| Popis: |
Sex hormones can dramatically modulate immune responses and influence both susceptibility and clinical disease course in autoimmune disease. In multiple sclerosis (MS), sex determines susceptibility and clinical presentation, while pregnancy has profound therapeutic actions over currently approved MS treatments. The objectives of this thesis were to determine the influences of sex hormones on the induction of an immune response using experimental autoimmune encephalomyelitis (EAE). The influence of sex hormones and genetics on EAE was evaluated using multiple mouse strains with different MHC class II haplotypes. We identified a new model of sexually dimorphic EAE and a model for primary progressive multiple sclerosis. Male B10.PL mice had increased clinical severity, mortality and histopathological infiltrates associated with an increased pathogenic Th1 immune response. Additionally, female sex hormones at the time of disease induction are protective, suggesting that sex hormones present at disease induction are important in influencing EAE. Since DCs are uniquely able to drive naïve Th0 cell differentiation to shape adaptive immune responses, we evaluated the influence of the pregnancy specific hormone estriol (E3) on DCs and EAE induction. DCs were expanded in vivo in the presence of pregnancy levels of E3. E3 DCs had an “activated regulatory” phenotype (i.e. increased CD80, CD86, PD-L1, PD-L2, B7-H3 and B7-H4), decreased mRNA levels of proinflammatory IL-12, TNF-alpha and NF-kappaB and increased mRNA levels of immunoregulatory IL-10 and IDO. E3 DCs produced less IL-12 and Th0 cells proliferated less in vitro with E3 DCs. Mice receiving E3 DCs were protected from EAE, having decreased severity, decreased CDS and complete resolution of clinical signs compared to mice receiving Pb DCs. This effect is dose-dependent and, importantly, E3 DCs maintain their protective phenotype in the face of potent inflammatory stimuli (i.e. in vitro LPS and in vivo adjuvants). Mice receiving E3 DCs are protected by increased IL-4 and decreased IFN-gamma with no contribution from CD4+CD25+FoxP3+ regulatory T cells. Taken together, these results demonstrate that sex hormones present during disease induction can influence the clinical course of EAE. Sex hormones generate regulatory DCs that may have important therapeutic applications in the treatment of inflammatory and autoimmune disease. |
