[Show abstract][Hide abstract] ABSTRACT: Insulin has been reported as a major autoantigen in both human and murine type 1 diabetes (T1D). Insulin1-knockout NOD mice with only insulin2 are protected against the development of autoimmune diabetes, suggesting that insulin1 has strong immunogenicity and insulin2 has weak immunogenicity or a possible protective role in the pathogenesis of type 1 diabetes. In this study, we have developed fiber-mutant adenovirus vectors that express murine proinsulin1 or proinsulin2 (named Ad.Pins1-RGD/Ad.Pins2-RGD) and administered those virus vectors to the NOD mouse to evaluate modulation of autoimmune responses. The intravenous administration of either Ad.Pins1-RGD or Ad.Pins2-RGD at 3 and 5 weeks of age strongly suppressed the development of overt diabetes, accompanied by a significant reduction of insulin autoantibody (IAA), and suppression of disease was similar between administration of Ad.Pins1-RGD and that of Ad.Pins2-RGD. Our study suggests that systemic administration of fiber-mutant adenovirus vectors, which induce transient expression of proinsulin, may be applicable to a gene therapy inducing tolerance to insulin.
No preview · Article · Jan 2009 · Annals of the New York Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: CD4(+)CD25(+) T cells (Tregs) play a critical role in maintaining dominant peripheral tolerance, and pathogenic autoreactive T cells may be frequent in the CD25-negative fraction of peripheral blood mononuclear cells (PBMCs) from patients with autoimmune disease. We therefore investigated whether T cell autoimmune responses to recombinant GAD65 can be detected by the use of ELISPOT assay in the CD25-negative fraction of PMBCs from Japanese type 1 diabetes (T1D) patients. The frequency of CD4(+)CD25(+) T cells was not different among patients with newly developed T1D, established T1D, and healthy controls. The CD25 positive cell-depleted fraction was obtained by negative selection with antihuman CD25 magnetic beads, reducing the number of CD4(+)CD25(+) T cells from 4-5% to less than 1%. In whole PBMC fraction, there was a significant elevation of IFN-gamma spots in PBMCs from recently diagnosed patients with T1D (P < 0.05), whereas the number of IFN-gamma spots from patients with established T1D was not significant. In the CD25-negative fraction, unlike whole PBMCs, we observed the significant IFN-gamma spots to GAD65 in the fraction from patients with established T1D (P < 0.05), but not in those with recently diagnosed disease. The phenomena were not observed for IL-4 spots. Our data suggest a possible role of Tregs maintaining dominant peripheral tolerance in T1D and application of further improved T cell assay detecting autoimmunity even in established T1D.
No preview · Article · Dec 2008 · Annals of the New York Academy of Sciences
[Show abstract][Hide abstract] ABSTRACT: InsulinB:9-23 peptide (insB:9-23) reactive T cells has been reported as crucial for type 1 diabetes. In this study, experimental autoimmune diabetes (EAD) mice, which subcutaneous immunization of ins1 or 2B:9-23 induced autoimmune diabetes in F1(B7.1B6 x BALB/c), was investigated for antigen specific therapy to delete pathogenic T cells. Intravenous injection of ins1 or 2B:9-23 significantly delayed the development of diabetes on the corresponding peptide-induced EAD (ins1EAD or ins2EAD) concomitant with reduced insulitis and insulin autoantibodies expression. Population of Foxp3(+) CD4(+) T cell was unchanged whereas the level of anti-insB:9-23 specific IgG(2a) but not IgG(1) were specifically decreased, suggesting reduction of pathogenic insB:9-23 reactive T cells. Most interestingly, intravenous administration of ins2B:9-23, whose amino acid sequence had one amino acid difference at position 9 delayed the development of diabetes in both ins1EAD and ins2EAD whereas ins1B:9-23 administration delayed diabetes in the ins1EAD but not ins2EAD, suggesting that one amino acid difference gives critical influence on the effect of intravenous injection of antigenic peptide for type 1 diabetes.
No preview · Article · Sep 2008 · Biochemical and Biophysical Research Communications
[Show abstract][Hide abstract] ABSTRACT: We reported an 83-year-old woman, who suffered from bacterial meningitis and subsequent vasculitis. She experienced episodes of loss of consciousness several times in July, 2006. She also had recurrent fever and was admitted to a local hospital. Routine examinations, including brain MRI and electroencephalogram, were negative and urinary tract infection was diagnosed. After successful antibiotic therapy, she was transferred to a rehabilitation hospital. After transfer, she had no headache, but presented fever again, and a reduced level of consciousness. Cerebrospinal fluid test showed that cell counts were high with a predominance of neutrophils, and her glucose level was low. She received antibiotic therapy on her suspicion of bacterial meningitis. Bacterial cultures of CSF and blood were negative, probably due to the previous antibiotic therapy. Repeated CSF analysis showed a decrease in cell counts, but her lower consciousness did not improve. Moreover, neurological symptoms such as left pyramidal tract sign appeared. She was transferred to our hospital on the suspicion of vasculitis. Diffusion MRI showed high intensity in the right middle cerebral artery (MCA) area and CT angiography showed the stenosis of the right MCA at the M3 portion. Two courses of steroid pulse therapy were performed. Her consciousness gradually improved and eventually could talk although cognitive decline remained as a residual deficit. Our patient failed to be diagnosed early because of atypical symptoms of meningitis. Caution seems necessary for elderly cases presenting with atypical initial symptoms of meningitis. Steroid pulse therapy was effective for the subsequent vasculitis, as reported previously.
No preview · Article · Aug 2008 · Nippon Ronen Igakkai Zasshi Japanese Journal of Geriatrics