Immune cell interactions in the Inflamed CNS

Around 80,000 people in the UK suffer from multiple sclerosis (MS). Although the precise mechanism that underlie this disease are still poorly understood, there is a consensus that in its early stages there is an ?autoimmune? attack on the brain with immune cells causing inflammation that ultimately destroys the nerves. From a mouse model of MS, called EAE, we know that CD4+ T cells are important both in the development of the disease and in the recovery from disease that can occur. Two types of CD4+ T cells are involved in promoting EAE, so-called Th1 and Th17 cells, and a third type ? T regulatory (Treg) cells are involved in recovery. However, we do not know how these three populations interact during the disease. We have developed new EAE models that allow us to identify and track each cell population within the brain, to determine whether Th1 and Th17 cells work together, independently, or perhaps even against each other to cause the disease. The models will also show how Treg cells can stop the damage caused by Th1 and Th17 cells and will allow us to develop new therapeutic approaches to boost Treg activity. These will also be tested for the ability to promote the repair of damaged nerves. We will also search for new ?biomarkers? which might indicate whether the disease will progress or will recover, and which could be used to better predict the course of MS in patients.

CD4+ T cells have a powerful capacity to either promote or restrain autoimmune inflammation. Classically Th1 cells, characterized by the production of IFN-gamma, were believed to drive inflammation in most autoimmune diseases, but recent evidence (largely from gene knockout studies) has given rise to the belief that such inflammatory diseases are driven primarily by the actions of IL-17-producing Th17 cells. CD4+ T regulatory (Treg) cells expressing the foxp3 transcription factor have a key role in preventing widespread autoimmune disease. Moreover, Th1 cells are believed to suppress generation of Th17 cells, based on studies of in vitro differentiation from na?ve T cells. So far there has been no methodical analysis of how effector cells (Th1 and Th17) and Treg cells interact within an inflamed organ. We have begun to define this using murine experimental autoimmune encephalomyelitis (EAE), the primary pre-clinical model for multiple sclerosis. Using distinguishable Th1, Th17 and Treg populations we have recently shown that a) Th1 cells preferentially access the non-inflamed CNS to initiate the EAE lesion; b) this allows Th17 and Treg cells to enter the inflamed CNS; c) the action of Tregs within the CNS is essential in driving disease resolution and d) therapeutic administration of myelin-responsive Tregs can be curative in ongoing chronic EAE models.
In this project we will use traceable populations to determine precisely how these three CD4+ T cell populations influence each other in vitro and during inflammation in vivo. We will determine the basis for the Th1 cells? preferential access to the non-inflamed CNS and how they make the CNS accessible to other cells. We will investigate how Th1 and Th17 effector cells influence the function of each other in the CNS. We have established a novel in vitro assay system that is providing evidence for surprising synergistic, rather than antagonistic effects between Th1 and Th17 cells and these will now be explored in vivo. Finally we will test a novel model for Treg function in vivo, determine whether their effects can promote remyelination in EAE and assess whether the presence of foxp3+ cells correlates with remyelination in MS lesions. This project aims to give the most complete picture of the natural history of EAE as a model autoimmune disease. It will provide a basis for the informed development of novel therapeutics and should provide new biomarkers for disease phenotype, progression and resolution.