Multiple Sclerosis ….how neuroscience has been translated to treatment

1. Multiple Sclerosis….how neuroscience has been translated to treatment Dr Rosie Jones Bristol MS Research Unit Frenchay Hospital

2. This session • Understanding MS • Demographics • Pathology • Understanding the immuno-pathology • Understanding myelin damage • Understanding axonal damage • Using the information to design treatment • Possible CNS repair mechanisms • Some examples of the effects of MS on patients

3. MS Demographics • Prevalence between 10/100,000 and 170/100,000 (around 100,000 in the UK , 3 million world wide) • Most common in temperate latitudes • 2:1 women:men • Diagnosed in early adulthood (teens to 30s, range “x” to 70 years) Childhood MS now acknowledged. • Familial (genetic) susceptibility + unidentified factors • Significantly more common in Caucasian populations • Multiple symptoms-sensory and motor • Progressive with or without relapses Relapse Remitting, Primary Progressive Secondary Progressive (RR PP SP)

4. POPULATION STUDIES Some examples of prevalence figures world-wide: UK 99-178/100,000 (Orkney 287/100,00?) France 50/100,000 Italy 35-50/100,000 USA 70-165/100,000 (New Mexico 22/100/000) Australia 11-40/100,000 New Zealand 24-77/100,000 Middle East 20 -50/100,000 (?)

5. Environment: MIGRATION STUDIES Studies of migration from high prevalence area to low prevalence area: • South Africa and Israel are both low prevalence areas. • Europeans migrating to these areas retain high prevalence risk unless they migrate before the age of 15 years.

6. Environment: EXPOSURE • Levels of sunlight/Vit D • Global distribution, lack of exposure to sun-genetic link?? • Exposure to chemicals • Solvents, fuel pollution, smoking • Exposure to (viral) infections • Measles, hepatitis, herpes etc. vaccinations • Exposure to stress/trauma • MS may occur/worsen after giving birth, physical injury traumatic life events • Population Dietary differences • High saturated fat levels-lack of polyunsaturated fats in diet.

7. SPMS Clinical Impairment MRI-Defined Plaque Burden Occurrence, Extent of Severity Late RRMS Early RRMS Enhancements Time Progression of DisabilityMS Courses as Redefined by MRI Adapted with permission from Dr. J.S. Wolinsky.

8. Brain Imaging

9. Natural History of MS • Relapse remitting stage- intermittent clinical events 1 to 4/year -5 to 10 years • Secondary progressive phase-few or no relapses, steady progression in disability levelling off by about 20 years after diagnosis • Primary progressive –steady increase in disability with or without relapses. • Fulminate-very rare. Fast progression to wheelchair/ bed-bound in 3 to 10 years

10. Pathology Development of an MS Plaque Inflammation, Demyelination Axonal damage

11. Characteristics of MS pathology “Autoimmune mediated inflammation resulting in”: • Loss of myelin/loss of Oligodendrocytes? • Axonal damage • Axonal degeneration • Loss of brain bulk

12. Myelin and Nerve Conduction

13. Demyelination: Myelin and Oligodendrocytes in the CNS • Myelination in the CNS is by Oligodendrocytes-(peripheral myelin produced by Schwann cells-not present in CNS and not affected by MS) • Each Oligodendrocyte produces myelin extensions that wrap around several nerve axons • What happens to Oligodendrocytes in MS?

14. OLIGODENDROCYTES Oligodendrocyte in culture (Immunofluorescence for galactocerebroside)

15. Brain Imaging

16. PATHOLOGY Not all aspects of MS pathology are understood • Blood brain barrier disruption- immune cells move into CNS. • Complex inflammatory responses • Localised CNS damage-demyelination, axonal damage

17. Pathology Local infiltration of inflammatory cells across blood vessel walls requires: • Adhesion to blood vessel epithelium • Transit across blood vessel wall • Migration into local brain tissue

19. William Lindsey and Jerry Wolinsky

20. Evidence that MS is an Autoimmune disease. Immune activity overview • Activated T lymphocytes appear in the blood and CSF. Reactive to myelin proteins e.g. MOG • Activated T cells and macrophages seen in MS plaques • Increased CD4+ (helper) to CD8+ (suppresser) T cell ratio. • Local IgG production seen in CSF Possible antibody candidates: MOG (Oligodendrocyte glycoprotein), MBP (myelin basic protein), viral infection?

22. Immune markers Increased circulating levels of immune markers of immune activity during MS exacerbations observed including: • T cell activation markers • Markers of macrophage activation • Markers of cellular adhesion • Markers of extracellular matrix breakdown • Markers of inflammatory cellular amplification

23. T cell activation markers Markers of T Helper cell (Th-1) activation • Activated T helper cells release IL-2 (soluble IL-2 receptors detected) • IL-4 is associated with T cell activation • Interferon-gamma (INF) is associated with T cell activation • Macrophage activation follows

24. Macrophage activation Macrophage demyelination in vitro is mediated by tumour necrosis factor-(TNF ) and Interferon (INF) • TNF is increased in MS during relapse • INF and TNF act synergistically to heighten immune responses • TNF damages Oligodendrocytes in vitro Beta interferon, INF, counteracts the influence of TNFand INF

25. Aims of Disease Modifying Drugs DMDs are designed to break a key link or links in the presumed pathway to tissue destruction in active disease Links include • Immune cell activation (PB, CNS other?) • Immune cell adhesion and migration (BBB) • Immune cell clonal expansion (PB or CNS) • Immune cell/cytokine cycle amplification

26. William Lindsey and Jerry Wolinsky

28. Aims of Disease Modifying Drugs DMDs are designed to break a key link or links in the presumed pathway to tissue destruction in active disease Links include • Immune cell activation (PB, CNS other?) • Immune cell adhesion and migration (BBB) • Immune cell clonal expansion (PB or CNS) • Immune cell/cytokine cycle amplification

29. Treatments based on modifying immune function • Some tested disease modifying agents • Beta interferon- (betaseron betaferon, Avonex) • Glatiramir acetate (Copaxone, copolymer 1) • Natalizumab (Tysabri)-affects adhesion molecules • Campath H (Alemtuzumab) Depletes T cells • Fingolimod (Gilyena) sequesters activated T cells in lymph nodes • Peptide modulation? • Stem cells??

30. Clinical outcome of some DMDs • Reduction in number of relapses in early RR MS • Reduction in new MRI (enhancing) CNS lesions in early RR MS • Reduction in progression of disease by 9 to 12 months • Changes broadly reverse when treatments stops.

31. Current treatments • Inflammatory phase-steroids • Non –acute phases • General immunosuppressant agents • e.g. Azathioprine, Cyclosporine • Possible immuno-suppressants • e.g. diet, lifestyle changes • Statins?

32. BBB Action of Adhesion Molecules Peripheral circulation T cells express adhesion molecules e.g. LFA-1 VLA-4 Basementmembrane CNS Blood vessel Blood vessels express Adhesion molecules e.g. E-Selectin Matrix degrading enzymes e.g. matrix metallo-proteinases LFA- Leukocyte function associated antigen-1 VLA Very late antigen-4

33. Clonal cell expansion-promotion of cellular reactivity? Mechanisms for clonal expansion of auto-reactive immune cells and cellular amplification/restriction unclear • Following BBB breach other cells follow: In plaques-mostly T cells and macrophages • Macrophage activation: e.g. osteopontin, Macrophage inflammatory proteins • Pro-inflammatory cytokines detected in lesions • TNFa, INf-g, IL-2,IL-6,Il12.

34. In summary • Creation of auto-reactive immune cells by unknown mechanism • Failure to destroy auto-reactive immune cells in circulation • Breach of Blood brain barrier-entry of Specialised cells Unspecialised cells • Amplification of reaction • Restriction of reaction

35. Damage to nerve cells

36. Myelin damage and axonal loss in MS

37. Fate of axons and nerve cells It is now clear that axonal loss and damage are major features of MS • Presence of NAA (N-acetyle aspartate) in MR spectroscopy • Loss of brain bulk • Increasing disability • Alterations in physiological measures

38. Neuronal/axonal damage Axonal damage thought to be secondary to myelin damage. Loss of trophic support or direct injury to axon BUT In some models of MS axonal damage appears early with or without evidence of demyelination. AND Reduction in CNS bulk continues in absence of demyelination episodes (e.g. Progressive MS)

39. Possible causes of axonal loss Damage by • Proteases • Inflammatory cytokines • Nitric oxide • Glutamine Evidence of up-regulation of all these possible mechanisms seen in active MS.

40. Possible mechanisms of repair

41. Remyelination Remyelination requires: • Viable myelin making cells (oligodendrocytes) • Intact nerve processes • Suitable environment for cellular survival and activation

42. Oligodendrocyte - development ?

43. Features of Oligodendrocytes • Progenitor cells +ve for 04 mabs. Present throughout CNS. Undifferentiated. • Precursor cells +ve for Galacto-cerebroside (GalC). Earliest OG specific marker to be expressed. Large pale nucleus. • May produce myelin processes. • Mature cell +ve for myelin oligodendrocyte glycoprotein MOG. Small dense nucleus.

44. Possibilities for promoting remyelination • Stimulate cell activity/differentiation • Block progenitor cell inhibitory factors • Block agents that kill myelin-making cells • Transplant new OG cells-stem cells

45. Oligodendrocytes and myelin Extensive remyelination does not occur despite presence of intact axons and GalC+ve cells in the same lesion area. • GalC +ve cells do not appear to mature into MOG +ve cells to form new myelin • Cells appear quiescent. Die before they can mature? • GalC and MOG +ve cells appear to be destroyed in long term plaques • MOG+ve (mature) cells are destroyed selectively • Possibilities for treatment- stimulate cell activity/differentiation block inhibitory/cytotoxic factors Induce/transplant new OG cells?

46. Nerve cell repair Loss of axonal capability to repair may be : • Intrinsic-no mechanism in mature CNS • Due to Nogo-A mediated damage-Block or ablate. • Lack of access to or response to nerve growth factors • Hostile cytotoxic soup-too many factors to control Neurotrophic support may be developed e.g. ciliary neurotrophic factor.

47. Stem cells Can stem cells be used to effect repair in MS? • Types of possible stem cells • Resident oligodendrocyte precursor cells. • Used in early repair? Depeleted? • Embryonic stem cells • ethical and cross reactivity issues. Tumours • Other stem cells-e.g. haematopioetic • Autologous and relatively easy to obtain

48. C. What is known about adult stem cell differentiation? Figure 2. Hematopoietic and stromal stem cell differentiation. Click here for larger image.

49. Symptom management in MS Multiple symptoms both motor and sensory • Muscle weakness, fatigue, stiffness (spasticity) contracture • Sensory changes pain, burning/ tightness/numbness. Vision. Joint position. • Loss of motor control-ataxia tremor • Continence problems • Cognitive changes • Other behavioural and mood changes

50. Physical fatigue Neuromuscular fatigue Illustrated as change in force output with time. Loss of force may be due to central or peripheral (muscle) fatigue.