Blockade of very late antigen-4 integrin binding to fibronectin with connecting segment-1 peptide reduces accelerated coronary arteriopathy in rabbit cardiac allografts.

Molossi, Silvana; Elices, Mariano J.; Arrhenius, Thomas; Diaz, RM; Coulber, Claire; Rabinovitch, Marlene

doi:10.1172/jci117962

Cited by 102 publications

(69 citation statements)

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“…The results imply that therapeutic interventions targeted at interactions between T cells and ECMP (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) will be only partially effective in collagenous tissues if they do not block the costimulatory effects of type I collagen. This possibility is supported by the reports that VLA-4-blocking peptide and mAb are unable to inhibit cutaneous contact hypersensitivity, delayed-type hypersensitivity, or adjuvant arthritis in rodents by more than 35-60% (14,15,20,25).…”

Section: Discussionmentioning

confidence: 99%

“…The evidence that VLA-4 is a ligand for the alternatively spliced connecting segment 1 domain of fibronectin, and for VCAM-1, which both deliver costimulatory signals in T cells, has identified this integrin as a therapeutic target. This has led to multiple reports of the development and testing of potentially therapeutic VLA-4 Abs and peptide ligands, both in vitro and in animal models of inflammatory and autoimmune diseases, and transplantation (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Early human studies with VLA-4 targeting agents are also in progress, for example in patients with multiple sclerosis (26,27).…”

mentioning

confidence: 99%

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Potent Costimulation of Effector T Lymphocytes by Human Collagen Type I

Rao

Hales

Camp

2000

The Journal of Immunology

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Purified, resting peripheral blood T lymphocytes were previously reported to undergo β1 integrin-dependent activation when cultured with anti-CD3 mAb coimmobilized with fibronectin, but not type I collagen. However, the extravascular T cells that encounter immobilized extracellular matrix proteins and are involved in disease pathogenesis have different properties from resting peripheral blood cells. In this study, we confirm that resting CD4+ and CD8+ T cells from peripheral blood are costimulated by immobilized fibronectin, but not type I collagen. In contrast, Ag- or mitogen-stimulated CD4+ and CD8+ T cell lines, used as models of the effector cells involved in disease, are more potently costimulated by type I collagen than fibronectin. The collagen-induced effects are similar in assays with serum-free medium and in more physiological assays in which anti-CD3 mAb is replaced by a threshold concentration of Ag and irradiated autologous PBMC as APC. The responses are β1 integrin dependent and mediated largely by very late Ag (VLA) 1 and 2, as shown by their up-regulation on the T cell lines as compared with freshly purified resting PBL, and by the effects of blocking mAb. Reversed phase HPLC located the major costimulatory sequence(s) in the α1 chain of type I collagen, the structure of which was confirmed by amino acid sequencing. The results demonstrate the potential importance of type I collagen, an abundant extracellular matrix protein, in enhancing the activation of extravascular effector T cells in inflammatory disease, and point to a new immunotherapeutic target.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Potent Costimulation of Effector T Lymphocytes by Human Collagen Type I

Rao

Hales

Camp

2000

The Journal of Immunology

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“…In conclusion, the study reported by Molossi et al (1) in this issue of The Journal is highly significant and represents a careful and well-planned first step towards preventing atherogenic changes in grafted organs. Like any good piece of research, however, their studies raise fundamental biological questions to which we have, as yet, no answers.…”

Section: Editorialmentioning

confidence: 80%

“…It was with a great deal of trepidation that I agreed to comment on the report by Molossi et al (1) in this issue of The Journal. Not being trained as a physician or a cardiologist and never having seen a person with a transplanted heart, I was hesitant (even though the Editors told me that this was my chance "to be famous").…”

Section: Editorialmentioning

confidence: 84%

“…In this issue of The Journal, Molossi et al (1) describe a series of experiments in which transplantation arteriopathy is markedly reduced after the application of a synthetic peptide mimetic of the CS1 (connecting segment) of fibronectin. Initially, they hypothesized that "cellular fibronectin plays a pivotal role in the progression of allograft arteriopathy by directing the transendothelial trafficking of inflammatory cells through interactions of the CS1 motif with the VLA-4 integrin."…”

Section: Editorialmentioning

confidence: 99%

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What's potentially more effective than a Roto-Rooter and less toxic than Drano? Anti-adhesion mimetics!

Buck¹

1995

J. Clin. Invest.

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Absorption and disposition of a tripeptoid and a tetrapeptide in the rat

Wang¹,

Lin²,

Tullman³

et al. 1999

Biopharm. Drug Dispos.

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The present study is concerned with the absorption and disposition of a tripeptoid (N‐substituted glycine derivative) and a tetrapeptide in the rat. The two compounds have similar backbone structures but differ with respect to the presence or absence of peptide bond. [3H]tripeptoid and [3H]tetrapeptide were administered orally (30 mg kg−1) and intravenously (i.v.) (30 or 3 mg kg−1) to Sprague Dawley rats. Blood, urine and feces were collected at designated times for radioactivity and parent drug analysis. The intestinal absorptive clearances of the tripeptoid and tetrapeptide were studied using an in situ rat intestinal perfusion model. The octanol/water partition coefficient of these two compounds was also determined. The results showed that the peptoid and peptide have similar absorptive clearance and octanol/water partitioning, but different in vivo absorption and disposition characteristics. The absorptive clearances of the tripeptoid and tetrapeptide were 6.7 and 4.8×10−4 mL min−1 cm−1, respectively, and the corresponding octanol/water partition coefficients were 0.39 and 0.30. The extent of oral absorption of the tripeptoid was only 3–8%, consistent with its low absorptive clearance. In contrast, the apparent absorption of the tetrapeptide was >75% of the radioactive dose. The peptide was completely metabolized within 2 h after an i.v. dose, whereas the peptoid was stable in blood and was primarily eliminated in feces as intact drug. In conclusion, the difference in in vivo absorption and disposition between the peptoid and peptide was apparently due to the presence or absence of a peptide bond. The tetrapeptide was subject to rapid metabolism in the body. Its relatively high absorption appeared to represent the absorption of metabolized radioactive fragments. The peptoid appears to have advantages over the peptide in term of metabolic stability, but its low oral absorption and rapid biliary excretion present additional challenges in the selection of an optimal drug candidate. Copyright © 1999 John Wiley & Sons, Ltd.

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Blockade of very late antigen-4 integrin binding to fibronectin with connecting segment-1 peptide reduces accelerated coronary arteriopathy in rabbit cardiac allografts.

Cited by 102 publications

References 46 publications

Potent Costimulation of Effector T Lymphocytes by Human Collagen Type I

Potent Costimulation of Effector T Lymphocytes by Human Collagen Type I

What's potentially more effective than a Roto-Rooter and less toxic than Drano? Anti-adhesion mimetics!

Absorption and disposition of a tripeptoid and a tetrapeptide in the rat

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