scholarly journals Salicylates Inhibit Adhesion and Transmigration of T Lymphocytes by Preventing Integrin Activation Induced by Contact With Endothelial Cells

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2389-2398 ◽  
Author(s):  
Roberto Gerli ◽  
Cristina Paolucci ◽  
Paolo Gresele ◽  
Onelia Bistoni ◽  
Stefano Fiorucci ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Function ◽  
Static System ◽  
Functional Changes ◽  
And Migration ◽  
T Cell Adhesion

The inhibition of cyclooxygenase does not fully account for the spectrum of activities of nonsteroidal antiinflammatory drugs. It is evident, indeed, that regulation of inflammatory cell function may contribute in explaining some of the effects of these drugs. Tissue recruitment of T cells plays a key role in the development of chronic inflammation. Therefore, the effects of salicylates on T-cell adhesion to and migration through endothelial cell monolayers on collagen were analyzed in an in vitro static system. Aspirin and sodium salicylate reduced the ability of unstimulated T cells to adhere to and transmigrate through cytokine-activated endothelium. Although salicylates did not modify the expression of integrins on T cells, they blunted the increased adherence induced by the anti-β2monoclonal antibody (MoAb) KIM127 and prevented the appearance of an activation-dependent epitope of the CD11/CD18 complex, recognized by the MoAb 24, induced by contact with endothelial cells. Salicylates also induced an increase of intracellular calcium ([Ca2+]i) and activation of protein kinase C (PKC) in T cells, but not cell proliferation and interleukin (IL)-2 synthesis. The reduction of T-cell adhesiveness appears to be dependent on the increase in[Ca2+]i levels, as it could be reversed by blocking Ca2+ influx, but not by inhibiting PKC. Moreover, ionomycin at concentrations giving an increase in [Ca2+]i similar to that triggered by aspirin, strictly reproduced the T-cell phenotypic and functional changes induced by salicylates. Aspirin reduced T-cell adhesion and migration also ex vivo after infusion to healthy volunteers. These data suggest that the antiinflammatory activity of salicylates may be due, at least in part, to an interference with the integrin-mediated binding of resting T lymphocytes to activated endothelium with consequent reduction of a specific T-cell recruitment into inflammatory sites.

scholarly journals Salicylates Inhibit Adhesion and Transmigration of T Lymphocytes by Preventing Integrin Activation Induced by Contact With Endothelial Cells

Blood ◽  
1998 ◽  
Vol 92 (7) ◽  
pp. 2389-2398 ◽  
Author(s):  
Roberto Gerli ◽  
Cristina Paolucci ◽  
Paolo Gresele ◽  
Onelia Bistoni ◽  
Stefano Fiorucci ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Function ◽  
Static System ◽  
Functional Changes ◽  
And Migration ◽  
T Cell Adhesion

Abstract The inhibition of cyclooxygenase does not fully account for the spectrum of activities of nonsteroidal antiinflammatory drugs. It is evident, indeed, that regulation of inflammatory cell function may contribute in explaining some of the effects of these drugs. Tissue recruitment of T cells plays a key role in the development of chronic inflammation. Therefore, the effects of salicylates on T-cell adhesion to and migration through endothelial cell monolayers on collagen were analyzed in an in vitro static system. Aspirin and sodium salicylate reduced the ability of unstimulated T cells to adhere to and transmigrate through cytokine-activated endothelium. Although salicylates did not modify the expression of integrins on T cells, they blunted the increased adherence induced by the anti-β2monoclonal antibody (MoAb) KIM127 and prevented the appearance of an activation-dependent epitope of the CD11/CD18 complex, recognized by the MoAb 24, induced by contact with endothelial cells. Salicylates also induced an increase of intracellular calcium ([Ca2+]i) and activation of protein kinase C (PKC) in T cells, but not cell proliferation and interleukin (IL)-2 synthesis. The reduction of T-cell adhesiveness appears to be dependent on the increase in[Ca2+]i levels, as it could be reversed by blocking Ca2+ influx, but not by inhibiting PKC. Moreover, ionomycin at concentrations giving an increase in [Ca2+]i similar to that triggered by aspirin, strictly reproduced the T-cell phenotypic and functional changes induced by salicylates. Aspirin reduced T-cell adhesion and migration also ex vivo after infusion to healthy volunteers. These data suggest that the antiinflammatory activity of salicylates may be due, at least in part, to an interference with the integrin-mediated binding of resting T lymphocytes to activated endothelium with consequent reduction of a specific T-cell recruitment into inflammatory sites.

Selective differences in vascular endothelial- vs. airway epithelial-T cell adhesion mechanisms

1994 ◽  
Vol 267 (4) ◽  
pp. L422-L432 ◽  
Author(s):  
S. Nakajima ◽  
D. C. Look ◽  
W. T. Roswit ◽  
M. J. Bragdon ◽  
M. J. Holtzman
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Epithelial Cell ◽  
Vascular Endothelial ◽  
Airway Epithelial ◽  
Beta 2 ◽  
T Cell Adhesion

The basis for T cell adhesion to airway epithelial and vascular endothelial cells was studied using a quantitative flow cytometry-based assay that avoids extensive leukocyte purification and labeling. Compared with standard cell-labeling methods, the flow cytometry-based assay yielded a lower level of constitutive T cell adhesion, despite a similar level of stimulated adhesion (after T cell activation with phorbol dibutyrate) using endothelial or epithelial cell monolayers. Endothelial T cell adhesion was further increased by monolayer treatment with tumor necrosis factor-alpha (less so with interleukin-1 beta and least with interferon-gamma), whereas epithelial T cell adhesion was most sensitive to interferon-gamma. Cytokine stimulation of adhesion was invariably concentration dependent and closely matched to the cellular levels of intracellular adhesion molecule-1 (ICAM-1). Accordingly, stimulated T cell adhesion was markedly inhibited by anti-ICAM-1 or anti-beta 2-integrin antibody (95-97% inhibition for epithelial cells and 57-67% inhibition for endothelial cells) directed against ICAM-1 interaction with lymphocyte function-associated antigen-1 (LFA-1; alpha L beta 2-integrin). Residual endothelial T cell adhesion that correlated with endothelial vascular cell adhesion molecule-1 (VCAM-1) levels was blocked by an anti-alpha 4-integrin antibody directed against VCAM-1 interaction with very late activation antigen-4 (VLA-4; alpha 4 beta 1-integrin). The results suggest that 1) peripheral blood T cells without exogenous activation exhibit little LFA-1- or VLA-4-dependent adherence except to endothelial or epithelial cells expressing high levels of ICAM-1 and/or VCAM-1; and 2) differences in endothelial vs. epithelial cell mechanisms to bind activated and unactivated T cells (e.g., dependence on a mixed- vs. a single-ligand system and distinct cytokine-responsiveness of ligand levels) may help to coordinate T cell traffic to epithelial barriers.

Potent Effector Function of Tumor-Sensitized L-Selectinlow T Cells against Subcutaneous Tumors Requires LFA-1 co-Stimulation

2001 ◽  
Vol 124 (4) ◽  
pp. 436-441 ◽  
Author(s):  
Brook M. Seeley ◽  
Steve W. Barthel ◽  
Wyatt C. To ◽  
JØrgen Kjaergaard ◽  
Gregory E. Plautz
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Lymphocytes ◽  
Adhesion Molecule ◽  
Adoptive Transfer ◽  
Cell Adhesion Molecule ◽  
Cell Function ◽  
Effector Function ◽  
T Cell Subsets

OBJECTIVE: Animal tumor models have demonstrated that adoptive transfer of tumor-draining lymph node (TDLN) T lymphocytes can cure established tumors in many anatomic sites. However, subcutaneous tumors are relatively refractory and have required maximally tolerated doses of cells. The goals of this study were to determine whether a subset of TDLN T lymphocytes varying in expression of the cell adhesion molecule L-selectin (CD62L) had augmented therapeutic efficacy and to determine the co-stimulatory requirements for trafficking and anti-tumor effector function. STUDY DESIGN: TDLNs were recovered from mice bearing progressive MCA 205 fibrosarcomas, and the T lymphocytes were segregated into CD62Llow and CD62Lhigh subsets and activated ex vivo with anti-CD3 mAb and IL-2. Mice bearing established subcutaneous MCA 205 tumors were treated with activated T cell subsets and in some experiments with additional mAb against cell adhesion molecules. RESULTS: Adoptive transfer of as few as 5 × 10 6 activated cells cured mice bearing 3-day subcutaneous MCA 205 tumors initiated with 6 × 10 6 cells, and the tumors demonstrated a dense infiltrate of CD62Llow cells. In marked contrast, adoptive transfer of 10 times as many T cells derived from the reciprocal CD62Lhigh compartment had no effect on tumor growth. The effector function of the CD62Llow T cells was clearly dependent on co-stimulation through the cell adhesion molecule LFA-1, because anti-LFA-1 mAb completely abrogated the antitumor reactivity of the transferred cells against subcutaneous tumors and inhibited tumor infiltration. In contrast, blockade of ICAM-1, VLA-4, or VCAM-1 had no inhibitory effect on the anti-tumor function. CONCLUSION: These studies demonstrate the high therapeutic activity of the CD62Llow subset of tumor-draining LN T cells against subcutaneous tumors, a relatively refractory site, and confirm the essential role of LFA-1 for effector T cell function. SIGNIFICANCE: Identification of the phenotype and requirements for effector function of T lymphocytes sensitized to tumor antigens has implications for clinical trials of adoptive immunotherapy for head and neck carcinoma using a similar approach.

scholarly journals Four molecular pathways of T cell adhesion to endothelial cells: roles of LFA-1, VCAM-1, and ELAM-1 and changes in pathway hierarchy under different activation conditions.

1991 ◽  
Vol 113 (5) ◽  
pp. 1203-1212 ◽  
Author(s):  
Y Shimizu ◽  
W Newman ◽  
T V Gopal ◽  
K J Horgan ◽  
N Graber ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
T Cell Subsets ◽  
Molecular Pathways ◽  
T Cell Adhesion

T cell adhesion to endothelium is critical to lymphocyte recirculation and influx into sites of inflammation. We have systematically analyzed the role of four receptor/ligand interactions that mediate adhesion of peripheral human CD4+ T cells to cultured human umbilical vein endothelial cells (HUVEC): T cell LFA-1 binding to ICAM-1 and an alternative ligand ("ICAM-X"), T cell VLA-4 binding to VCAM-1, and T cell binding to ELAM-1. Contributions of these four pathways depend on the activation state of both the T cell and HUVEC, and the differentiation state of the T cell. ELAM-1 plays a significant role in mediating adhesion of resting CD4+ T cells to activated HUVEC. LFA-1 adhesion dominates with PMA-activated T cells but the strength and predominant LFA-1 ligand is determined by the activation state of the HUVEC; while ICAM-1 is the dominant ligand on IL-1-induced HUVEC, "ICAM-X" dominates binding to uninduced HUVEC. Adhesion via VLA-4 depends on induction of its ligand VCAM-1 on activated HUVEC; PMA activation of T cells augments VLA-4-mediated adhesion, both in the model of T/HUVEC binding and in a simplified model of T cell adhesion to VCAM-1-transfected L cells. Unlike LFA-1 and VLA-4, ELAM-1-mediated adhesion is not increased by T cell activation. Differential expression of adhesion molecules on CD4+ T cell subsets understood to be naive and memory cells also regulates T/HUVEC adhesion. Naive T cell adhesion to HUVEC is mediated predominantly by LFA-1 with little or no involvement of the VLA-4 and ELAM-1 pathways. In contrast, memory T cells bind better to HUVEC and utilize all four pathways. These studies demonstrate that there are at least four molecular pathways mediating T/HUVEC adhesion and that the dominance/hierarchy of these pathways varies dramatically with the activation state of the interacting cells and the differentiation state of the T cell.

scholarly journals Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes.

1992 ◽  
Vol 176 (6) ◽  
pp. 1595-1604 ◽  
Author(s):  
P S Linsley ◽  
J L Greene ◽  
P Tan ◽  
J Bradshaw ◽  
J A Ledbetter ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Lymphocytes ◽  
T Cell Subsets ◽  
T Cell Proliferation ◽  
Activated T Cells ◽  
Activated T Lymphocytes ◽  
T Cell Adhesion

T cell costimulation by molecules on the antigen presenting cell (APC) is required for optimal T cell proliferation. The B7 molecule on APC binds the T lymphocyte receptor CD28, triggering increased interleukin 2 (IL-2) production and subsequent T cell proliferation. CTLA-4 is a predicted T cell membrane receptor homologous to CD28, which also binds the B7 counter receptor, but whose distribution and function are unknown. Here we have developed monoclonal antibodies (mAbs) specific for CTLA-4 and have investigated these questions. mAbs were produced that bound CTLA-4 but not CD28, and that blocked binding of CTLA-4 to B7. CTLA-4 expression as measured by these mAbs was virtually undetectable on resting T cells, but was increased several hundred-fold during T cell activation. On activated lymphocytes, CTLA-4 was expressed equally on CD4+ and CD8+ T cell subsets and was coexpressed with CD25, CD28, and CD45RO. CTLA-4 expression was lower than that of CD28, reaching a maximum of approximately 1/30-50 the level of CD28. Despite its lower expression, CTLA-4 was responsible for much of the B7 binding by large activated T cells. Anti-CTLA-4 mAb 11D4 and anti-CD28 mAb 9.3 acted cooperatively to inhibit T cell adhesion to B7, and to block T cell proliferation in primary mixed lymphocyte culture. When coimmobilized with anti T cell receptor (TCR) mAb, anti-CTLA-4 mAbs were less effective than anti-CD28 mAb 9.3 at costimulating proliferation of resting or activated T cells. However, coimmobilized combinations of anti-CD28 and anti-CTLA-4 were synergistic in their ability to augment anti-TCR-induced proliferation of preactivated CD4+ T cells. These results indicate that CTLA-4 is coexpressed with CD28 on activated T lymphocytes and cooperatively regulates T cell adhesion and activation by B7.

Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice

2000 ◽  
Vol 279 (3) ◽  
pp. F525-F531 ◽  
Author(s):  
Hamid Rabb ◽  
Frank Daniels ◽  
Michael O'Donnell ◽  
Mahmud Haq ◽  
Sabiha R. Saba ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Lymphocytes ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Pathophysiological Role ◽  
Renal Tubular ◽  
T Cell Adhesion

Mononuclear cell infiltrates are found in human renal ischemia-reperfusion injury (IRI), and peritubular T lymphocytes have been identified in experimental IRI. However, the role of T cells in the pathogenesis of renal IRI is unknown. We hypothesized that T cells are one of the important mediators of renal IRI. To test this hypothesis, we used an established mouse model of renal IRI, and evaluated mice with genetically engineered deficiency of both CD4+ and CD8+ T cells. At 48 h postischemia, CD4/CD8-knockout (KO) mice had marked improvement in renal function compared with control C57BL/6 mice (serum creatinine: 0.7 ± 0.4 vs. 2.5 ± 0.3 mg/dl, respectively; P < 0.05). Neutrophil infiltration into postischemic kidney was reduced in CD4/CD8 KO mice, compared with control mice, at both 24 h [polymorphonuclear neutrophils (PMNs)/10 high power fields: 714 ± 354 vs. 3,514 ± 660, respectively; P < 0.05] and 48 h (88 ± 32 vs. 1,979 ± 209, respectively; P< 0.05). Tubular necrosis score in CD4/CD8 KO mice, compared with control mice, was significantly less at 48 h (0.4 ± 0.1 vs. 2.4 ± 0.2, respectively; P < 0.05). Because adhesion between T cells and renal tubular epithelial cells (RTECs) may underlie the pathophysiological role of T cells in renal IRI, we also measured T cell adhesion to primary murine RTECs in vitro. Exposure of RTECs to 2 h of hypoxia followed by 1 h of reoxygenation increased T cell adhesion more than twofold. Phorbol ester treatment, which activates integrins, increased T cell adhesion threefold. These data suggest that T lymphocytes can mediate experimental renal IRI. Moreover, adhesion of infiltrating T cells to renal tubular cells may provide a potential mechanism underlying postischemic tubular dysfunction.

scholarly journals Expression of CD86 on Human Islet Endothelial Cells Facilitates T Cell Adhesion and Migration

2008 ◽  
Vol 181 (9) ◽  
pp. 6109-6116 ◽  
Author(s):  
Biliana Lozanoska-Ochser ◽  
Nigel J. Klein ◽  
Guo C. Huang ◽  
Raymond A. Alvarez ◽  
Mark Peakman
Keyword(s):  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Human Islet ◽  
Cell Adhesion And Migration ◽  
And Migration ◽  
T Cell Adhesion

Pathogenesis-Based Development of Potential Mitigation Strategies for Blinatumomab-Associated Neurologic Events (NEs)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1589-1589 ◽  
Author(s):  
Matthias Klinger ◽  
Gerhard Zugmaier ◽  
Virginie Naegele ◽  
Mariele Goebeler ◽  
Christian Brandl ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
B Cells ◽  
Low Grade ◽  
Employment Equity ◽  
Equity Ownership ◽  
Dose Step ◽  
T Cell Adhesion

Abstract Introduction: Blinatumomab (blin), a CD19/CD3 bispecific T-cell engager (BiTE®) antibody construct, has shown clinical efficacy in patients with both B-precursor acute lymphoblastic leukemia (ALL) and B-cell non-Hodgkin lymphoma (NHL). NEs are known blin-associated adverse drug reactions; most NEs occur early during the first treatment cycle and are transient and fully reversible. While NEs are manageable in ALL (favorable risk/benefit profile at a maximum target dose of 28 µg/day), NEs increase in frequency and were dose-limiting in low-grade NHL. The maximum tolerated dose in NHL was 112 µg/day. Here we present translational and single-patient data for potential mitigation strategies for blin-associated NEs. Methods: Pharmacokinetic and pharmacodynamic data from blin clinical studies in NHL and ALL were combined to develop a pathogenetic model for blin-associated NEs. The mitigation potential of substances with antiadhesive properties was studied in vitro in a flow chamber system mimicking blin-induced T-cell redistribution. Three patients with low-grade NHL who had a higher risk of developing NEs due to their low peripheral blood B/T-cell ratios received concomitant pentosan polysulfate (PPS) at infusion start and dose step. ClinicalTrials.gov NCT00274742, NCT00560794, NCT01209286, NCT01471782. Results: T-cell redistribution occurred at infusion start and dose step of blin irrespective of circulating B cells. Concurrently, T cells upregulated the activation marker CD69 and the T-cell adhesion molecule LFA-1 switched from its low to intermediate affinity isoform as shown by binding of soluble ICAM-1. Blood vessel endothelial cells were activated as indicated by release of angiopoietin-2 and clinical signs of peripheral edema. Monocyte and thrombocyte redistribution were also observed. Both B and T cells were detected in cerebrospinal fluid (CSF) of some patients with NEs, and quantifiable blin concentrations were measured in CSF of some patients independent of blood-CSF barrier integrity. A low B/T-cell ratio in peripheral blood (NHL) and/or bone marrow (ALL) has been identified as a potential risk factor for developing NEs. In flow chamber experiments, addition of blin mimicked T-cell redistribution as indicated by reduced T-cell rolling velocity and increased T-cell adhesion to brain microvascular endothelial cells and by upregulation of P-selectin and ICAM-1 adhesion molecules on endothelial cells. Substances potentially interfering with interactions between T cells and endothelial cells (eg, PPS, minocycline) reversed the above-described effects to levels seen without the addition of blin. T-cell kinetics of three patients receiving concomitant PPS at infusion start and dose step showed delayed T-cell redistribution (without circulating B cells) compared with patients without PPS coadministration. These altered T-cell kinetics correlated with less severe NEs; no treatment interruptions or discontinuations were necessary. Finite PPS coadministration had no apparent negative impact on clinical response as two patients achieved an objective response, including one patient who has been in ongoing remission for more than six years. Conclusion: We propose an evidence-based model for the development of blin-associated NEs: 1) First exposure to blin or dose steps increase endothelial adhesiveness of circulating T cells. 2) Adhering T cells activate the endothelium and start extravasating; activated endothelium attracts other circulating leukocytes. 3) At low B/T-cell ratios, extravasated T cells first encountering (rare) B cells in the brain are activated by blin in the perivascular space to locally secret cytokines and chemokines that induce transient neuroinflammation including transmigration of monocytes. 4) Attracted non-T cells and other released factors enhance transient neurotoxicity. Based on this model, T-cell adhesion to blood vessel endothelial cells is the first necessary (but not sufficient) step in the pathogenesis of blin-associated NEs. Coadministration of substances with antiadhesive properties at infusion start and dose steps may offer opportunities to mitigate blin-associated NEs to further improve the safety and efficacy of blin therapy. Disclosures Klinger: Amgen Research (Munich) GmbH: Employment, Equity Ownership, Patents & Royalties: Blinatumomab. Zugmaier:Amgen: Employment, Patents & Royalties. Naegele:Amgen Research (Munich) GmbH: Employment, Equity Ownership, Patents & Royalties. Goebeler:GEmoAb: Consultancy; Novartis: Consultancy; Roche: Consultancy. Brandl:Amgen: Employment. Kufer:AMGEN Research Munich: Employment, Equity Ownership, Patents & Royalties.

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