α4 integrins mediate lymphocyte attachment and rolling under physiologic flow

Berlin, C; Bargatze, Robert F.; Campbell, James J.; Andrian, Ulrich H. von; Szabo, M C; Hasslen, Sharon R.; Nelson, Robert D.; Berg, Ellen L.; Erlandsen, Stanley L.; Butcher, Eugene C.

doi:10.1016/0092-8674(95)90491-3

Cited by 944 publications

(625 citation statements)

References 29 publications

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“…Co-immobilization with ICAM-1, a molecule distinct from VCAM-1 in that it is not able to mediate leukocyte capture under shear conditions (but can support firm adhesion) [39], had no effect on adhesion to exFKN-AP. This suggests that the ability to tether from the blood flow is the limiting factor for fractalkine-mediated adhesion at physiological shear forces.…”

Section: Discussionmentioning

confidence: 98%

Human fractalkine mediates leukocyte adhesion but not capture under physiological shear conditions; a mechanism for selective monocyte recruitment

et al. 2003

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Fractalkine is a unique chemokine possessing a long mucin-like stalk and a transmembrane region that has been proposed to act as an adhesion molecule. We investigated the ability of fractalkine to recruit leukocytes from whole blood, using an immobilized fractalkine fusion protein in the parallel-plate flow-chamber assay. Significant adhesion of leukocytes to fractalkine peaked at 2 dynes/cm 2 but was minimal at 10 dynes/cm 2 . In contrast, VCAM-1 could recruit cells from whole blood at 10 dynes/cm 2 . Co-immobilization of fractalkine and VCAM-1 at 10 dynes/cm 2 resulted in a twofold increase in adherent cells compared with VCAM-1 alone, suggesting that fractalkine can mediate adhesion at high shear if combined with a molecule that can mediate leukocyte tethering. Pretreatment of blood with pertussis toxin eliminated this increase in adhesion, implicating intracellular signaling in fractalkinemediated mechanisms of adhesion to co-immobilized fractalkine/VCAM-1. Analysis of the cell types recruited to fractalkine alone at low shear, or to fractalkine and VCAM-1 at 10 dynes/cm 2 , revealed that monocytes were recruited to fractalkine with the highest specificity. In conclusion, fractalkine is unlikely to act alone at shear forces found in most vascular beds where it most likely co-operates with tethering molecules, e.g. VCAM-1, in the recruitment of monocytes.

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Section: Discussionmentioning

confidence: 98%

Human fractalkine mediates leukocyte adhesion but not capture under physiological shear conditions; a mechanism for selective monocyte recruitment

et al. 2003

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“…To determine this, recipients received the tolerogenic regimen along with mAbs to the VLA-4␣ (CD49d) integrin, responsible for homing to vascular and lymphatic endothelium, through binding to its ligands fibronectin, VCAM-1, and mucosal addressin cell adhesion molecule-1 (30,31), or mAbs to CD44, the mucin receptor, responsible for homing to endothelium (32). The results (Fig.…”

Section: Anti-cd62l Mab Prevents Tolerance Induction and Has No Costimentioning

confidence: 99%

L-Selectin-Dependent Lymphoid Occupancy Is Required to Induce Alloantigen-Specific Tolerance

Bai

Liu

Wang

et al. 2002

The Journal of Immunology

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Maneuvers that interfere with signals 1, 2, 3, or Ag processing can result in indefinite allograft survival. However, they are not applicable to all tissues, strains, or species, suggesting that there are additional levels of immune regulation. We hypothesized that secondary lymphoid organs are important for interactions among lymphocytes, alloantigen, and immunosuppressants that lead to tolerance. To explore this, cardiac allografts were performed with a tolerogenic immunosuppressive regimen. Concurrent administration of anti-L-selectin (CD62L) Ab, which prevents lymph node homing, prevents indefinite allograft survival and tolerance. Anti-CD62L Ab is not costimulatory, and Fab and F(ab′)2 anti-CD62L have similar activities. Flow cytometry and histologic examination show that Ab shifts T cells away from lymph nodes and into spleen, peripheral blood, and graft. Tolerance is not induced in CD62L−/− mice, and adoptive transfer of CD62L−/−, but not CD62L+/+, T cells prevents tolerization in wild-type recipients. FTY720, an immunosuppressant that promotes chemokine-dependent, but CD62L-independent, lymph node homing, reverses the Ab effect. Blockade of other homing receptors also prevents tolerization. These results indicate that T lymphocytes use CD62L-dependent migration for alloantigen-specific tolerance, and suggest that lymph nodes or other lymphoid tissues are an important site for peripheral tolerization to alloantigen.

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“…Leukocyte recruitment from the blood into tissue is regulated by sequential interactions of adhesion and signaling molecules on leukocytes and endothelial cells and a4-integrins and their endothelial counter-receptors have a unique role in this multistep cascade. a4-integrins are the only molecules known to be able to mediate two steps, namely the initial tethering/rolling and the secondary firm arrest of the leukocyte on the endothelium upon G-protein dependent avidity change of integrins [14,15].…”

Section: Anti A4-integrin Therapy Of Inflammatory Bowel Diseasementioning

confidence: 99%

Therapeutic targeting of α4-integrins in chronic inflammatory diseases: tipping the scales of risk towards benefit?

Engelhardt

Briskin

2005

Eur. J. Immunol.

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Inhibition of leukocyte trafficking via a4-integrin antibody blockade has recently become a validated therapeutic approach for several inflammatory diseases, including multiple sclerosis, ulcerative colitis and Crohn's disease. In the midst of this recent success, 3 patients receiving chronic treatment with the anti-a4 antagonist natalizumab (Tysabri) for the treatment of multiple sclerosis or Crohn's disease, developed JC-virus related progressive multifocal leukoencephalopathy (PML). These unforeseen consequences suggest that long term blockade of a4-integrins might prevent trafficking of non-pathogenic lymphocytes that are essential for viral immunosurveillance. In the current issue of the European Journal of Immunology Bjursten and colleagues report that long term treatment with anti-a4-integrin antibodies results in exacerbation of the murine model of colitis induced by the targeted deletion of the heterotrimeric G protein subunit Gai2. In order to properly evaluate the efficacy and safety of anti-a4-integrin therapy, the relationship between these observations in an immunologically altered animal model and human clinical disease needs to be carefully measured.

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α4 integrins mediate lymphocyte attachment and rolling under physiologic flow

Cited by 944 publications

References 29 publications

Human fractalkine mediates leukocyte adhesion but not capture under physiological shear conditions; a mechanism for selective monocyte recruitment

Human fractalkine mediates leukocyte adhesion but not capture under physiological shear conditions; a mechanism for selective monocyte recruitment

L-Selectin-Dependent Lymphoid Occupancy Is Required to Induce Alloantigen-Specific Tolerance

Therapeutic targeting of α4-integrins in chronic inflammatory diseases: tipping the scales of risk towards benefit?

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