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    • Spingosine phosphate receptors which mediate the action

    2018-11-01

    Spingosine-1-phosphate receptors, which mediate the action of fingolimod and the alpha-4 integrin (CD49d), blocked by natalizumab, have broad expression not only on lymphocytes but also in other mononuclear cells (Marta and Giovannoni, 2012; Martin et al., 2016). Lymphocyte depleting agents could shed light on the mechanism of highly active disease, but apparent confusion emerges as cladribine and alemtuzumab deplete both T and THZ531 cost (Cohen et al., 2012; Kasper et al., 2013; Marta and Giovannoni, 2012; Rieckmann et al., 2009), rituximab/ocrelizumab deplete primarily B cells (Hauser et al., 2008; Kappos et al., 2011; Marta and Giovannoni, 2012), whilst daclizumab inhibits activated T cells and augments natural killer cell function (Kappos et al., 2015; Marta and Giovannoni, 2012; Martin et al., 2016).
    Inhibiting Memory B Cell Function Blocks Relapsing MS Alemtuzumab is one of the most effective drugs and can induce long-term no evident disease activity following a 5 then 3day course of 12mg/day, one year apart (Cohen et al., 2012; Deiß et al., 2013; Marta and Giovannoni, 2012). Based on lymphocyte effects of alemtuzumab, T cells are most affected and CD19 B cell numbers are normal by 6 months post-treatment (Cohen et al., 2012; Kasper et al., 2013). However, it is evident that the CD19+ B cell response is a composite of different B cell subsets (Fig. 3) and there is early and marked hyper-repopulation of immature B cells followed by a later mature B cell response, with a continued marked depletion of CD19+, CD27+ B memory cells (Fig. 4) (Thompson et al., 2010). Consequently this raises the question whether T cells or memory B cell depletion mediated the therapeutic effect, especially as it is reported that disease activity is unrelated to CD4/CD8 levels (Kousin-Ezewu et al., 2014). Whilst, the rapid repopulation of immature B cells, during a period of marked depletion of absolute numbers of regulatory T cells (Cox et al., 2005; Thompson et al., 2010), may account for the secondary B cell autoimmunities following alemtuzumab (Cohen et al., 2012; Cox et al., 2005; Krupica et al., 2006), inhibition of MS could relate to the depletion of the memory B cell subsets (Fig. 4) (Thompson et al., 2010). Phenotypic analysis from the oral cladribine studies indicated that CD4 T cells were only depleted in the range of 40–45% and CD8 T cells were depleted by about 15–20% from baseline, over the first year of treatment with effective doses of oral cladribine (Duddy et al., 2007; Giovannoni et al., 2010). In contrast depletion of CD19 B cells was most marked (Duddy et al., 2007).In the oral cladribine studies there was a clear dose-effect between the 5.25mg/kg and 3.5mg/kg dose arms in terms of both CD4 and CD8 T cell populations, but no dose-effect in relation to the B-cell population (Duddy et al., 2007). As the 5.25mg/kg and 3.5mg/kg dose were equally effective (Giovannoni et al., 2010), this would argue that the effect of cladribine is via B cell depletion. It has been found that B cell depletion with CD20-specific mAb is effective at inhibiting relapsing MS (Hauser et al., 2008; Kappos et al., 2011; Sorensen et al., 2014) thereby arguing against the importance of targeting T cells to control MS. To reconcile this difference, it has been suggested either these B cell depleting reagents block antigen presentation to T cells to limit their disease-inducing activity (Fig. 2) or that the therapeutic antibodies target T cells (Graves et al., 2014; Martin et al., 2016; Palanichamy et al., 2014). However, whilst CD20+ B cells are markedly depleted following rituximab treatment, CD4 and CD8 T cells populations are depleted only by about 10–25% in the blood (Graves et al., 2014; Palanichamy et al., 2014; Piccio and Naismith, 2010). Unless the cells responsible for driving MS activity consist of a very selective subpopulation, this level of depletion would be insufficient, given the fact that 60–70% depletion of CD4 T cells by CD4-depleting antibody had a marginal impact on relapses (van Oosten et al., 1997). In contrast to the blood levels, analysis of the T and B cell levels within the cerebrospinal fluid has reported a marked (over 50%) reduction of T cells that can occur following rituximab treatment (Piccio and Naismith, 2010). Whilst this could be a reason for effective disease control, we feel this is more likely a consequence of effective disease control, causing both a reduction in T and B cell levels in the CNS (Piccio and Naismith, 2010).