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 α₄ 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 α₄ 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 α₄ 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.