Johanne Kaplan is an employee of Genzyme, a Sanofi Company

Johanne Kaplan is an employee of Genzyme, a Sanofi Company. Search Strategy and Selection Criteria References for this review were identified through searches of PubMed with the search terms alemtuzumab and multiple sclerosis or lymphocyte or CD52 or regulatory from 1998 until May 2012. been historically considered the predominant mediator of neuropathology in MS, more recent studies indicate that CD8+ T cells also play an important role [11-13]. Adoptive transfer of activated myelin-specific CD8+ T cells induces experimental autoimmune encephalomyelitis (EAE), an animal model of MS [11]. CD8+ T-cell perivascular infiltrates are common in MS plaques SB 242084 hydrochloride [12], with some CD8+ T-cell clones persisting in the brain, cerebrospinal fluid, and blood for SB 242084 hydrochloride years [13]. Studies by Bitsch et al. and Medana et al. have shown that CD8+ T cells may be involved in neuronal damage [4,14]. Increasing evidence supports a substantial role for B lymphocytes in the pathogenesis of MS. Post-mortem studies have exhibited that autoantibodies recognizing myelin oligodendrocyte glycoprotein (MOG) were found in high concentrations in the CNS parenchyma of patients with chronic CNS inflammation, suggesting that B cells may participate in demyelination through local production of pathogenic antibodies [15]. Besides their role in acute demyelination, B cells may contribute to the disease progression through their antigen presentation and cytokine secretion [16,17]. The formation of ectopic B-cell follicles has been reported in the cerebral meninges of a substantial proportion of MS patients with a chronic progressive disease [18]. However, perhaps the most compelling evidence that B cells contribute to the pathogenesis of MS is usually that rituximab, a depleting anti-CD20 monoclonal antibody specific for B cells, decreased inflammation and reduced the number of relapses within several months of the treatment onset in patients with MS [19]. Although studies of the pathogenesis of MS have traditionally focused on the adaptive immune system, an important role for the innate immune system is also recognized. Dendritic cells (DCs) participate in both innate and adaptive immune responses [20]. Other innate immune cells, including natural killer (NK) cells, may also modify the inflammatory process in RRMS [21]. Activated microglia may also activate T cells and release cytotoxic cytokines that destroy oligodendrocytes [5]. Alemtuzumab is a humanized monoclonal antibody directed against CD52, a glycosylated, glycosylphosphatidylinositol-anchored, cell-surface protein that is expressed at high levels on T and B lymphocytes [22,23]. CD52 is also expressed at lower levels on NK cells, monocytes, DCs, macrophages, and eosinophils, with little to no expression on neutrophils, plasma cells, and bone marrow stem cells [22]. The function of CD52 is unknown, but evidence suggests it may be involved in T-cell co-stimulation [24] and migration [25]. Alemtuzumab can deplete CD52-positive cells through antibody-dependent cell-mediated cytolysis (ADCC) [22,26], complement-dependent cytolysis (CDC), and induction of apoptosis [27]. This selective cell depletion is the first step in a series of immunological changes that may contribute to the long-term benefit of alemtuzumab in MS patients. Efficacy of Alemtuzumab in MS Clinical Trials Based on the hypothesis that a brief course of alemtuzumab may result in depletion of lymphocytes and disrupt the inflammatory processes of MS, Coles et al. began treating MS SB 242084 hydrochloride patients with alemtuzumab in 1991 [28]. In a small exploratory clinical trial, they have demonstrated that this antibody effectively suppressed clinical activity (relapse rate) in both the RR and secondary progressive (SP) Rabbit Polyclonal to Acetyl-CoA Carboxylase stages of MS [28]. In contrast to RRMS patients who experienced significant reductions in disability at 6 months, patients with SPMS treated with a single course of alemtuzumab did not experience a noticeable improvement in their disability. Therefore, the subsequent 3-year, CAMMS223 Phase II study (“type”:”clinical-trial”,”attrs”:”text”:”NCT00050778″,”term_id”:”NCT00050778″NCT00050778) [29] examined the clinical effects of alemtuzumab in previously untreated patients with early RRMS. Compared with subcutaneous (SC) IFN-1a 44 g injections three times a week, two annual courses with alemtuzumab resulted in significant reductions in relapse frequency, sustained accumulation of disability (SAD), and T2 lesion burden over the 36-month study [29]. Findings of the CAMMS223 trial were confirmed in the Phase III Comparison of Alemtuzumab and Rebif? Efficacy in Multiple Sclerosis (CARE-MS) studies, in which alemtuzumab showed superior efficacy compared with SC IFN-1a 44 g over 2 years in RRMS patients (Table 1) [30,31]. In CARE-MS I (“type”:”clinical-trial”,”attrs”:”text”:”NCT00530348″,”term_id”:”NCT00530348″NCT00530348), which enrolled treatment-na?ve patients, alemtuzumab reduced the relapse rate by 55% (studies in wild-type mice unfeasible. Therefore, a transgenic mouse model expressing huCD52 was created on an outbred CD1 background (CD1) [22]. Histological evaluation of the resulting transgenic mouse showed that expression of.