein signal, and concurrently the effects of iron were blunted. The membrane-impermeable chelator, diethylenetriamine pentaaceticacid, failed to negate iron effects, even after 48 hours of treatment. Furthermore, only membrane-permeable superoxide or hydroxyl radical scavengers were capable of preventing HUVEC activation by iron. CONCLUSIONS: Non-transferrin-bound iron increases the level of intracellular labile iron, which promotes monocyte recruitment to endothelium and may thereby contribute to the pathogenesis of atherosclerosis. Iron-induced adhesion molecule expression was observed, and this event may involve the production of oxygen radicals.

Cell Adhesion↗
PubMed2004

Neointimal smooth muscle cells display a proinflammatory phenotype resulting in increased leukocyte recruitment mediated by P-selectin and chemokines.

Leukocyte recruitment is crucial for the response to vascular injury in spontaneous and accelerated atherosclerosis. Whereas the mechanisms of leukocyte adhesion to endothelium or matrix-bound platelets have been characterized, less is known about the proadhesive role of smooth muscle cells (SMCs) exposed after endothelial denudation. In laminar flow assays, neointimal rat SMCs (niSMCs) supported a 2.5-fold higher arrest of monocytes and "memory" T lymphocytes than medial SMCs, which was dependent on both P-selectin and VLA-4, as demonstrated by blocking antibodies. The increase in monocyte arrest on niSMCs was triggered by the CXC chemokine GRO-alpha and fractalkine, whereas "memory" T cell arrest was mediated by stromal cell-derived factor (SDF)-1alpha. This functional phenotype was paralleled by a constitutively increased mRNA and surface expression of P-selectin and of relevant chemokines in niSMCs, as assessed by real-time PCR and flow cytometry. The increased expression of P-selectin in niSMCs versus medial SMCs was associated with enhanced NF-kappaB activity, as revealed by immunofluorescence staining for nuclear p65 in vitro. Inhibition of NF-kappaB by adenoviral IkappaBalpha in niSMCs resulted in a marked reduction of increased leukocyte arrest in flow. Furthermore, P-selectin expression by niSMCs in vivo was confirmed in a hypercholesterolemic mouse model of vascular injury by double immunofluorescence and by RT-PCR after laser microdissection. In conclusion, we have identified a NF-kappaB-mediated proinflammatory phenotype of niSMCs that is characterized by increased P-selectin and chemokine expression and thereby effectively supports leukocyte recruitment.

Animals↗
PubMed2006

Rho GTPases and leukocyte adhesion receptor expression and function in endothelial cells.

Rho family GTPases are key signal transducers that regulate cell adhesion and migration and a variety of other cellular responses, including changes in gene expression. In this review, we discuss how Rho GTPases regulate signaling by endothelial cell receptors involved in leukocyte extravasation. First, Rho GTPases affect the expression of some leukocyte adhesion molecules on endothelial cells, such as intracellular adhesion molecule-1 and E-selectin, that can be induced by proinflammatory mediators, hypoxia, or shear stress. Second, Rho GTPases are activated by engagement of several leukocyte adhesion receptors and contribute to both early morphological changes and subsequent alterations in gene expression. Rho GTPases are therefore candidate targets for inhibiting leukocyte transendothelial migration in heart disease and chronic inflammatory disorders.

Animals↗
PubMed2006

CD73/ecto-5'-nucleotidase protects against vascular inflammation and neointima formation.

BACKGROUND: Although CD73/ecto-5'-nucleotidase has been implicated in maintaining vasoprotection, its role in regulating endothelial adhesion molecule or inflammatory monocyte recruitment (eg, in the context of vascular injury) remains to be defined. METHODS AND RESULTS: Compared with wild-type mice, CD73-deficient (CD73(-/-)) mice exhibit increased luminal staining and protein and transcript expression for vascular cell adhesion molecule (VCAM)-1 in carotid arteries. In vitro, aortic endothelial cells (ECs) from CD73(-/-) mice display an upregulation of mRNA and protein expression of VCAM-1, associated with increased nuclear factor (NF)-kappaB activity, as determined by chromatin cross-linking and immunoprecipitation or quantitative p65 binding assays. CD73(-/-) ECs and carotid arteries perfused ex vivo supported increased monocyte arrest under flow conditions, which was mediated by alpha(4beta1) integrin. After wire injury of carotid arteries, CD73 expression and activity were upregulated in wild-type mice, whereas neointimal plaque formation and macrophage content were increased in CD73(-/-) mice versus wild-type mice, concomitant with elevated NF-kappaB activation, luminal VCAM-1 expression, and soluble VCAM-1 concentrations. In contrast, reconstitution of wild-type mice with CD73(-/-) versus CD73(+/+) BM did not significantly exacerbate neointima formation. Treatment with the specific A2A receptor agonist ATL-146e reversed the increased VCAM-1 transcript and protein expression in CD73(-/-) ECs and inhibited monocyte arrest on CD73(-/-) ECs. Continuous infusion of ATL-146e prevented neointima formation in CD73(-/-) mice. CONCLUSIONS: Our data epitomize the importance of vascular CD73 in limiting endothelial activation and monocyte recruitment via generation of adenosine acting through the A2A receptor, providing a molecular basis for therapeutic protection against vascular inflammation and neointimal hyperplasia.

5'-Nucleotidase↗
PubMed2003

A small molecule very late antigen-4 antagonist can inhibit ovalbumin-induced lung inflammation.

A nonpeptidyl small molecule antagonist, compound A, to nonactivated very late antigen-4 (VLA4) was examined in lung inflammation induced by a single dose of ovalbumin challenge. Compound A presented a good pharmacokinetic property, when given intratracheally, and the blood cells from such pharmacokinetic study showed good receptor occupancy of the compound for approximately 8 hours. Compound A was then tested in an ovalbumin-induced airway inflammation model by intranasal or intravenous route of administration. There was a dose-dependent inhibition of eosinophilia in the bronchiolar lavage fluid, when compound A was given intranasally but not when it was given intravenously. For comparison, antibody to VLA4 and another compound, BIO1211, which reacts only with activated VLA4, were examined in this system. Immunohistochemical analyses of the lung tissue substantiated the findings in the bronchiolar lavage fluid. Specific staining of the major basic protein of eosinophils showed peribronchiolar infiltration of eosinophils. Some of these eosinophils were also positive for nitrotyrosine, suggesting activation of eosinophils in the lung interstitium. There was deposition of major basic protein and nitrotyrosine at the base of the perivascular endothelium, indicative of degranulation of eosinophils in the area. After intranasal treatment with compound A, eosinophils in the lungs and their activation products were substantially decreased, documenting its effectiveness in inhibiting lung inflammation.

Administration, Inhalation↗
PubMed2003

Effect of heparin II domain of fibronectin on aqueous outflow in cultured anterior segments of human eyes.

PURPOSE: To determine whether an integrin/syndecan-binding domain of fibronectin, called the heparin II (Hep II) domain, affects outflow facility in the human eye. METHODS: Anterior segments of human eyes were placed in perfusion organ culture. One eye of each pair received the Hep II domain, and the fellow eye received DMEM or a heat-denatured Hep II domain. The Hep II domain was produced as a recombinant glutathione S-transferase (GST)-fusion protein. Microscopic changes were assessed. RESULTS: Outflow facility in anterior segments treated with Hep II domain increased by 93% compared with that in anterior segments treated with DMEM. In contrast, facility in anterior segments treated with the heat-denatured Hep II domain showed very little change. Outflow facility remained high during Hep II domain perfusion and returned to baseline after removal of the protein. Electron microscopy revealed disruptions in the endothelial lining of Schlemm's canal in anterior segments fixed during maximum effect and in anterior segments after facility had returned to baseline. Scattered disruptions of canal cells were noted in control anterior segments. Trabecular cells in other regions looked normal. Major changes in the extracellular matrix of the juxtacanalicular tissue were not observed. Repeated doses of the Hep II domain administered after facility returned to baseline increased facility in two of three anterior segments. CONCLUSIONS: The Hep II domain of fibronectin increases outflow facility in the human anterior segment. This suggests that fibronectin-mediated interactions may have a role in modulating aqueous hydrodynamics. Such interactions may represent avenues of novel therapeutic interventions for glaucoma.

Aged↗
PubMed2005

Administration of a peptide inhibitor of alpha4-integrin inhibits the development of experimental autoimmune uveitis.

PURPOSE: Recruitment of lymphocytes into the retina and to the vitreous during the development of experimental autoimmune uveitis (EAU) is governed by factors such as the state of activation of inflammatory cells and the repertoire of adhesion molecules expressed by the local vascular endothelia. alpha4 Integrins and their receptors play an important role during homing of cells to the inflammatory site. In the present study, the effect of alpha4-integrin inhibitor on the development of EAU was investigated. METHODS: EAU was induced either by immunizing B10.RIII mice with the 161-180 peptide or by adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP)-specific uveitogenic T cells. Animals were treated with an active peptide inhibitor (alpha4-api) or a peptide control at different time points after induction of disease. EAU was evaluated by histology 21 to 49 days after immunization. Antigen-specific cell proliferation was evaluated by thymidine incorporation. Cytokine synthesis in culture supernatants and anti-IRBP-specific serum IgG1 and IgG2a were evaluated by ELISA. Delayed-type hypersensitivity was evaluated by ear challenge 2 days before the termination of the experiment. RESULTS: Treatment with alpha4-api had a significant ameliorating effect on EAU. The anti-IRBP antibody response and cellular proliferation were not affected by the treatment, whereas delayed-type hypersensitivity was significantly diminished. Cytokine synthesis was not changed by treatment, except for a decrease in IL-10 levels. CONCLUSIONS: The results show that small-molecule inhibitors of alpha4-integrins can act therapeutically in EAU, possibly by interfering with cell adhesion events involved in the development of the disease.

Adoptive Transfer↗
PubMed2006

Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis.

Recent evidence has indicated that leptin, an adipocyte-secreted hormone belonging to the helical cytokine family, significantly influences immune and autoimmune responses. We investigate here the mechanisms by which in vivo abrogation of leptin effects protects SJL/J mice from proteolipid protein peptide PLP(139-151)-induced EAE, an animal model of MS. Blockade of leptin with anti-leptin Abs or with a soluble mouse leptin receptor chimera (ObR:Fc), either before or after onset of EAE, improved clinical score, slowed disease progression, reduced disease relapses, inhibited PLP(139-151)-specific T cell proliferation, and switched cytokine secretion toward a Th2/regulatory profile. This was also confirmed by induction of forkhead box p3 (Foxp3) expression in CD4 T cells in leptin-neutralized mice. Importantly, anti-leptin treatment induced a failure to downmodulate the cyclin-dependent kinase inhibitor p27 (p27) in autoreactive CD4 T cells. These effects were associated with increased tyrosine phosphorylation of both ERK1/2 and STAT6. Taken together, our data provide what we believe is a new molecular basis for leptin antagonism in EAE and envision novel strategies of leptin-based molecular targeting in the disease.

Animals↗
PubMed2004

Estimating mass balance for inhaled drugs in humans: an example with a VLA-4 antagonist, IVL745.

IVL745 is an inhaled VLA-4 antagonist developed for the treatment of asthma. Following inhalation (Inh), a fraction of the drug is deposited in the oropharynx, and the rest is deposited in the lungs. For inhaled drugs, it is technically and ethically difficult to formulate and administer radiolabeled drugs. Hence, if the drug is metabolically stable in the lungs, mass balance and metabolism of inhaled drugs, such as IVL745, can be determined by administering radiolabeled intravenous (IV) and oral drugs and by comparing with the data following Inh administration. The study was a three-period crossover design in 6 healthy subjects to evaluate the absorption, distribution, metabolism, and elimination following IV and oral administration of (14)C-IVL745 (4 mg/50 microCi) and inhaled (10-mg) dose. Serial sampling of blood and excreta was performed maximally up to 168 hours postdose. Plasma IVL745 concentrations were determined using a liquid chromatography tandem mass spectrometry (LC/MS/MS) method with a minimum quantifiable limit of 10 pg/mL. Overall, the drug was safe and well tolerated. The recovery of the radioactive dose varied from 94.8% to 117% for both IV and oral administration. Following IV administration, 90.2% of the radioactive dose was recovered in the feces, suggesting extensive biliary excretion of the drug. After oral administration, 99.7% of the radioactivity was recovered in the feces, and no radioactivity was detected in plasma, suggesting lack of absorption of the drug. Negligible (14)C-radioactivity concentrations were observed in the red blood cell fractions. The mean t(1/2) values were 1.6, 1.5, and 4.4 hours following IV, oral, and Inh administration, respectively. The oral bioavailability of IVL745 was low (< 2%), and the inhaled bioavailability was 26%. The volume of distribution at steady state (V(ss)) was low (19.0 L). The predicted blood clearance of IVL745 was 86 L/h, which was comparable to the commonly used liver blood flow value of 90 L/h. Only a minor fraction of the dose was excreted in the urine with low to moderate renal clearance. The parent drug accounted for 77% to 89% of the dosed radioactivity in excreta. Two major metabolites observed in excreta were mono-o-desmethyl IVL745 and di-o-desmethyl IVL745. The data showed that the drug had negligible oral bioavailability, low oral absorption, 26% inhaled bioavailability, low extent of metabolism, high biliary excretion, and low renal clearance. This knowledge may aid in the prediction of potentially relevant drug-drug interactions and dosing adjustments in high-risk populations for IVL745.

Administration, Inhalation↗
PubMedDate not supplied

Evidence for cell adhesion-mediated drug resistance of multiple myeloma cells in vivo.

BACKGROUND/AIMS: Multiple myeloma is an incurable disease and patients eventually die of disease progression due to drug resistance. VLA-4 (very late antigen 4), VCAM (vascular adhesion molecule), LFA-1 (leukocyte function-associated antigen 1), and ICAM-1 (intercellular adhesion molecule 1)-mediated adhesion of myeloma cells to bone marrow stromal cells induces primary multidrug resistance in vitro. Based on these preclinical data we hypothesized that myeloma cells with strong adhesion - due to strong expression of adhesion molecules on the cell surface - are selected by chemotherapy in patients. To prove this hypothesis we determined the expression levels of adhesion molecules in 31 multiple myeloma patients by flow cytometry. METHODS: A 3-color stain with CD38, CD138 and antibodies against VLA-4, ICAM-1, LFA-1, and VCAM was performed. The patients were either at diagnosis (chemo-naive; n=17) or at relapse (pre-treated; n=15). Furthermore, the response to the next chemotherapy of chemo-naive patients was correlated with the expression levels of adhesion molecules. RESULTS: ICAM-1, VLA-4, and VCAM expression was higher in pre-treated patients than in chemo-naive patients and the expression levels increased with the number of chemotherapy regimens. Primarily multidrug-resistant patients had significantly higher expression levels of VLA-4 and ICAM-1 than responders. CONCLUSION: This study suggests that multiple myeloma cells expressing high levels of VLA-4 and ICAM-1 are drug resistant and that such a subpopulation of cells is selected by chemotherapy.

ADP-ribosyl Cyclase 1↗
PubMed2006

Progressive multifocal leukoencephalopathy: lessons from AIDS and natalizumab.

The dramatic increase in the incidence of progressive multifocal leukoencephalopathy (PML) that occurred as a consequence of the AIDS pandemic and the recent association of PML with the administration of natalizumab, a monoclonal antibody to alpha4 integrin that blocks inflammatory cell entry into the brain, has stimulated a great deal of interest in this previously obscure viral demyelinating disease. The etiology of this disorder is JC virus (JCV), a polyoma virus, observed in 80% of the population worldwide. Seroepidemiological studies indicate that infection with this virus typically occurs before the age of 20 years. No primary illness owing to JCV infection has been recognized and the means of spread from person to person remains obscure. Following infection, the virus becomes latent in bone marrow, spleen, tonsils and other tissues. Periodically the virus reactivates during which time it can be demonstrated in circulating peripheral lymphocytes. The latter is significantly more commonly observed in immunosuppressed populations than that in normal subjects. Despite the large pool of people infected with JCV, PML remains a relatively rare disease. It is seldom observed in the absence of an underlying predisposing illness, typically one that results in impaired cellular immunity. A variety of factors are likely responsible for the unique increase in frequency of PML in HIV infection relative to other underling immunosuppressive disorders. Preliminary data suggests that natalizumab appears to distinctively predispose recipients to PML relative to other infectious complications. Studies in these populations will be invaluable in understanding the mechanisms of disease pathogenesis.

Acquired Immunodeficiency Syndrome↗
PubMed2003

The role of G-protein signaling in hematopoietic stem/progenitor cell mobilization.

The directed migration of mature leukocytes to inflammatory sites and the lymphocyte trafficking in vivo are dependent on G protein-coupled receptors and delivered through pertussis toxin (Ptx)-sensitive Gi-protein signaling. In the present study, we explored the in vivo role of G-protein signaling on the redistribution or mobilization of hematopoietic stem/progenitor cells (HPCs). A single injection of Ptx in mice elicits a long-lasting leukocytosis and a progressive increase in circulating colony-forming unit-culture (CFU-C) and colony-forming unit spleen (CFU-S). We found that the prolonged effect is sustained by a continuous slow release of Ptx bound to red blood cells or other cells and is potentially enhanced by an indirect influence on cell proliferation. Plasma levels of certain cytokines (interleukin 6 [IL-6], granulocyte colony-stimulating factor [G-CSF]) increase days after Ptx treatment, but these are unlikely initiators of mobilization. In addition to normal mice, mice genetically deficient in monocyte chemotactic protein 1 (MCP-1), matrix metalloproteinase 9 (MMP-9), G-CSF receptor, beta2 integrins, or selectins responded to Ptx treatment, suggesting independence of Ptx-response from the expression of these molecules. Combined treatments of Ptx with anti-very late activation antigen (anti-VLA-4), uncovered potentially important insight in the interplay of chemokines/integrins, and the synergy of Ptx with G-CSF appeared to be dependent on MMP-9. As Ptx-mobilized kit+ cells display virtually no response to stromal-derived factor 1 (SDF-1) in vitro, our data suggest that disruption of CXCR4/SDF-1 signaling may be the underlying mechanism of Ptx-induced mobilization and indirectly reinforce the notion that active signaling through this pathway is required for continuous retention of cells within the bone marrow. Collectively, our data unveil a novel example of mobilization through pharmacologic modulation of signaling.

Animals↗
PubMed2003

LFA-1 is required for retention of effector CD8 T cells in mouse lungs.

The adhesion molecules involved in the migration and retention of activated effector CD8 T cells in the lung microcirculation and their recruitment into lung tissue are largely unknown. Here, we have analyzed the role of lymphocyte function-associated antigen-1 (LFA-1) and very late antigen-4 (VLA-4) on adhesion of influenza hemagglutinin (HA)-specific CD8 T-cell clone D4 under shear conditions in an in vitro binding assay and in an in vivo homing assay to the lungs of naive or transgenic Balb/c mice expressing HA (HA-Tg) by a lung-specific promoter. Blocking LFA-1 or intercellular adhesion molecule 1 (ICAM-1) significantly inhibited adhesion of D4 cells to lung vascular endothelium and parenchyma of lung sections. However, blocking VLA-4 or vascular cell adhesion molecule 1 (VCAM-1) had no effect on cell adhesion. Blocking LFA-1 in vivo significantly delayed lethal injury following adoptive transfer of D4 cells into HA-Tg mice as assessed by weight loss and histology. Residence time of adoptively transferred Indium 111 (111In)-labeled D4 cells in lungs of normal and HA-Tg mice as analyzed by dual modality imaging revealed a significantly shorter transit time of 4 hours for the D4 cells upon in vivo blockade of LFA-1. These results demonstrate a crucial role for LFA-1 in retention of activated CD8 T cells in normal mouse lungs and in the progression of lethal injury in HA-Tg mice.

Adoptive Transfer↗
PubMed2003

Transforming growth factor-beta1 down-regulates expression of chemokine stromal cell-derived factor-1: functional consequences in cell migration and adhesion.

Chemokine stromal cell-derived factor-1 (SDF-1) is expressed by bone marrow (BM) stromal cells and plays key roles in BM cell migration. Modulation of its expression could affect the migratory capacity of cells trafficking the BM, such as hematopoietic progenitor and leukemic cells. Transforming growth factor-beta1 (TGF-beta1) is present in the BM environment and constitutes a pivotal molecule controlling BM cell proliferation and differentiation. We used the BM stromal cell line MS-5 as a model to investigate whether SDF-1 expression constitutes a target for TGF-beta1 regulation and its functional consequences. We show here that TGF-beta1 down-regulates SDF-1 expression, both at the mRNA level, involving a decrease in transcriptional efficiency, and at the protein level, as detected in lysates and supernatants from MS-5 cells. Reduction of SDF-1 in supernatants from TGF-beta1-treated MS-5 cells correlated with decreased, SDF-1-dependent, chemotactic, and transendothelial migratory responses of the BM model cell lines NCI-H929 and Mo7e compared with their responses to supernatants from untreated MS-5 cells. In addition, supernatants from TGF-beta1-exposed MS-5 cells had substantially lower efficiency in promoting integrin alpha4beta1-mediated adhesion of NCI-H929 and Mo7e cells to soluble vascular cell adhesion molecule-1 (sVCAM-1) and CS-1/fibronectin than their untreated counterparts. Moreover, human cord blood CD34+ hematopoietic progenitor cells displayed SDF-1-dependent reduced responses in chemotaxis, transendothelial migration, and up-regulation of adhesion to sVCAM-1 when supernatants from TGF-beta1-treated MS-5 cells were used compared with supernatants from untreated cells. These data indicate that TGF-beta1-controlled reduction in SDF-1 expression influences BM cell migration and adhesion, which could affect the motility of cells trafficking the bone marrow.

3T3 Cells↗
PubMed2003

Differential effects of treatment with a small-molecule VLA-4 antagonist before and after onset of relapsing EAE.

Interaction of very late antigen-4 (VLA-4) with its ligand vascular cell adhesion molecule-1 (VCAM-1) is required for central nervous system (CNS) migration of encephalitogenic T cells in relapsing experimental autoimmune encephalomyelitis (R-EAE). Anti-VLA-4 monoclonal antibody (mAb) treatment prior to EAE onset inhibits disease induction; however, treatment initiated after the appearance of clinical symptoms increases relapse rates, augments Th1 responses, and enhances epitope spreading perhaps due to the activation of costimulatory signals. To negate the potential costimulatory activity of intact anti-VLA-4, we examined the ability of BIO 5192, a small-molecule VLA-4 antagonist, to regulate active proteolipid protein 139-151 (PLP139-151)-induced R-EAE. BIO 5192 administered one week after peptide priming (ie, before clinical disease onset) delayed the clinical disease onset but led to severe disease exacerbation upon treatment removal. BIO 5192 treatment initiated during disease remission moderately enhanced clinical disease while mice were on treatment and also resulted in posttreatment exacerbation. Interestingly, BIO 5192 treatment begun at the peak of acute disease accelerated entrance into disease remission and inhibited relapses, but treatment removal again exacerbated disease. Enhanced disease was caused by the release of encephalitogenic cells from the periphery and the rapid accumulation of T cells in the CNS. Collectively, these results further demonstrate the complexity of VLA-4/VCAM interactions, particularly in a relapsing-remitting autoimmune disease.

Amino Acid Sequence↗