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The pathogenesis of multiple sclerosis (MS) could involve an autoimmune response to proteolipid protein (PLP). Immunization of experimental animals with this major myelin protein can lead to experimental allergic encephalomyelitis. To identify a possible role of PLP as target antigen in MS, we evaluated T cell immunity to PLP in blood and cerebrospinal fluid (CSF) from patients with MS and controls by counting cells which in response to PLP in short-term cultures secreted interferon-gamma. The PLP-specific B cell response was analyzed by counting cells secreting anti-PLP antibodies. PLP-reactive T cells were detected in blood of most MS patients (mean value 1 per 20,408 mononuclear cells), and at 41-fold higher numbers in CSF (mean 1 per 500 CSF cells). Anti-PLP IgG antibody-secreting cells were detected in blood from most MS patients (mean 1 per 30,303 cells), but such cells were 49-fold more frequent in CSF (mean 1 per 625 cells). PLP-reactive T and B cells were also detected in blood and CSF from control patients, but at much lower numbers. A strong and persistent autoimmune response to PLP as well as to other myelin proteins, enriched in CSF, is proposed to be pathogenetically important in MS.

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Oral administration of the uveitogenic peptide (aa 336-351) derived from human HSP60 induced clinical and histological manifestations of uveitis in 65.8% (48/73) of Lewis rats. Uveitis was significantly decreased to 16.7% (11/66) in parallel experiments with the peptide linked to recombinant cholera toxin B subunit (rCTB), also given by mouth ( £ 2 =34.2, p X 0.0001). The protective efficacy between tolerized and immunized animals was 74.7%. Adoptive transfer of mesenteric lymph node cells from tolerized rats prevented the development of uveitis. A significantly higher proportion of regulatory CD4+ subset of Th2 memory cells were found in the mesenteric lymph nodes (p X 0.005) and spleens (p X 0.05) of tolerized rats without uveitis, as compared with immunized rats and uveitis. In situ hybridization studies of mesenteric lymph nodes and/or the uveal tract showed significant increases in IL-10 and TGF-g mRNA but decreases in IFN-+ and IL-12 mRNA in tolerized, as compared with immunized animals. Thus, the mechanism of tolerance, preventing the development of uveitis may involve a regulatory subset of memory cells and a shift from Th1 to Th2 and Th3 cytokines. We suggest that mucosally induced uveitis can be prevented by oral administration of the peptide-rCTB conjugate.

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The accumulation of misfolded α-synuclein in dopamine (DA) neurons is believed to be of major importance in the pathogenesis of Parkinson's disease (PD). Animal models of PD, based on viral-vector-mediated over-expression of α-synuclein, have been developed and show evidence of dopaminergic toxicity, providing us a good tool to investigate potential therapies to interfere with α-synuclein-mediated pathology. An efficient disease-modifying therapeutic molecule should be able to interfere with the neurotoxicity of α-synuclein aggregation. Our study highlighted the ability of an autophagy enhancer, trehalose (at concentrations of 5 and 2% in drinking water), to protect against A53T α-synuclein-mediated DA degeneration in an adeno-associated virus serotype 1/2 (AAV1/2)-based rat model of PD. Behavioral tests and neurochemical analysis demonstrated a significant attenuation in α-synuclein-mediated deficits in motor asymmetry and DA neurodegeneration including impaired DA neuronal survival and DA turnover, as well as α-synuclein accumulation and aggregation in the nigrostriatal system by commencing 5 and 2% trehalose at the same time as delivery of AAV. Trehalose (0.5%) was ineffective on the above behavioral and neurochemical deficits. Further investigation showed that trehalose enhanced autophagy in the striatum by increasing formation of LC3-II. This study supports the concept of using trehalose as a novel therapeutic strategy that might prevent/reverse α-synuclein aggregation for the treatment of PD.

Background and Purpose-Cerebral ischemia is associated with inflammation involving accumulation of polymorphonuclear neutrophils. T cells have been suggested to contribute to the secondary progression of ischemic brain injury. Dendritic cells (DC) are potent regulators of immunity by activating and tolerizing T cells. DC have previously been detected in rat meninges and choroid plexus. Hypothesizing that DC are involved in inflammation associated with cerebral ischemia, we investigated DC in the brain of Sprague-Dawley rats after permanent middle cerebral artery occlusion (pMCAO) versus sham operation. Methods-All experimental rats (nϭ24) had the right MCA permanently occluded by inserting a nylon monofilament through the right external carotid artery. Immunohistochemistry was used to detect DC (OX62 ϩ ), microglia/macrophages (OX42 ϩ ) that developed into DC, and activated DC expressing major histocompatibility complex class II (OX6 ϩ ) in the brain hemispheres at 1 hour to 6 days after pMCAO or sham operation. Results-Levels of DC were elevated at 1 hour in the ischemic versus sham hemispheres (PϽ0.001) and ischemic versus nonischemic hemispheres (PϽ0.001). Activated DC expressing major histocompatibility complex class II (OX62 ϩ OX6 ϩ ) were still elevated at 6 days after pMCAO in the ischemic versus nonischemic hemispheres (PϽ0.01). The area of brain lesion correlated with numbers of OX62 ϩ DC per 100-mm 2 brain tissue section (rϭ0.79; PϽ0.0001). Conclusions-Increased levels of DC in the brain after pMCAO and correlation between DC numbers and brain lesion area indicate a role for DC in cerebral ischemia. This observation could constitute a basis for further studies on the role of DC in inflammation related to cerebral ischemia.