Aims/hypothesis. A population-based sample was studied to define immune abnormalities in individuals at risk of Type II (non-insulin-dependent) diabetes mellitus because of impaired glucose tolerance. Methods. A total of 1653 individuals aged 55 to 74 years participated in a population based survey in Southern Germany (KORA Survey 2000). Those without a history of diabetes were subjected to an OGTT. Randomly selected subjects with IGT (n=80) were compared with non-diabetic control subjects (n=77) and patients with Type II diabetes (n=152) of the same population-based sample after matching for age and sex. Immune parameters were analysed in serum with rigidly evaluated ELISA. Results. Serum pro-inflammatory cytokine interleukin 6 (IL-6) concentrations were higher in subjects with IGT and Type II diabetes than in the control subjects (median 1.8 and 2.5 vs 0.8 pg/ml, p<0.0001). Soluble IL-6 receptors potentiate IL-6 bioactivity and their concentrations were mildly increased in Type II diabetes (p<0.05). These immune changes seem relevant because IL-6 dependent acute-phase proteins C-reactive protein, serum amyloid A protein and fibrinogen were also increased in IGT and Type II diabetes. Circulating concentrations of TNF-α and its two receptors sTNF-R60 and sTNF-R80 were not increased in IGT subjects compared with the control subjects. Conclusion/interpretation. Our study shows systemic up-regulation of selected inflammatory mediators in patients with Type II diabetes and IGT. The pattern observed is non-random and fits with an IL-6 associated rather than TNF-α associated response. [Diabetologia (2002) 45:805-812]
One of the major causes of morbidity and mortality in man and economically important animals is bacterial infections of the gastrointestinal (GI) tract. The emergence of difficult-to-treat infections, primarily caused by antibiotic resistant bacteria, demands for alternatives to antibiotic therapy. Currently, one of the emerging therapeutic alternatives is the use of lytic bacteriophages. In an effort to exploit the target specificity and therapeutic potential of bacteriophages, we examined the utility of bacteriophage tailspike proteins (Tsps). Among the best-characterized Tsps is that from the Podoviridae P22 bacteriophage, which recognizes the lipopolysaccharides of Salmonella enterica serovar Typhimurium. In this study, we utilized a truncated, functionally equivalent version of the P22 tailspike protein, P22sTsp, as a prototype to demonstrate the therapeutic potential of Tsps in the GI tract of chickens. Bacterial agglutination assays showed that P22sTsp was capable of agglutinating S. Typhimurium at levels similar to antibodies and incubating the Tsp with chicken GI fluids showed no proteolytic activity against the Tsp. Testing P22sTsp against the three major GI proteases showed that P22sTsp was resistant to trypsin and partially to chymotrypsin, but sensitive to pepsin. However, in formulated form for oral administration, P22sTsp was resistant to all three proteases. When administered orally to chickens, P22sTsp significantly reduced Salmonella colonization in the gut and its further penetration into internal organs. In in vitro assays, P22sTsp effectively retarded Salmonella motility, a factor implicated in bacterial colonization and invasion, suggesting that the in vivo decolonization ability of P22sTsp may, at least in part, be due to its ability to interfere with motility… Our findings show promise in terms of opening novel Tsp-based oral therapeutic approaches against bacterial infections in production animals and potentially in humans.
These results demonstrate, for the first time, that an increased Th2 pattern in the non-diabetic stage preceding a Th1 shift is associated with the development of diabetes in naive NOD mice. Serum cytokines correlate with disease progression and pancreatic cytokine expression during prediabetes. Soluble cytokines measured in the periphery are therefore promising surrogate markers of diabetes development.
At onset of type 1 diabetes, the islet autoantibody status of patients has been reported to predict progression of the disease. We therefore tested the hypothesis that the systemic immunoregulatory balance, as defined by levels of circulating cytokines and chemokines, is associated with islet autoantibody status. In 50 patients with recent-onset type 1 diabetes, antibodies to GAD and insulinoma-associated antigen 2 (IA-2) were analyzed by radioimmunoassay; cytoplasmic islet cell antibodies were determined by indirect immunofluorescence.
RANTES (regulated on activation, normal T-cell expressed and secreted) is a T-helper type 1 (Th1) chemokine that promotes T-cell activation and proliferation. RANTES is genetically associated with asthma, sarcoidosis and multiple sclerosis. The concentration of RANTES is increased at inflammation sites in different autoimmune diseases. Type 1 diabetes (T1D) is a Th1-mediated disease with complex genetic predisposition. We tested RANTES as a candidate gene for association with T1D using three single-nucleotide polymorphism (SNP) variants (rs4251719, rs2306630 and rs2107538) to capture haplotype information. The minor alleles of all SNPs were transmitted less frequently to T1D offspring (transmission rates 37.3% (P ¼ 0.002), 38.7% (P ¼ 0.007) and 41.0% (P ¼ 0.01)) and were less frequently present in patients compared to controls (P ¼ 0.009, 0.03 and 0.04, respectively). A similar protective effect was observed for the haplotype carrying three minor alleles (transmission disequilibrium test (TDT): P ¼ 0.003; odds ratio (OR) ¼ 0.55; confidence interval (CI): 0.37-0.83; case/control: P ¼ 0.03; OR ¼ 0.74; CI: 0.55-0.98). Both patients and controls carrying the protective haplotype express significantly lower serum levels of RANTES compared to non-carriers. Subsequently, we tested a cohort of 310 celiac disease patients, but failed to detect association. RANTES SNPs are significantly associated with RANTES serum concentration and development of T1D. The rs4251719*A-rs2306630*A-rs2107538*A haplotype associated with low RANTES production confers protection from T1D. Our data imply that RANTES is associated with T1D both genetically and functionally, and contributes to diabetesprone Th1 cytokine profile.
Relatives at high risk of developing Type 1 diabetes mellitus have abnormal cellular immune regulation at the level of systemic chemokines. The up-regulation of CCL3 and CCL4 vs. down-regulation of CCL2 suggests opposed functions of these chemokines in the disease process. These findings need to be confirmed by independent studies.
We conclude that the systemic immunoregulatory state at diagnosis of T1D is predictive of clinical improvement during the remission phase. There was no general change in systemic immune reactivity in the months after diagnosis and initiation of insulin therapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.