title: Blockade of hyaluronan inhibits IL-2-induced vascular leak syndrome and maintains effectiveness of IL-2 treatment for metastatic melanoma.
abstract: Vascular leak syndrome (VLS) is a life-threatening toxicity induced during IL-2 treatment of cancer patients. The mechanism of IL-2-induced VLS is still poorly understood. At present, there is no specific therapy for VLS. Previous studies from our laboratory demonstrated that hyaluronan (HA), a large glycosaminoglycan, abundant in the extracellular matrix and on the cell surface, caused a marked increase of IL-2-induced VLS in the lungs and liver of C57BL/6 mice. Conversely, blockade or knockout of its major receptor, CD44, resulted in a marked decrease of VLS, thereby suggesting a role for HA in VLS. In this study, we report a novel means to prevent IL-2-induced VLS by blocking endogenous HA with HA-specific binding peptide, Pep-1, a newly isolated peptide which specifically binds to soluble, cell-associated, and immobilized forms of HA. Our results demonstrated that blocking HA with Pep-1 dramatically inhibited IL-2-induced VLS in both normal mice as well as in mice bearing melanoma. Moreover, Pep-1 treatment maintained the effectiveness of IL-2 and prevented the metastasis of melanoma. IL-2-induced emigration of lymphocytes across the endothelium and cytotoxicity against tumor by lymphokine-activated killer cells were not affected by Pep-1. Instead, use of Pep-1 maintained endothelial integrity and reduced their apoptosis during IL-2-induced VLS. These data suggested that HA plays a critical role in regulating endothelial cell damage and induction of IL-2-mediated VLS. Also, blockade of HA using Pep-1 could constitute a novel therapeutic modality to prevent IL-2-mediated toxicity, thereby facilitating the effectiveness of high-dose IL-2 in the treatment of metastatic melanomas.
authors.affiliation: Department of Pathology, University of South Carolina School of Medicine, Columbia, SC 29209, USA.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Guan
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Nagarkatti
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology; D019559:Capillary Leak Syndrome / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000473:pathology; D005260:Female; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000502:physiology; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology / Q000276:immunology; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins