SEARCH:   Advanced

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kubes, P. Articles by Kerfoot, S. M. Search for Related Content PubMed Articles by Kubes, P. Articles by Kerfoot, S. M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 June 2003, Vol. 101, No. 12, pp. 4648-4649 New targets for antiadhesion therapy of human multiple sclerosis Multiple sclerosis (MS) is a debilitating inflammatory disease of the central nervous system (CNS). There has been a lot of interest in the use of antiadhesion molecule therapy to prevent the recruitment of inflammatory cells to the CNS, thereby attenuating disease. Based on observations that blockade of 4 integrin was beneficial in animal models of MS, interest has focused exclusively on this molecule in the treatment of human patients, and clinical trials are now under way (Miller et al, New Engl J Med. 2003;348:15-23). Promising initial results have provided an impetus for exploring other antiadhesion pathways. The P-selectin–PSGL-1 pathway is extremely effective at tethering various leukocytes to the vessel wall, particularly at the high shear rates found in the CNS. Despite this, a role for P-selectin in MS has been largely dismissed, based on observations that selectin blockade alone had no apparent effect on the clinical development of a murine model of MS (Engelhardt et al, Blood. 1997;90:4459-4472). But by visualizing the cerebral microvasculature using intravital microscopy, a number of groups have identified a critical role for P-selectin or its ligand, PSGL-1, in the recruitment of leukocytes to the CNS in a number of models of inflammation, including a model of MS (Piccio et al, J Immunol. 2002;168: 1940-1949; Kerfoot and Kubes, J Immunol. 2002;169:1000-1006). Of course, some caution is necessary when one extends mouse data to human disease. In this issue, Battistini and colleagues (page 4775) use a novel zoonotic approach to observe the recruitment of human leukocytes from MS patients to inflamed murine brain microvessels and, for the first time, demonstrate a possible role for the P-selectin ligand PSGL-1 in human disease. In particular, the authors determined that CD8+ T cells from MS patients were more prone to adhesion than CD4+ T cells via predominantly a P-selectin–PSGL-1, and not an 4 integrin–VCAM-1, pathway. An alternative approach to using LPS to induce P-selectin and VCAM-1 on the mouse brain microvessels would have been to induce experimental autoimmune encephalomyelitis. But the levels of these adhesion molecules are similar in these two models in our laboratory. Although the transmigration of these cells was not investigated, CD8+ T cells are found in high numbers in active MS lesions, highlighting the potential benefit of including blockade of PSGL-1–P-selectin along with 4 integin blockade in the treatment of MS. This paper reminds us of the complexity of MS, which includes the infiltration of multiple leukocyte subsets that almost certainly will have different adhesive profiles. Combination therapy blocking multiple pathways of recruitment (including the P-selectin–PSGL-1 pathway) may prove to be of greater benefit. Paul Kubes, and Steven M. Kerfoot University of Calgary CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: CD8+ T cells from patients with acute multiple sclerosis display selective increase of adhesiveness in brain venules: a critical role for P-selectin glycoprotein ligand-1 Luca Battistini, Laura Piccio, Barbara Rossi, Simona Bach, Simona Galgani, Claudio Gasperini, Linda Ottoboni, Donatella Ciabini, Maria D. Caramia, Giorgio Bernardi, Carlo Laudanna, Elio Scarpini, Rodger P. McEver, Eugene C. Butcher, Giovanna Borsellino, and Gabriela Constantin Blood 2003 101: 4775-4782. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kubes, P. Articles by Kerfoot, S. M. Search for Related Content PubMed Articles by Kubes, P. Articles by Kerfoot, S. M. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

	Copyright © 2003 by American Society of Hematology         Online ISSN: 1528-0020