Multiple Sclerosis and Neuroinflammation: Considering Gender differences to design therapeutic agents HALINA OFFNER

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1 Multiple Sclerosis and Neuroinflammation: Considering Gender differences to design therapeutic agents HALINA OFFNER

2 Sex differences in autoimmune disease Ratio Target Sex distribution of major autoimmune diseases Rose N. Am J Path 173(3) % of the people affected with autoimmune diseases are women affecting 5 to 8% of the population or 14.7 to 23.5 million people Numbers above bars-total number of disease cases (X 1,000,000) in the U.S. Whitacre C. Nature Immunology 2(9) 2001

3 Understanding Multiple Sclerosis and EAE MS - is a severe disorder of the CNS -characterized by chronic inflammation, myelin loss, gliosis, varying degrees of axonal and oligodendrocyte pathology and progressive neurological dysfunction Experimental autoimmune encephalomyelitis (EAE)- is the prevailing animal model for MS -induced in genetically susceptible rodent strains, upon immunization with spinal cord homogenates, myelin or specific myelin peptides in combination with adjuvant (active EAE) -and by adoptive transfer of encephalitogenic CD4+ T cells (passive EAE) Typically thought of as a Th1/Th17-mediated disease -although other cellular players (eg, APC) also play a role in the early and progressive events of the immune reaction leading to inflammation and CNS damage

4 Increased numbers of antigen presenting cells in the CNS increase susceptibility to and severity of EAE in female mice T cell response to foreign antigens increases numbers of activated T cells in female vs. male CNS (may be influenced by sex steroids) CNS T cells recruit higher numbers of APC Increased APCs enhance encephalitogenic activity of myelin-specific T cells, thus producing high susceptibility phenotype

5 Gender-based Immune differences Stronger immune response Higher APC, CD4 + Th2 and immunoglobulin responses (under estrogen influence) Severe inflammation and enhanced CD4 + Th1 & CD8 + T cell activity (under androgen influence) Fundamental differences in immune function may require different immunomodulatory strategies in females vs. males

6 Complex regulatory balance between the detrimental and beneficial effects of immune cells in MS Th2 IFN-g, TNF-a, IL-6, IL-17 Th1 IL-4, IL-10 T reg NK?? CD8 + T Mast Protection Disease

7 A model for the multifactorial nature of autoimmune disease- Sex hormones represent an important modulatory factor in the immune and autoimmune response Whitacre C. Nature Immunology 2(9) 2001

8 Recent increase in the incidence rates of MS onset in females as compared to males Figure: Annual age- and sex-adjusted incidence rate (95% CI) of multiple sclerosis in Lorraine, France according to year of onset. Debouverie M. Journal of Neurological Sciences

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13 Do the benefits of vitamin D 3 show a female bias in humans?

14 Facts that link vitamin D and MS 1921: MS cases increase with distance from the equator (C.B. Davenport) The decrease in MS cases with increasing UV light has been documented in q USA q UK q Australia

15 MS cases decrease with increasing UV light exposure MS risk (cases per 100,000 people) UV light availability (December 25)

16 Vitamin D levels decrease with distance from the equator MS risk (cases per 100,000 people) UV light availability (December 25) Low Serum 25-hydroxyvitamin D 3 High Low

17 UV light catalyzes the first step in vitamin D 3 synthesis Calcitriol OH OH OH OH 25-hydroxylase 1a-hydroxylase 24-hydroxylase OH OH Serum 25-hydroxyvitamin D 3 levels correlate with exposure to UV light

18 The benefits of vitamin D 3 showed a female bias in mice with EAE Female spinal cord histopathology ~12 nmol/l ~82 nmol/l serum 25-OH-D 3 Spach & Hayes, J. Immunol. 175:4119, 2005

19 Estrogen was needed for vitamin D 3 to inhibit EAE in female mice Ovariectomy eliminated vitamin D 3 - mediated inhibition of EAE Estrogen replacement restored vitamin D 3 -mediated inhibition of EAE

20 If humans have a similar gender difference in vitamin D metabolism in the CNS ( less CYP24A1 transcripts in females), then sunlight deprivation would increase the MS risk more significantly in women then in men. Which could explain higher incidence of MS in females.

21 Hypotheses There may be a female bias in the protective effects of vitamin D 3 in MS Vitamin D 3 insufficiency may contribute to the high female:male sex ratio in MS Life style changes linked to insufficient sunlight exposure may be increasing the female:male sex ratio in MS q q q Women in the work force Indoor life style Sunscreen use Declining ovarian function and limited vitamin D 3 supplies may be driving the transition from RRMS to CPMS

22 Recombinant T-Cell Receptor Ligand MHC II Molecule General RTL Molecule RTL Molecular Structure Antigenic Peptide Interchangeable Peptide p- β linker a1 b1 a 1 b 1 a2 a 2 b2 b 2 Targets antigen-specific receptors on T-Cells a1 b1 MHC II α-β linker Antigen Presenting Cell α2 and β2 subunits deleted Peptide = 10-20aa α-βlinker = 0-10aa P-βlinker = 14aa MW = 25,000 (210aa) Produced in E. coli MS Collaborative Research Group

23 RTL treatment of EAE at the onset of disease FEMALES MALES

24 RTL551 Reverses T-cell Infiltration in Spinal Cords of Male and Female C57BL/6 Mice with EAE Onset 3 days post-treatment Vehicle T Cell Infiltration 3 days post-treatment RTL MS Collaborative Research Group

25 Major Inclusion Criteria for Phase I Study Fulfill McDonald Criteria for MS Confirmed diagnosis of RRMS or SPMS EDSS 0.0 to 6.5 No clinical exacerbations within 8 wks HLA-DR2 positive males and females >18 and <65 years of age MS Collaborative Research Group

26 Trial Design and Sites Six cohorts (escalating doses ranging from 2mg to 200mg) q Up to six subjects/cohort (4 drug; 2 placebo) q DSMB review q 34 subjects (males and females) enrolled and followed over 90 days Clinical Sites: q University of Maryland, College Park q OHSU, Portland q Kansas University, Kansas City q Indiana University, Indianapolis q Yale, New Haven q Seattle Evergreen MS Collaborative Research Group

27 Results: No MS Disease Activity Included as a safety endpoint to determine if RTL1000 increases MS disease activity q q q q q q Neurologic exam Extended Disability Status Score (EDSS) 25-ft timed walk 9-hole peg test Gadolinium-enhanced magnetic resonance imaging (MRI) Reports of MS exacerbation RTL1000 did not increase MS disease activity by any measure in either females or males MS Collaborative Research Group

28 When and how should sex differences be considered? Sex matters in many clinical diseases and animal disease models (eg. Vitamin D but not RTLs) Pre-clinical studies should include both sexes Disease models such as EAE have mainly used a single gender or gender unspecified animals q Justified as a means of decreasing experimental variability caused by female hormone cycling q Based on assumption that disease mechanisms or treatment effects would be the same for both genders

29 ACKNOWLEDGMENT I would like to thank Colleen E. Hayes, Ph.D., Professor of Biochemistry, University of Wisconsin-Madison for the use of her data in my presentation.

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