Multiple Sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system (CNS) and is a major cause of disability in young adults. 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 an inflammatory cascade that results in the 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 of the immune system responsible for CNS damage have been identified in MS. Furthermore, the apparent 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. EAE has been widely explored model of MS, due to the fact that animal systems allow extensive freedom of experimental manipulations. On the other hand, the only experimental manipulation that is possible within the ethical constrains of human research is the application of therapies. Therefore, therapeutic trials, especially those that investigate novel therapeutic agents, represent a unique opportunity to investigate which perturbations of the biological system (in our case especially of the immune system) are beneficial and which are deleterious for the MS disease process. The goal of this project is to carefully study the biological perturbations induced by the application of novel therapeutic agents in investigator-initiated Phase I/II clinical trials in MS in order to define mechanisms of CNS tissue injury, but also those mechanisms 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, and with functional data as measured by clinical outcomes, we can understand which biological processes are beneficial and which are harmful in the MS disease process. 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. Currently, we are studying immunomodulatory properties of four therapeutic agents: daclizumab, rolipram, idebenone and rituximab by analyzing fresh or cryopreserved peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) derived from patients before and during application of these therapies. Our results and future directions 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. In two investigator-initiated Phase II clinical trials (protocols 99-N-0169 and 04-N-0019), we have demonstrated that daclizumab is highly effective in suppressing MS-related inflammatory activity. However, this therapeutic effect was not paralleled by functional inhibition of T cells. Instead, we determined that daclizumab selectively expands and activates 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. Currently, we are defining mechanism by which the NK cells are activated by daclizumab and also multiple complex mechanisms that CD56bright NK cells utilize to control adaptive immunity. Full understanding of these immunoregulatory mechanisms is prerequisite for more efficient utilization of CD56bright NK cells in the treatment of human immune-mediated diseases. Rolipram is a phosphodiesterase 4 (PDE-4) inhibitor previously defined as a highly effective therapy for multiple animal models of Th1/Th17-mediated autoimmune diseases, including EAE. Through enhancement of cAMP signaling, rolipram efficiently suppresses human Th1 T cells in-vitro. Unfortunately, we had to terminate our investigator-initiated Phase I/II clinical trial prematurely because of concern that rolipram enhances, rather than inhibits brain-inflammatory activity in MS. Understanding the mechanisms for this highly unexpected finding through analysis of immunomodulatory effects of rolipram in-vivo represents an opportunity to better define differences in pathophysiology between EAE and MS. We determined that rolipram was highly therapeutically active in treated MS patients, in the expected manner: it suppressed T cell activation and very potently suppressed pro-inflammatory CD4+ Th1/Th17 T cells, which argues against currently-accepted notion that pro-inflammatory CD4+ T cells mediate blood-brain barrier (BBB) disruption in MS. Instead, we observed that rolipram had an activating effect on several other cell types and we are currently analyzing which of these activating effects could represent mechanism for BBB breakdown in MS. Rolipram thus represents another example that argues for pathophysiological differences between EAE and MS. Full understanding of these crucial pathophysiological differences will allow us to develop animal models that may better predict therapeutic efficacy in MS patients. Idebenone is a lipid soluble synthetic analogue of coenzyme-Q (CoQ). As such, it both improves mitochondrial metabolism and has an antioxidant effect. Primary-progressive MS (PP-MS) is resistant to therapy by immunomodulatory agents. Additionally, the contrast-enhancing lesions (CEL), which precede development of focal MS plaques and are pathologically characterized by perivenular immune infiltrates, are typically absent in the majority of PP-MS patients. This prompted search for additional pathophysiological mechanisms that may underlie CNS tissue destruction in PP-MS. Mitochondrial dysfunction coupled with oxidative stress has been proposed as one of the top candidates. Therefore, we initiated double-blind phase I/II clinical trial of idebenone versus placebo (actively-recruiting protocol 09-N-0197) to test the hypothesis of whether mitochondrial dysfunction and oxidative stress contribute to development of neurological disability in PP-MS. The trial has an adaptive design and explores novel neuroimaging and molecular biomarkers as outcome measures. 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 monoclonal Ab which is used for the treatment of B cell malignancies. Additionally, rituximab has also profound inhibitory effect on inflammatory activity in MS patients with evidence of BBB breakdown. We are investigating complex mechanisms of B cell depletion and the immunomodulatory effects of rituximab on the human immune system. Additionally, we are currently developing double blind, placebo-controlled phase I/II clinical trial of intrathecal rituximab in MS patients with intact BBB (clinical protocol T-N-1235) to test the hypothesis that ectopic B cell follicles may participate in CNS tissue destruction in secondary-progressive MS (SP-MS) by intrathecal sequestration of the pathogenic immune responses. As outlined above, this project is highly collaborative and depends on close partnership of all units/sections of NIB as well as outside collaborators.
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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 |
| 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 |
| Komori, Mika; Lin, Yen Chih; Cortese, Irene et al. (2016) Insufficient disease inhibition by intrathecal rituximab in progressive multiple sclerosis. Ann Clin Transl Neurol 3:166-79 |
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