title: Regulation of interleukin-2-induced vascular leak syndrome by targeting CD44 using hyaluronic acid and anti-CD44 antibodies.
abstract: Previous studies from our laboratory demonstrated that CD44 knockout mice exhibit marked decrease in interleukin (IL)-2-induced vascular leak syndrome (VLS), thereby suggesting a role for CD44 in VLS. In the current study, we tested whether treatment with mAbs against CD44 or hyaluronic acid (HA), the ligand for CD44, can abrogate IL-2-induced VLS. Interestingly, administration of HA caused a marked increase in IL-2-induced VLS in the lungs and liver of C57BL/6 mice. In contrast, use of anti-CD44 mAbs reduced IL-2-induced VLS in the lungs and liver. Treatment with HA enhanced the IL-2-induced edema and lymphocytic infiltration in these organs and caused marked increase in IL-2-induced lymphokine-activated killer (LAK) cell activity, whereas administration of anti-CD44 mAbs caused a significant decrease in edema and LAK activity but similar levels of lymphocytic infiltration. Anti-CD44 mAbs, but not HA caused marked downregulation of CD44 expression on LAK cells. These studies demonstrate that molecular targeting of CD44 may serve as a useful tool to selectively alter the LAK activity and to prevent endothelial cell injury induced by IL-2.
authors.affiliation: Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
authors.forename: Amjad
authors.initials: A
authors.lastname: Mustafa
authors.forename: Robert J
authors.initials: RJ
authors.lastname: McKallip
authors.forename: Michael
authors.initials: M
authors.lastname: Fisher
authors.forename: Robert
authors.initials: R
authors.lastname: Duncan
authors.forename: Prakash S
authors.initials: PS
authors.lastname: Nagarkatti
authors.forename: Mitzi
authors.initials: M
authors.lastname: Nagarkatti
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D019559:Capillary Leak Syndrome / Q000188:drug therapy / Q000628:therapy*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004396:Coloring Agents / Q000493:pharmacokinetics; D004487:Edema / Q000139:chemically induced; D005070:Evans Blue / Q000493:pharmacokinetics; D005260:Female; D018960:Hyaluronan Receptors / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D006820:Hyaluronic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D007167:Immunotherapy / Q000009:adverse effects; D007376:Interleukin-2 / Q000494:pharmacology / Q000633:toxicity*; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology; D008099:Liver / Q000098:blood supply; D008168:Lung / Q000098:blood supply; D016131:Lymphocyte Subsets / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D013154:Spleen / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D004396:Coloring Agents; D018960:Hyaluronan Receptors; D007376:Interleukin-2; D011994:Recombinant Proteins; D005070:Evans Blue; D006820:Hyaluronic Acid