LPAM-1 (integrin α4β7)-ligand binding: overlapping binding sites recognizing VCAM-1, MAdCAM-1 and CS-1 are blocked by fibrinogen, a fibronectin-like polymer and RGD-like cyclic peptides

Yang, Yi; Cardarelli, Pina M.; Lehnert, Klaus; Rowland, Shelley A.; Krissansen, Geoffrey W.

doi:10.1002/(sici)1521-4141(199803)28:03<995::aid-immu995>3.0.co;2-d

Cited by 24 publications

(25 citation statements)

References 36 publications

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“…The major α 4 β 7 ligand MAdCAM-1 is expressed not only in HEVs, but also in the bone marrow (38) and SP (39). Other than the gut-associated lymphoid tissues, α 4 β 7 can also interact with the VCAM-1 and fibronectin expressed in various tissues (40,41). Although the default nonadhesive α 4 β 7 prevents WT cells from firmly adhering to ligands outside the gut, aberrant activation of β 7 (D146A) might allow α 4 β 7 to firmly bind to ligands in diverse tissue types.…”

Section: Discussionmentioning

confidence: 99%

Aberrant activation of integrin α4β7 suppresses lymphocyte migration to the gut

Park¹,

Mora²,

Carman³

et al. 2007

J. Clin. Invest.

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Integrin adhesion molecules mediate lymphocyte migration and homing to normal and inflamed tissues. While the ligand-binding activity of integrins is known to be modulated by conformational changes, little is known about how the appropriate balance of integrin adhesiveness is maintained in order to optimize the migratory capacity of lymphocytes in vivo. In this study we examined the regulation of the gut homing receptor α 4 β 7 integrin by manipulating at the germline level an integrin regulatory domain known as adjacent to metal ion-dependent adhesion site (ADMIDAS). ADMIDAS normally serves to raise the activation threshold of α 4 β 7 , thereby stabilizing it in the default nonadhesive state. Lymphocytes from knockin β 7 (D146A) mice, which harbor a disrupted ADMIDAS, not only expressed an α 4 β 7 integrin that persistently adhered to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), but also exhibited perturbed cell migration along MAdCAM-1 substrates resulting from improper de-adhesion of the lymphocyte trailing edge. In vivo, aberrantly activated α 4 β 7 enhanced adhesion to Peyer's patch venules, but suppressed lymphocyte homing to the gut, diminishing the capacity of T cells to induce colitis. Our results underscore the importance of a proper balance in the adhesion and de-adhesion of the α 4 β 7 integrin, both for lymphocyte trafficking to the gut and for colitis progression.

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Section: Discussionmentioning

confidence: 99%

Aberrant activation of integrin α4β7 suppresses lymphocyte migration to the gut

Park¹,

Mora²,

Carman³

et al. 2007

J. Clin. Invest.

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“…TRACHOMATIS IN ENTERIC AND NONENTERIC MUCOSAEand the practical options for delivery of vaccines against mucosal pathogens. Trafficking of intestinally primed ␣4␤7 ϩ T and B lymphocytes is theoretically unrestricted since the ␣4␤7 integrin carries binding sites for MAdCAM as well as the related VCAM molecule (15,52), allowing homing of intestinal lymphocytes to any tissue or organ that expresses at least one of these ligands. The tendency of intestinally primed mice to generate significant serum IgG titers may be one reflection of this broad trafficking potential (12,18,20,25,45).…”

Section: Vol 69 2001mentioning

confidence: 99%

“…has been made for the existence of vascular addressin splice variants (21,39), the extensive promiscuity of relevant receptor-ligand interactions (15,31,52), or the potential existence of undiscovered adhesion molecules that could contribute to mucosal versus systemic tissue trafficking. Nevertheless, it appears that expression of the MAdCAM addressin in mucosal tissues may be limited, which would suggest that it may not serve as a vascular marker for a common mucosal immune system.…”

Section: Fig 5 Inflammatory Responses Withinmentioning

confidence: 99%

Inflammation and Clearance ofChlamydia trachomatisin Enteric and Nonenteric Mucosae

2001

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Immunization(s) fostering the induction of genital mucosa-targeted immune effectors is the goal of vaccines against sexually transmitted diseases. However, it is uncertain whether vaccine administration should be based on the current assumptions about the common mucosal immune system. We investigated the relationship between mucosal sites of infection, infection-induced inflammation, and immune-mediated bacterial clearance in mice using the epitheliotropic pathogen Chlamydia trachomatis. Chlamydial infection of the conjunctival, pulmonary, or genital mucosae stimulated significant changes in tissue architecture with dramatic up-regulation of the vascular addressin, VCAM, a vigorous mixed-cell inflammatory response with an influx of ␣4␤1 ؉ T cells, and clearance of bacteria within 30 days. Conversely, intestinal mucosa infection was physiologically inapparent, with no change in expression of the local MAdCAM addressin, no VCAM induction, no histologically detectable inflammation, and no tissue pathology. Microbial clearance was complete within 60 days in the small intestine but bacterial titers remained at high levels for at least 8 months in the large intestine. These findings are compatible with the notion that VCAM plays a functional role in recruiting cells to inflammatory foci, and its absence from the intestinal mucosa contributes to immunologic homeostasis at that site. Also, expression of type 1 T cell-mediated immunity to intracellular Chlamydia may exhibit tissue-specific variation, with the rate and possibly the mechanism(s) of clearance differing between enteric and nonenteric mucosae. The implications of these data for the common mucosal immune system and the delivery of vaccines against mucosal pathogens are discussed.

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Melanoma complicating treatment with Natalizumab (Tysabri) for multiple sclerosis

2009

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Sirs,Natalizumab (Tysabri, Biogen Idec and Elan Pharmaceuticals) is a humanized monoclonal antibody which targets the a4 subunits of the cellular adhesion molecules a4b1 and a4b7 integrins, blocking their interaction with their co-receptors VCAM-1, CS-1 and MadCAM-1 [3,15]. This action reduces leukocyte trafficking into the brain and gut and mediates the beneficial effect of natalizumab in multiple sclerosis (MS) and Crohn's disease [3]. The efficacy of natalizumab in patients with relapsing remitting MS was demonstrated in two phase III studies, AFFIRM and SENTINAL [10,12]. These studies showed that when natalizumab was used as mono therapy or in combination with interferon beta-1a (Avonex) it significantly reduced relapse rate and slowed the progression of disability. Natalizumab was well tolerated with the most common adverse effects being headache, infusion reactions and a modest increase in urinary and respiratory tract infections [10,12]. Neither trial identified any apparent increase in cancer incidence.We report on a patient with MS who developed malignant melanoma following treatment with natalizumab. This was a 48-year-old female who was randomised into the active arm of the AFFIRM Study [10]. She received 30 infusions of natalizumab (300 mg every 4 weeks) and was subsequently enrolled in the open label phase of the trial and received an additional five infusions. The treatment was stopped thereafter when the trial was put on hold following the reporting of the three cases of progressive multifocal leukoencephalopathy (PML) [1]. Five months later, she noticed an increase in the size of a mole which was present on the lateral aspect of her right shin for many years. The patient had no previous history of melanoma or atypical naevi. She did not receive prior immunosuppressant therapy and had no history of melanoma. On examination, the lesion appeared flat, with a darker centre and regular borders. It was not ulcerated and there were no satellite lesions. She underwent local excision and histopathological examination revealed an in situ malignant melanoma with a potential invasive component. There was no evidence of metastasis. Margin re-excision of the biopsy site was undertaken. No recurrence has since been detected.Natalizumab was approved by the US Food and Drug Administration in 2004. Since then, three cases of melanoma associated with its use have been reported. Polman et al.[10] reported a patient in the AFFIRM study who died of malignant melanoma. This was a 38-year-old male with MS who had a past history of malignant melanoma excised from the left shoulder. Following the first dose of natalizumab, a new skin lesion was noticed. He received four additional doses before the diagnosis of malignant melanoma was confirmed. Mullen et al. [7] reported two further cases. The first was a 46-year-old woman with MS who had a mole on her shoulder. Shortly after the first infusion of natalizumab, she noticed a rapid change in its appearance. Further assessment confirmed this to be malignant melanoma with metas...

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LPAM-1 (integrin α4β7)-ligand binding: overlapping binding sites recognizing VCAM-1, MAdCAM-1 and CS-1 are blocked by fibrinogen, a fibronectin-like polymer and RGD-like cyclic peptides

Cited by 24 publications

References 36 publications

Aberrant activation of integrin α4β7 suppresses lymphocyte migration to the gut

Aberrant activation of integrin α4β7 suppresses lymphocyte migration to the gut

Inflammation and Clearance ofChlamydia trachomatisin Enteric and Nonenteric Mucosae

Melanoma complicating treatment with Natalizumab (Tysabri) for multiple sclerosis

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