Multiple Sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS). The etiology of MS remains unclear, but the disease develops in genetically susceptible individuals exposed to environmental triggers. The long favored hypothesis in MS implicates autoreactive T cells generated in the periphery that access the CNS, where they induce injury of previously normal neural tissues. However, in contrast to the animal model experimental autoimmune encephalomyelitis (EAE), neither the target(s) of the immune response nor the cells responsible for CNS damage have been identified in MS. Furthermore, the failure of some MS treatments targeting processes that underlie the development of CNS tissue destruction in EAE (e.g. IFN-g, TNF-a inhibitors) indicates that different mechanisms may cause the development of disability in MS versus EAE. Therefore, there is a need to identify pathophysiological mechanisms that are specific for MS, but may not be predicted from EAE. Therapeutic trials, especially those that investigate novel therapeutic agents, represent a unique opportunity to investigate how specific perturbations of the biological system affect MS disease process. The goal of this project is to carefully study the biological perturbations induced by the application of novel therapeutic agents in Phase I/II clinical trials in MS in order to define mechanisms of CNS tissue injury, but also those that underlie beneficial immunoregulation and immune-mediated neuroprotection. By correlating changes measured in the biological system (e.g. different functions of the T cells or other immune cell subsets) with structural changes of CNS destruction or repair (measured by neuroimaging modalities), and with clinical outcomes, we can understand which biological processes are beneficial and which are harmful in the MS pathogenesis. Additionally, understanding which effects of applied therapies underlie their therapeutic benefit will allow us to define biomarkers that are indicative, and ideally also predictive of the full therapeutic response. We are currently studying immunomodulatory properties of three therapeutic agents: daclizumab, idebenone and rituximab in 3 investigator-initiated Phase I/II clinical trials performed under Investigational New Drug (IND) application (PI, Bibiana Bielekova). Our results are briefly summarized below: Daclizumab is a humanized monoclonal Ab against CD25, which is the alpha chain of the IL-2 receptor (IL-2R). CD25 is highly upregulated on activated T cells and contribution of CD25 to high-affinity IL-2 signaling was believed to be paramount for expansion of effector T cells. Thus, it was expected that daclizumab therapy will result in inhibition of T cell functions. While we have demonstrated that daclizumab is highly effective in suppressing MS-related inflammatory activity, this effect was not paralleled by inhibition of T cells. Instead, daclizumab selectively expands CD56bright natural killer (NK) cells and that this human-specific NK cell population has immunoregulatory function through its ability to kill activated autologous T cells. CD56bright NK cells utilize new mechanism (Granzyme-K;GzK) for killing T cells and GzK expression is selectively upregulated by daclizumab treatment. The expansion of CD56bright NK cells correlated with treatment outcome, suggestive that it can be utilized as biomarker of therapeutic response. This observation has now been fully reproduced in two double-blind, placebo-controlled multicenter Phase II/IIb trials of daclizumab in MS. We continue to study the mechanism of action (MOA) of daclizumab in MS in therapeutic trial of DAC-HYP (second generation of daclizumab) in patients with MS (protocol 10-N-0125), with the goal to determine all effects of daclizumab on human immune system. Through this work we described two novel MOA, which also revealed novel aspects of IL-2 biology: 1. daclizumab blocks activation of T cells by inhibiting CD25 expression on activated (i.e. mature) myeloid dendritic cells (mDCs). mDCs express CD25 and can produce IL-2, but cannot consume it because they lack another important singling chain, CD122. Instead, mDCs use their CD25 to transpresent IL-2, which they secrete into immune synapse, to a T cell that is being activated in antigen-specific manner. This IL-2 signal, given in conjunction with T cell receptor and costimulatory stimuli then allows T cell to enter proliferation cycle and clonally expand. 2. Finally, we recently described that daclizumab therapy also alters development of innate lymphoid cells (ILCs), by skewing differentiation of their common precursor away from pro-inflammatory lymphoid tissue inducer (LTi) cells and toward immunoregulatory CD56bright NK cells. This effect is paradoxical, by promoting IL-2 signaling via intermediate affinity IL-2R. Furthermore, we demonstrated that this effect of daclizumab normalizes enhanced levels of circulating LTi cells in MS patients to levels comparable to those observed in healthy subjects. Thus our data for the first time implicate LTi cells in human autoimmunity and suggest that their regulation may represent valid therapeutic target. In addition of mechanistic studies of daclizumab, in other two clinical trials we are trying to understand which mechanisms drive progression of disability and CNS tissue destruction in progressive MS. Primary-progressive MS (PP-MS) is resistant to therapy by immunomodulatory agents. Mitochondrial dysfunction coupled with oxidative stress has been proposed as one of the top alternative hypotheses underlying pathophysiology of PP-MS. Idebenone is a synthetic analogue of coenzyme-Q with lower lipophilicity, which allows its reduction by cytosolic enzymes that are upregulated under oxidative stress, such as NQO1. As such, it can improve mitochondrial metabolism under conditions with dysfunctional ETC complex I. Therefore, in protocol 09-N-0197, we test the hypothesis whether mitochondrial dysfunction and oxidative stress contribute to development of neurological disability in PP-MS. Efficacy of idebenone in suppressing oxidative stress intrathecally and its unexplored immunomodulatory effects are being measured by ex-vivo analysis of PBMC functions and CSF biomarkers in enrolled patients. Rituximab is a B cell depleting chimeric monoclonal Ab and has inhibitory effect on MS disease activity in patients with evidence of blood-brain barrier (BBB) breakdown. The current leading hypothesis is that B cells collaborate with antigen-specific T cells and support T cell activation through antigen-presentation functions and mutual co-stimulation. Furthermore, there is evidence that in secondary-progressive MS (SP-MS) patients B cells and T cells form tertiary lymphoid follicles deep within the brain sulci. These ectopic lymphoid follicles recapitulate activation of antigen-specific T and B cells within the intrathecal compartment. Unfortunately, because majority of progressive MS patients do not have overt BBB disruption, only about 0.1% of systemically administered rituximab gains access to CNS compartment, which is not sufficient to deplete CNS B cells. Therefore, we are testing the hypothesis that intrathecal administration of rituximab in patients with SP-MS will effectively deplete B cells in the CNS compartment and this will translate into therapeutic effect of rituximab on biomarkers of CNS tissue injury in the placebo-controlled, Phase II trial of rituximab in low-inflammatory SP-MS (protocol 10-N-0212).
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| Bielekova, Bibiana (2018) Daclizumab Therapy for Multiple Sclerosis. Cold Spring Harb Perspect Med : |
| Waters, Ryan S; Perry, Justin S A; Han, SunPil et al. (2018) The effects of interleukin-2 on immune response regulation. Math Med Biol 35:79-119 |
| Weideman, Ann Marie; Barbour, Christopher; Tapia-Maltos, Marco Aurelio et al. (2017) New Multiple Sclerosis Disease Severity Scale Predicts Future Accumulation of Disability. Front Neurol 8:598 |
| Komori, Mika; Kosa, Peter; Stein, Jason et al. (2017) Pharmacodynamic effects of daclizumab in the intrathecal compartment. Ann Clin Transl Neurol 4:478-490 |
| Weideman, Ann Marie; Tapia-Maltos, Marco Aurelio; Johnson, Kory et al. (2017) Meta-analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments. Front Neurol 8:577 |
| Tanigawa, Makoto; Stein, Jason; Park, John et al. (2017) Finger and foot tapping as alternative outcomes of upper and lower extremity function in multiple sclerosis. Mult Scler J Exp Transl Clin 3:2055217316688930 |
| Kosa, Peter; Ghazali, Danish; Tanigawa, Makoto et al. (2016) Development of a Sensitive Outcome for Economical Drug Screening for Progressive Multiple Sclerosis Treatment. Front Neurol 7:131 |
| Bielekova, Bibi (2016) Perspective: Who dares, wins. Nature 540:S10 |
| Lin, Yen Chih; Winokur, Paige; Blake, Andrew et al. (2016) Patients with MS under daclizumab therapy mount normal immune responses to influenza vaccination. Neurol Neuroimmunol Neuroinflamm 3:e196 |
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