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    • br T Cell specific Immunotherapies Have Proved Ineffective a

    2018-10-23


    T Cell-specific Immunotherapies Have Proved Ineffective at Blocking Relapsing MS The question remains about the nature of the peripheral target for immunotherapy. There is abundant evidence to suggest that MS is a mainly CD4 Th1/Th17 T-cell mediated disease (Martin et al., 2016). This concept is largely based on autoimmune experimental encephalomyelitis (EAE) studies in animals (Martin et al., 2016; Rostami and Ciric, 2013; Volpe et al., 2015). Surprisingly whilst all treatments that affect MS can influence T cell function and T cell subset distribution (Martin et al., 2016), clinical trial data with specific CD4, Th1/Th17 immunotherapies have all largely failed to exhibit more than marginal impact on relapsing MS (Deiß et al., 2013; Segal et al., 2008; van Oosten et al., 1997). This may argue against a significant role for CD4 T MG 149 in the control of MS. However, CD4-depletion studies were undertaken when HIV/AIDS mechanisms uncovered the risks of CD4 lymphopenia, therefore deletion was targeted to maintain CD4 T cell numbers above 250cells/μL. Although there was some effect on relapse rate, the trials failed to show an effect in reducing new MRI lesion formation, with about a 60–70% CD4 T cell depletion (van Oosten et al., 1997). In the animal model, >85% CD4 T cell depletion inhibits EAE and depletion of 30% exhibits essentially no effect, whereas about a 60% depletion exhibits a marginal effect in an optimized system (von Kutzleben et al., 2016). This therefore creates a concern that the human studies failed to deplete sufficiently to control disease. Likewise, blockade of interleukin (IL)-12 and IL-23 with ustekinumab to inhibit Th1 and Th17 did not significantly affect the MRI lesion load in MS (Segal et al., 2008). Again, whilst blockade of IL-12/23-P40 inhibits the induction of EAE, it fails to inhibit spontaneous relapses, which is more relevant to use in MS (Heremans et al., 1999). Blockade of IL-17 in EAE usually exhibits a modest inhibitory effect (Kap et al., 2011; Mardiguian et al., 2013) and perhaps not surprisingly blockade of IL-17 with secukinumab only inhibited new MRI lesions by 49% and Gd+ lesions by 67% compared to placebo from 4 to 24weeks (Deiß et al., 2013), which is similar or worse to that achieved with other low-moderately effective DMD (Arnold et al., 2014). Highly effective DMD inhibit MRI lesion formation by over 85–90% (Kappos et al., 2011). Alemtuzumab has high efficacy in active relapsing MS and depletes 70–95% CD4 T cells during the whole course of the pivotal clinical trials (Cohen et al., 2012; Kasper et al., 2013). This suggests that, based on response to treatments, one should not completely dismiss the possibility that MS is a T cell-mediated disease as active immunotherapeutics all influence T cell activity (Martin et al., 2016). However, upon dissection of the impact of other effective DMD, a mechanism of action on B lymphocytes (Fig. 2) is perhaps more compelling (Fig. 2) (Disanto et al., 2012). CD20-specific B cell depleting agents were clearly active at inhibiting, not only new MRI lesion formation, but relapses and the accumulation of disability (Hauser et al., 2008; Kappos et al., 2011; Sorensen et al., 2014).
    Some MS DMD Exhibit Pleiotropic Effects, but Anti-proliferative Drugs Preferentially Target B Cells Because of Their Enhanced Proliferative Activity Some DMD exert such pleiotropic effects that their putative mechanisms of action have often followed changes in scientific dogma. As such, their actions have been ascribed to mechanisms such as: CD8 T suppressor cells activity, anergy, Th1 to Th2 switching, T regulatory cell induction (Compston and Coles, 2002; Marta and Giovannoni, 2012; Martin et al., 2016). Whilst many putative mechanisms have their origins in T cell biology (Deiß et al., 2013; Marta and Giovannoni, 2012; Martin et al., 2016), since the efficacy exhibited by CD20-specific monoclonal antibodies (mAb) (Hauser et al., 2008; Kappos et al., 2011; Sorensen et al., 2014), many mechanisms of action have been re-evaluated in the context of B lymphocyte function (Ireland et al., 2014; Rizzo et al., 2016; Schubert et al., 2015). Teriflunomide inhibits both proliferating T and B cells (Li et al., 2013) and the vast majority of cytostatic agents, such as mitoxantrone and cyclophosphamide, described to target activated T cells, actually preferentially inhibit B cells, including memory B cells (Fig. 3), by virtue of their more rapid proliferation kinetics compared to T cells (Duddy et al., 2007; Tangye et al., 2003).