Novel Immunotherapies and Immunoregulation in a Chronic Inflammatory Disease of the Central Nervous System
Abstract: Multiple sclerosis (MS) is a chronic inflammatory disease of central nervous system (CNS) which is thought to arise from a breakdown of immunological tolerance in CD4 cells. The aim of this thesis is to improve our understanding of regulation mechanisms of T cell-dependent chronic inflammation in the CNS and explore ways to overcome the onset and progression of the disease, which can be an important step forward in the treatment of MS. We have utilized the Experimental Autoimmune Encephalomyelitis (EAE), as a mouse model for MS. Chronic EAE was induced by immunization with the myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide. MOG-reactive inflammatory CD4+ T cells infiltrate the CNS and, in concert with other mononuclear cells, cause inflammation and progressive paralysis. The focus of the first study was to evaluate the immunoregulatory role of CD1d-restricted T cells by using CD1d deficient mice. Our results suggest a regulatory role of CD1d-restricted T cells in EAE. This regulation functions through limiting the autoreactive T cell cytokine responses and enhancing TGF-beta1 production in the CNS. In another study, we investigated the therapeutic potential of monoclonal antibody (H57-597 mAb) against the T cell receptor (TCR) alpha/beta. We demonstrated that short term administration of anti-TCR alpha/beta can protect mice from EAE and is tolerogenic in established chronic EAE. We concluded that treatment with anti-TCR alpha/beta restores self-tolerance through a transient deletion of T cells including the autoreactive populations and a selective expansion of regulatory NKT cells. Finally, we evaluated the immunosuppressive potential of various probiotic bacteria strains in chronic EAE. We showed that oral administration of Lactobacillus paracasei DSM 13434, Lactobacillus plantarum DSM 15312 or Lactobacillus plantarum DSM 15313 suppressed EAE development by down-regulating autoreactive Th1 cells. The protective effect of the probiotic treatment was shown to be associated with an expansion of regulatory T cells in mesenteric lymph nodes and spleen followed by an increased production of IL-4, IL-10 and TGF-beta. We further demonstrated the powerful therapeutic potential of these bacteria in diseased animals when treating with a combination of these probiotic strains.
CLICK HERE TO DOWNLOAD THE WHOLE DISSERTATION. (in PDF format)