Molecular and Functional Analysis of the relationship between T cell Myelin Epitopes and Disease in Multiple Sclerosis

Multiple Sclerosis is an inflammatory disease of the nervous system characterised by damage to myelin which coats the nerves. Through an abnormal immune response, white blood cells (T-cells), attack myelin fragments (‘epitopes‘). Treatments are being sought that specifically block this immune response. The approach assumes a detailed understanding of the immune response underlying MS - in fact, that information is patchy. Designing experiments to prove whether or not a particular immune response measured in the test tube is responsible for a patient‘s MS is challenging. This project will study the immune response in MS patients at different stages of their disease, aiming to answer the questions: i) Do patients with newly diagnosed MS have T-cells recognizing different myelin epitopes compared to long-term patients? and ii) Can the functional role of these cells in the disease process be pinned down, in terms of the inflammatory chemicals they make (cytokines) and by looking for evidence that they were strongly stimulated while they were in the blood of the patient during the disease process in studies of ‘telomere length‘ - the idea that long lived immunologically active cells can be identified by looking at the length of their eroded chromosomes

BACKGROUND - Multiples Sclerosis is a disease of the CNS in which inflammation causes damage to the myelin sheath leading to axonal degeneration. A common view is that the inflammatory damage results from autoimmune attack of myelin epitopes by self-reactive T lymphocytes. Many current hopes for treatment of MS rest on specific immunotherapeutics, capable of blocking the autoimmune response without global immunosuppression. However, this rationale assumes a clear understanding of the specific autoimmune responses responsible for the disease. While an enormous amount of data has previously been generated on T lymphocyte immune responses during MS, the causal relationship between these rather heterogeneous myelin responses and pathogenesis is unclear. In murine experimental models, important information about this has come from analysis of epitope spread during disease. AIMS AND OBJECTIVES - The proposed study will examine the difference between myelin-specific immune responses of patients at different stages of disease. This will allow the investigation of a number of specific issues pertinent to pathogenesis. Firstly, it will allow the acquisition of data in a case-controlled, retrospective, cross-sectional study of patient groups at different time points from diagnosis. The host laboratory previously reported a preliminary study of this type, though without functional data. Data from this training fellowship will, in the first instance, test the notion that the disease process is associated with spread of the T cell response through different myelin epitopes. This will be further investigated with respect to any differences in oligoclonality of T cell responses and patterns of cytokine responsiveness. A key goal of the study will be to correlate functional T cell responses with telomere length, as a means of drawing inferences about the replicative history of these T cell populations with respect to chronic antigen stimulation in vivo during the disease. DESIGN AND METHODOLOGY - Peripheral blood samples from MS patients with disease of short or long duration will be obtained from patients attending Charing Cross Hospital. Functional information on T cell responses to myelin epitopes will come from T cell proliferation assays, T cell receptor DNA sequence analysis, real-time qPCR, cytokine ELIspot analysis and, importantly, from flow cytometric analysis relating cytokine responses to telomere length. SCIENTIFIC AND MEDICAL OPPORTUNITIES - This will allow a more detailed appraisal of the functional relationship between specific autoimmune T cell responses and MS pathogenesis, paving the way for more specific therapies.