The Journal of Experimental Medicine
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Published online 18 September 2000.
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© The Rockefeller University Press, 0022-1007/2000/9/769/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 6, September 18, 2000 769-780

Original Article

Development of a Peptide Inhibitor of Hyaluronan-Mediated Leukocyte Trafficking

Mark E. Mummerta, Mansour Mohamadzadeha, Diana I. Mummerta, Norikatsu Mizumotoa, and Akira Takashimaa

a Department of Dermatology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9069
Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9069.214-648-3472214-648-3419

atakas{at}mednet.swmed.edu

Hyaluronan (HA), a high molecular weight glycosaminoglycan, is expressed abundantly in the extracellular matrix and on cell surfaces. Although HA is known to bind many adhesion molecules, little information has been available with respect to its direct physiological role. In this study, we developed a novel 12-mer (GAHWQFNALTVR) peptide inhibitor of HA, termed "Pep-1," by using phage display technology. Pep-1 showed specific binding to soluble, immobilized, and cell-associated forms of HA, and it inhibited leukocyte adhesion to HA substrates almost completely. Systemic, local, or topical administration of Pep-1 inhibited the expression of contact hypersensitivity responses in mice by blocking skin-directed homing of inflammatory leukocytes. Pep-1 also inhibited the sensitization phase by blocking hapten-triggered migration of Langerhans cells from the epidermis. These observations document that HA plays an essential role in "two-way" trafficking of leukocytes to and from an inflamed tissue, and thus provide technical and conceptual bases for testing the potential efficacy of HA inhibitors (e.g., Pep-1) for inflammatory disorders.

Key Words: glycosaminoglycan • leukocyte homing • contact hypersensitivity • Langerhans cell • phage display

M. Mohamadzadeh's present address is Baylor Institute for Immunology Research, Sammons Cancer Center, Dallas, TX 75204.

Abbreviations used in this paper: ANOVA, analysis of variance; CSA, chondroitin sulfate A; HA, hyaluronan; HAase, hyaluronidase; OX, oxazolone; RHAMM, receptor for hyaluronan-mediated motility; RP, random peptide.

© 2000 The Rockefeller University Press


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