Brain Vol. 127 No. 12 © Guarantors of Brain 2004; all rights reserved
Scientific Commentary |
Inhibiting leukocyte recruitment to the brain by IVIg: is it relevant to the treatment of demyelinating CNS disorders?
Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 4N248, 10 Center Dr. MSC 1382 Bethesda, MD 20892-1382 USA Email: dalakasm{at}ninds.nih.gov
Recruitment and migration of activated leukocytes into the brain is a fundamental process in the induction of various autoimmune CNS disorders, most notably multiple sclerosis. Although not all tissues use the same molecules for leukocyte recruitment (Alter et al., 2003
; Ransohoff et al., 2003), the information derived from experimental allegic encephalomyelitis (EAE), a T-cell-mediated animal model that resembles multiple sclerosis, has provided useful data on the key molecules associated with T-cell transmigration into the brain. The initial contact between a leukocyte and an endothelial cell is referred to as ‘tethering’, while the immediate subsequent interaction is described as ‘rolling’ [Fig. 1(1) and (2)] (von Andrian and MacKay, 2000). These steps, which allow the leukocyte to slow down and roll along the vascular wall, are mediated predominantly by selectins and facilitated by two 
-4 integrins, 4ß1 [very late antigen-4 (VLA-4)] and Lß2 [lymphocyte function-associated antigen-1 (LFA-1)]. The rolling leukocyte can stop only if it receives an activating signal, such as that provided by a chemokine on the endothelial surface. This signal switches the two -4 integrins to a high affinity state [Fig. 1(3)]. Thereafter, the -4 integrins bind to the counter-receptors vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) on the endothelial cells and adhere irreversibly [Fig. 1(4)]. Leukocytes can then transmigrate out of the microvasculature.
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A series of experiments has demonstrated the vital role of
-4 integrins in the immune activation network and in facilitating the influx of activated T-cells into the CNS. Intravital microscopy is used in a new technique to visualize these steps in the post-capillary venules, major sites of leukocyte recruitment, directly in the brains of EAE mice (Kubes and Ward, 2000). The fundamental understanding of T-cell recruitment can lead to identification of molecular targets for therapeutic interventions. Progress in this area has already identified drugs that successfully suppress EAE or treat relapsing–remitting multiple sclerosis. These include statins, which reduce the expression of LFA-1, or the monoclonal antibody natalizumab that blocks -4 integrins and prevents their interaction with VCAM-1 (Miller et al., 2003). In this issue of Brain, Lapointe et al. add intravenous immunoglobulin (IVIg) to the list of agents that inhibit leukocyte recruitment. Using intravital microscopy, the authors demonstrate in vivo that treatment with IVIg has a direct effect on -4 integrin-dependent interaction of leukocytes with endothelial cells, resulting in reduced leukocyte rolling and adhesion. Most importantly, the effect of IVIg on leukocytes was associated with clinical improvement. In a parallel in vitro flow chamber study, they showed that IVIg blocked the -4 integrin-dependent leukocyte recruitment on VCAM-positive endothelial cells and had a direct effect on the ability of leukocytes extracted from multiple sclerosis patients to roll and adhere to tumour necrosis factor- (TNF-)-activated endothelial cells. These results demonstrate the mode of action of IVIg on leukocyte recruitment to the CNS. The information is important to understanding the means by which IVIg exerts a beneficial effect in the treatment of autoimmune neurological disorders.
Do these findings justify the use of IVIg to treat multiple sclerosis or other CNS diseases? As reviewed (Kazatchkine and Kaveri, 2001; Dalakas, 2004a), IVIg acts in multiple ways on the immune repertoire by (i) modulation of pathogenic autoantibodies; (ii) inhibition of complement activation and interception of membranolytic attack complex formation; (iii) modulation of Fc receptors on macrophages; (iv) downregulation of pathogenic cytokines and adhesion molecules; (v) suppression of T-cell functions; and (v) interference with antigen recognition. These actions often operate in concert with each other, but for a given autoimmune disorder there appears to be a predominant mechanism dictated by the underlying immunopathogenetic cause (Dalakas, 2004b). When the newly described effect on leukocyte recruitment is added to the above resumé, IVIg becomes a very attractive drug for treating T-cell-dependent autoimmune neurological disorders. At the molecular level, the effect on leukocyte recruitment is analogous to that of the humanized monoclonal antibody natalizumab which saturates 4ß1 integrin-binding sites on the circulating T cells (Fig. 1) to such an extent that T-cell entry into the brain is reduced, lowering the number of gadolinium-enhanced MRI lesions, and reducing the frequency of attacks in patients with relapsing–remitting multiple sclerosis (Miller et al., 2003). By analogy, therefore, the efficacy of IVIg in multiple sclerosis patients is expected to be as good as, if not superior to, that of natalizumab because, in addition to inhibiting T-cell recruitment, IVIg affects complement activation, suppresses cytokines and modulates Fc receptors on macrophages involved in demyelination. However, the available clinical data on IVIg for the treatment of relapsing–remitting multiple sclerosis patients are fragmented and insufficient. Although four controlled clinical studies have shown beneficial effects—including a lower annual relapse rate, improvement in disability and a reduction in gadolinium-enhancing MRI lesions equivalent to those of the approved therapies (Sorensen et al., 2002)—IVIg remains a second- or third-line treatment for multiple sclerosis since, thus far, all studies have been small and not sufficiently powered, or incomplete due to lack (in some) of MRI data and the use (in most) of subtherapeutic doses of IVIg. The study of Lapointe et al. rekindles interest in proving that IVIg could yet be a viable alternative to ß-interferons in relapsing–remitting multiple sclerosis. The rationale is based on the effect of IVIg on multiple sclerosis lymphocytes in vitro and the noted favourable clinical benefit; its analogy to natalizumab in inhibiting T-cell recruitment; its multiplicity of actions on the immune network; and its impressive effect on demyelinating neuropathies, such as Guillain–Barr syndrome and chronic inflammatory demyelinating polyneuropathy, the PNS counterparts of multiple sclerosis. A systematic, large-scale study, using therapeutic doses of IVIg (1–2 g/kg) and gadolinium-enhanced MRI as surrogate biomarkers, will arguably be very costly but, if it was to show that IVIg is as effective and safe as ß-interferons or glatiramer acetate, it could influence the way we are treating relapsing–remitting multiple sclerosis. One infusion per month—especially if done at home—would be psychologically more acceptable than interferons for patients and might provide a superior quality of life. Further, IVIg can be effectively combined with steroids and may have the advantage of safer use during pregnancy.
At the cellular level, the work by Lapointe et al. has not clarified whether the effect on T-cell recruitment in vivo relates to inhibition of chemokines and chemokine receptors. Because IVIg inhibited the leukocyte–endothelial cell interaction in EAE, but not in a stroke model where selectins and integrins are also activated, it remains to be seen if it affects leukocyte adhesion, not at the integrin–VCAM interaction but rather via the chemokine network. An effect on chemokines will have more applications in suppressing inflammatory mediators associated with various other CNS or PNS disorders.
As the catalogue of actions exerted by IVIg increases, so too does the list of questions this information generates. IVIg has clearly changed the way we are treating autoimmune neuromuscular disorders, such as acute and chronic demyelinating neuropathies, neuromuscular transmission disorders and inflammatory myopathies, and has been effective in one CNS disease, the stiff person syndrome (Dalakas, 2004a). Substantiating further its efficacy in other autoimmune CNS disorders, especially multiple sclerosis, will be a major step forward. The study by Lapointe et al. provides the impetus to pursue this possibility.
References
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