Immune therapy in type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder directed against the β cells of the pancreatic islets. The genetic risk of the disease is linked to HLA-DQ risk alleles and unknown environmental triggers. In most countries, only 10-15% of children or young adults newly diagnosed with T1DM have a first-degree relative with the disease. Autoantibodies against insulin, GAD65, IA-2 or the ZnT8 transporter mark islet autoimmunity. These islet autoantibodies may already have developed in children of 1-3 years of age. Immune therapy in T1DM is approached at three different stages. Primary prevention is treatment of individuals at increased genetic risk. For example, one trial is testing if hydrolyzed casein milk formula reduces T1DM incidence in genetically predisposed infants. Secondary prevention is targeted at individuals with persistent islet autoantibodies. Ongoing trials involve nonautoantigen-specific therapies, such as Bacillus Calmette-Guérin vaccine or anti-CD3 monoclonal antibodies, or autoantigen-specific therapies, including oral and nasal insulin or alum-formulated recombinant human GAD65. Trial interventions at onset of T1DM have also included nonautoantigen-specific approaches, and autoantigen-specific therapies, such as proinsulin peptides. Although long-term preservation of β-cell function has been difficult to achieve in many studies, considerable progress is being made through controlled clinical trials and animal investigations towards uncovering mechanisms of β-cell destruction. Novel therapies that prevent islet autoimmunity or halt progressive β-cell destruction are needed

Baseline heterogeneity in glucose metabolism marks the risk for type 1 diabetes and complicates secondary prevention.

Non-diabetic children with multiple islet autoantibodies were recruited to a secondary prevention trial. The objective was to determine the predictive value of baseline (1) HbA1c and metabolic variables derived from intravenous (IvGTT) and oral glucose tolerance tests (OGTT), (2) insulin resistance and (3) number, type and levels of islet autoantibodies, for progression to type 1 diabetes

Locus-specific detection of HLA-DQ and -DR antigens by antibodies against synthetic N-terminal octapeptides of the β chain

Antibodies against synthetic peptides representing the class-II antigen HLA-DR and -DQ β chain N-terminal sequences were prepared in rabbits. The two octapeptides only share two amino acids and enzyme-linked immuno-assays showed the antisera only to bind to its own antigen. Both peptide antisera detected a 29 kDa component in immunoblots of Raji and AL-34 cell plasma membrane proteins separated by SDS gel electrophoresis. The binding of either N-terminal peptide antiserum was selectively inhibited only by the peptide used as antigen. Indirect immunofluorescence.analysis by flow cytofluorometry showed specific surface immunofluorescence in 1:100-1:1000 dilutions in lymphoblastoid and blood mononucleated cells. In the latter the binding was primarily confined to monocytes and a subpopulation of lymphocytes. It is concluded that locus-specific immunological reagents to distinguish between β chains of HLA-DR and -DQ have been prepared by the preparation by the production of antibodies against the N-terminal sequences of each polypeptide. © 1985

Temporal Variation of Ljungan Virus Antibody Levels in Relation to Islet Autoantibodies and Possible Correlation to Childhood Type 1 Diabetes

Viral infection may trigger islet autoimmunity, type 1diabetes (T1D), or both. Fluctuating population density of bank voles as a putative reservoir of Ljungan virus has been claimed to be associated with variations in T1D incidence rate (IR). We tested the hypothesis that Ljungan virus antibodies reflecting prior exposure(s) to the virus may be associated with islet autoimmunity, childhood diabetes or both. Incident, 0-18y, T1D patients (n = 63) were studied along with age and sample time matched controls (n = 126). The younger children (< 9 years) tended to have a higher incidence rate during winter (IR = 67.6, 95%CI 41.9-103.5) compared to summer (IR = 33.6, 95%CI 15.3-63.9) months. The proportion of children with high level antibodies against Ljungan virus (LVAb) were both younger compared to the rest of the children (p < 0.002) and correlated with half yearly T1D IR (r = 0.78, p = 0.005). High level LVAb fluctuating with season and correlating with T1D IR indicates that past exposure to Ljungan virus may be associated with T1D

HLA, infections and inflammation in early stages of atherosclerosis in children with type 1 diabetes

This prospective study focuses on risk factors for arterial damage in children with type 1 diabetes (T1D). Eighty children and adolescents with T1D were investigated twice, approximately 2 years apart, for carotid artery intima-media thickness (cIMT) and compliance (CAC), flow-mediated dilatation (FMD) of the brachial artery, and plasma levels of matrix metalloproteinase (MMP)-8. All subjects were genotyped for HLA. The number of respiratory tract infections (RTI) during the past year was obtained by a questionnaire in 56 patients. cIMT progression, defined as percentage (%) change of cIMT from baseline, correlated inversely with the % changes of both CAC (p = 0.04, r = - 0.3; n = 62) and FMD (p = 0.03, r = - 0.3; n = 47). In multivariate analysis, RTI frequency correlated significantly with cIMT progression irrespective of age, diabetes duration, BMI, and HbA1c (p = 0.03, r = 0.3). When patients were divided in relation to RTI, the association of DQ2/8 with cIMT progression remained significant in patients with over three infections/year (p = 0.04, r = 0.3). During follow-up, the group of DQ2/8 patients with hsCRP > 1 mg/l showed significantly higher levels of plasma MMP-8 than the non-DQ2/8 group. The diabetes-risk genotype DQ2/8 and systemic inflammation contribute to pro-atherosclerotic vascular changes in children and adolescents with T1D.Peer reviewe

Decreased cord-blood phospholipids in young age at onset type 1 diabetes.

Children developing type 1 diabetes may have risk markers already in their umbilical cord blood. It is hypothesized that the risk for type 1 diabetes at an early age may be increased by a pathogenic pregnancy and be reflected in altered cord-blood composition. In this study metabolomics was used to test if the cord-blood lipidome was affected in children diagnosed with type 1 diabetes before eight years of age. The present case-control study of 76 index children diagnosed with type 1 diabetes before eight years of age and 76 healthy controls matched for HLA risk, gender and date of birth as well as mother's age and gestational age revealed that cord-blood phosphatidylcholines and phosphatidylethanolamines were significantly decreased in children diagnosed with type 1 diabetes before four years of age. Reduced levels of triglycerides correlated to gestational age in both index and control children and to age at diagnosis only in the index children. Finally, gestational infection during the first trimester was associated with lower cord blood total lysophosphatidylcholines in both index and control children. In conclusion, metabolomics of umbilical cord blood may identify children at increased risk for type 1 diabetes. Low phospholipid levels at birth may represent key mediators of the immune system and contribute in early induction of islet autoimmunity