Protein kinase C (PKC) has been implicated in the Wnt signaling pathway; however, its molecular role is poorly understood. We identified novel genes encoding ␦-type PKC in the Xenopus EST databases. Loss of PKC␦ function revealed that it was essential for convergent extension during gastrulation. We then examined the relationship between PKC␦ and the Wnt pathway. PKC␦ was translocated to the plasma membrane in response to Frizzled signaling. In addition, loss of PKC␦ function inhibited the translocation of Dishevelled and the activation of c-Jun N-terminal kinase (JNK) by Frizzled. Furthermore, PKC␦ formed a complex with Dishevelled, and the activation of PKC␦ by phorbol ester was sufficient for Dishevelled translocation and JNK activation. Thus, PKC␦ plays an essential role in the Wnt/JNK pathway by regulating the localization and activity of Dishevelled.
Although multiple sclerosis is considered to be an autoimmune disease in the CNS, the immune responses that take place in the CNS and lymphoid organs remain to be elucidated. Here, we have successfully induced various subtypes of experimental autoimmune encephalitis (EAE) in LEW.1AV1 rats carrying RT1(av1) on the Lewis background genes by immunization with recombinant rat myelin oligodendrocyte glycoprotein (MOG) in various solutions with adjuvants. The purpose of the present study was to analyse in more detail the clinical and immunopathological features of MOG-induced EAE in LEW.1AV1 rats. Immunization with high doses of soluble MOG with pertussis toxin induced acute, frequently fatal EAE, whereas medium doses of partially aggregated MOG without pertussis toxin produced relapsing and remitting EAE. Secondary progressive EAE was induced in some rats by immunization with the immunization protocol having an intermediate nature between the above two. The optic nerve (approximately 60% of the immunized rats) and spinal cord (100%) were frequently involved and detectable both clinically and pathologically, while there was no lesion in the cerebrum. Histological examination revealed that, despite variety in the clinical subtypes, progression of the pathological processes was strikingly uniform, i.e. initial inflammation with minimal demyelination followed by predominant demyelination with minimal lymphocyte infiltration. These findings suggest that the lesion during the later stage is maintained by humoral factors. Taken together, this experimental system can serve as a model of neuromyelitis optica. Further analysis will provide useful information to elucidate the pathogenesis and to develop immunotherapy for neuromyelitis optica and multiple sclerosis.
It was recently demonstrated that amyloid  (A) peptide vaccination was effective in reducing the A burden in Alzheimer model mice. However, the clinical trial was halted because of the development of meningoencephalitis in some patients. To overcome this problem, anti-A antibody therapy and other types of vaccination are now in trial. In this study, we have developed safe and effective nonviral A DNA vaccines against Alzheimer's disease. We administered these vaccines to model (APP23) mice and evaluated A burden reduction. Prophylactic treatments started before A deposition reduced A burden to 15.5% and 38.5% of that found in untreated mice at 7 and 18 months of age, respectively. Therapeutic treatment started after A deposition reduced A burden toϷ50% at the age of 18 months. Importantly, this therapy induced neither neuroinflammation nor T cell responses to A peptide in both APP23 and wild-type B6 mice, even after long-term vaccination. Although it is reported that other anti-A therapies have pharmacological and͞or technical difficulties, nonviral DNA vaccines are highly secure and easily controllable and are promising for the treatment of Alzheimer's disease. (4) and the passive transfer of anti-A antibodies were also effective in reducing amyloid deposits (5). Moreover, vaccinated mice showed an improvement in memory loss (6, 7). Thus, A peptide vaccine therapy has been shown to be effective in animal models, and human clinical trials were started with Betabloc (AN-1792), composed of synthetic A1-42 and QS21 as an adjuvant (8). However, the phase II clinical trial was halted because of the development of acute meningoencephalitis that appeared in 18 (6%) of 298 vaccinated patients (9). Importantly, it was later demonstrated by autopsy that there was a significant reduction of amyloid deposition and disappearance of degenerative axons in a treated patient (10). At the same time, T cell-dominant meningeal encephalitis was present in the cerebral cortex. These findings suggest that the vaccine therapy is a promising strategy for human Alzheimer's disease if excessive immune reactions are minimized to avoid unwanted neuroinflammation.Recently, it was reported that naked plasmid DNAs encoding proteins are taken into cells and produce the proteins in a small amount for a relatively long period when injected into the muscle or skin (11). Then, the proteins that are released in the extracellular space induce antibodies against the proteins (12, 13). Thus, gentle and quiet immune reactions could be obtained by DNA vaccine administration. In our and other's laboratories, immune therapies with DNA vaccines have been examined in autoimmune disease models (14-17) and have been found to be effective in preventing the diseases without the use of adjuvants. Here, we developed nonviral A DNA vaccines and were able to reduce the amyloid burden in the cerebral cortex and hippocampus of Alzheimer's disease model (APP23) mice by vaccination. Importantly, the side effects, such as T cell proliferation and neuroin...
Severe experimental autoimmune myocarditis and subsequent dilated cardiomyopathy (DCM) were successfully produced in Lewis rats by immunization with recombinant cardiac C protein. Seventy-five percent of immunized rats died between days 15 and 49 postimmunization, and all of the survived rats showed typical DCM characterized by the presence of ventricular dilatation and extensive fibrosis. Immunopathological and chemokine analysis during the acute phase revealed that there were marked macrophage infiltration with myocyte necrosis and up-regulation of MCP-1 and IFN-γ-inducible protein-10 (IP-10). Based on these findings, we prepared plasmid DNAs encoding the binding site of CCR2 and CXCR3, which are receptors for MCP-1 and IP-10, respectively. The culture supernatant of cells transfected with these DNAs inhibited the migration of T cells and macrophages induced by MCP-1 and IP-10. Remarkably, administration of the DNAs to C protein-immunized rats prevented the disease progression and rescued animals from death. The present study has demonstrated for the first time that gene therapy targeting the chemokine receptor could be a powerful tool for the control of experimental autoimmune myocarditis and DCM.
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