Development of a Peptide Inhibitor of Hyaluronan-Mediated Leukocyte Trafficking

doi:10.1084/jem.192.6.769

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. Mummert^a, Mansour Mohamadzadeh^a, Diana I. Mummert^a, Norikatsu Mizumoto^a, and Akira Takashima^a

^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 cellsurfaces. Although HA is known to bind many adhesion molecules,little information has been available with respect to its directphysiological role. In this study, we developed a novel 12-mer(GAHWQFNALTVR) peptide inhibitor of HA, termed "Pep-1," by usingphage display technology. Pep-1 showed specific binding to soluble,immobilized, and cell-associated forms of HA, and it inhibitedleukocyte adhesion to HA substrates almost completely. Systemic,local, or topical administration of Pep-1 inhibited the expressionof contact hypersensitivity responses in mice by blocking skin-directedhoming of inflammatory leukocytes. Pep-1 also inhibited thesensitization phase by blocking hapten-triggered migration ofLangerhans cells from the epidermis. These observations documentthat HA plays an essential role in "two-way" trafficking ofleukocytes to and from an inflamed tissue, and thus providetechnical and conceptual bases for testing the potential efficacyof 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 ImmunologyResearch, 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.

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