From therapeutic mechanisms to unraveling the pathophysiology of MS

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications, trials & patents

Abstract

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-gamma, TNF-alpha inhibitors and others) indicates that different mechanisms may cause the development of disability in MS versus EAE. [unreadable] 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 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 disease process. As a result, our laboratory focuses on performing detailed analyses of the complex functions of the immune system in MS patients before and during application of novel immunomodulatory therapies. This approach allowed us in the past to gain important insight into immunoregulation in humans. E.g., while studying immune responses during treatment with a humanized monoclonal antibody against CD25 (daclizumab) we defined CD56bright NK cells as an immunoregulatory cell population that is capable of killing autologous activated T cells via perforin degranulation. The therapeutic expansion of this regulatory population correlated with the observed decrease in T cell numbers in treated MS patients and also correlated with the extent of therapeutic benefit, as measured by inhibition of contrast-enhancing lesions on brain MRI.[unreadable] 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. While only a minority of the therapeutic agents in early clinical development will confirm therapeutic benefit, we believe that the information collected from therapeutic failures is equally useful for defining pathophysiology of MS as information obtained from therapeutic successes. 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. Finally, the long-term goal of this project is to gain full understanding of the pathophysiological mechanisms that underlie CNS tissue destruction in different subtypes of MS, in order to develop more effective and pathophysiologically-targeted therapies for this debilitating disorder.