Intravenous immunoglobulins exposed to heme (heme IVIG) are more efficient than IVIG in attenuating autoimmune diabetes.

Intravenous immunoglobulins (IVIG) are known to have a therapeutic effect in some autoimmune diseases. We examined the effect of IVIG and heme-exposed IVIG on the development of immune mediated diabetes induced in C57BL/6 mice by multiple low doses of streptozotocin. IVIG were used in a dose of 200mg/kg daily for 15 days. Treatment with IVIG resulted in significant attenuation of diabetes induction as evaluated by glycemia, glycosuria and HbA1c level. Interestingly, heme-exposed IVIG had a still stronger antidiabetogenic effect. Serum levels of proinflammatory cytokines TNF-α, IFN-γ and IL17 were lower in IVIG treated animals when compared with controls, while IL10 level was higher. The number of CD4(+)Foxp3(+) cells was higher in pancreatic lymph nodes of heme-exposed IVIG treated mice. Our results show that IVIG may downregulate diabetes induction possibly by favouring induction of T regulatory cells and suggest enhanced effect upon heme-binding to IVIG.

Kidney protection against autoreactive CD8(+) T cells distinct from immunoprivilege and sequestration.

BACKGROUND: The kidney tubulointerstitium has been reported to be protected from T-cell--mediated damage by sequestration from the T-cell compartment. We examined the ability of autoreactive T cells to infiltrate the kidney in a transgenic mouse model. METHODS: RIP-mOVA transgenic mice express the model autoantigen, membrane-bound ovalbumin (mOVA), in kidney proximal tubular cells and pancreatic beta cells. OVA-specific CD8(+) T cells (OT-I cells) were transferred into these recipient mice and their immune response against pancreas and kidney tissue was compared. RESULTS: When OVA-specific CD8(+) T cells (OT-I cells) were injected into RIP-mOVA mice, they were activated in the renal and pancreatic lymph nodes by cross-presentation. These in vivo-activated OT-I cells caused the destruction of pancreatic islets leading to autoimmune diabetes, but did not infiltrate the kidney. Neither CD95--CD95 ligand interactions, which have been proposed to induce apoptosis in T cells infiltrating immunologically privileged sites, nor CD30 signaling was responsible for the lack of kidney infiltration. When OT-I cells were activated in vitro prior to injection, they could infiltrate the kidney and caused acute renal failure when injected in high numbers. CONCLUSIONS: A mechanism distinct from previously described organ-specific protective mechanisms such as sequestration of antigen or CD95-mediated immunoprivilege contributes to the protection of the kidney tubulointerstitium from infiltration by autoreactive CD8(+) T cell.

Glycosuria and insulitis in NOD mice expressing the HLA-DQw6 molecule.

To investigate HLA-linked genes controlling the susceptibility and resistance to insulin dependent diabetes mellitus (IDDM), HLA-DQ alleles of 45 Japanese patients with IDDM were analysed, using sequence specific oligonucleotide (SSO). DQA1*0301 and DQB1*04 were positively associated (R.R = 6.6, Pc less than 0.05 and R.R. = 4.7 Pc less than 0.01) and DQA1*0103 and DQB1*0104 were negatively associated (R.R. = 0.2, Pc less than 0.01) with IDDM. DQA1*0103 and DQB1*0104 were in strong linkage disequilibrium to encode for DQw6 molecule. Therefore, in a Japanese population, the DQw6 molecule seems to control the resistance to IDDM. To determine whether or not the DQw6 molecule itself can protect against glycosuria and insulitis in NOD mice, these animals were mated with HLA-DQw6 transgenic-C57BL/6 mice (DQw6-B6) and the F1 progeny expressing the DQw6 molecule were backcrossed with NOD mice. Eighty-five female backcross progenies were classified into four groups, according to the MHC classII phenotype; I-ANOD/I-ANOD DQw6(-), I-ANOD/I-ANOD DQw6(+), I-ANOD/I-Ab DQw6(-) and I-ANOD/I-Ab DQw6(+). At the age of 16 weeks, 9.1% of the DQw6(-) I-Ab(-) mice had a glycosuria whereas none of the DQw6(+) I-Ab(-) mice had a glycosuria. At the age of 30 weeks 13.6% of the DQw6(-) I-Ab(-) mice had a glycosuria and 7.7% of the DQw6(+) I-Ab(-) mice had a glycosuria. Histological examinations of the pancreas were performed in the 30 week old mice or after the development of glycosuria.(ABSTRACT TRUNCATED AT 250 WORDS)

Natural history of incidental hyperglycemia and glycosuria of childhood.

We prospectively followed 29 children and adolescents over a 1- to 8-year period who were referred for evaluation of hyperglycemia (in the absence of diabetes) or glycosuria found on routine screening or during acute illness. On initial examination, four subjects had islet cell autoantibodies, 4 of 22 had an abnormal intravenous glucose tolerance test result, 6 of 22 had low first-phase insulin release on intravenous glucose tolerance testing, and 10 of 20 had impaired glucose tolerance on oral glucose tolerance testing. On follow-up, insulin-dependent diabetes had developed in two of the four subjects with islet cell autoantibodies. The other two subjects with islet cell antibodies have had persistently abnormal glucose tolerance on both oral and intravenous glucose tolerance testing and have low first-phase insulin responses. Diabetes has developed in none of 25 subjects without islet cell antibodies, although two have persistently abnormal glucose tolerance or insulinopenia. All five subjects with islet cell antibodies or human leukocyte antigen DR3/DR4 with initial impaired glucose tolerance have either acquired diabetes or have abnormal glucose tolerance. In contrast, only one of five subjects with initial impaired glucose tolerance but lacking these markers has persistent glucose intolerance. We conclude that in the absence of islet cell antibodies or human leukocyte antigen DR3/DR4 heterozygosity, incidental hyperglycemia or glycosuria is unlikely to be associated with progression or diabetes.

Elevation of Factor VIII coagulant activity over Factor VIII coagulant antigen in diabetic children without vascular disease. A sign of activation of the Factor VIII coagulant moiety during poor diabetes control.

To investigate whether the elevation of factor VIII coagulant activity observed in children with poor control of diabetes is due to increased levels of the factor VIII coagulant moiety of the factor VIII complex or reflects activation of the factor VIII coagulant moiety, factor VIII coagulant activity (VIII C), factor VIII coagulant antigen (VIII C:Ag), and factor VIII-related antigen (VIII R:Ag) were determined in 75 insulin-dependent children. All children were without signs of vascular disease based on negative funduscopy, negative fluorescein angiography, normal serum creatinine levels, and absence of proteinuria. Children with poor actual control of diabetes had significantly higher VIII C values than did children with good actual control of diabetes based on HbA1 values, but VIII C:Ag values did not differ in children with good or poor actual control of diabetes. A significant elevation of VIII C over VIII C:Ag values was observed in children with poor actual control of diabetes, but no elevation of VIII C over VIII C:Ag was found in children with good actual control. VIII R:Ag values were higher in children with poor actual control. VIII C, VIII C:Ag, and VIII R:Ag did not differ significantly in children with short or long duration of clinical diabetes. Our observation of significantly higher VIII C values than VIII C:Ag levels strongly suggests intravascular activation of the factor VIII coagulant moiety during poor diabetes control. The process leading to activation of the coagulant moiety seems to be different from the process leading to the elevation of the other moiety of the factor VIII complex, the factor VIII-related antigen, in diabetic subjects.

[The HbA1c-determination with the aid of isoelectrofocusing method in the out patient control of juvenile diabetics (author's transl)]. / Die HbA1c-Bestimmung mit der Methode der Isoelektrofokussierung in der ambulanten Uberwachung juveniler Diabetiker.

In juvenile diabetics treated on an outpatient basis, the HbA1c value was determined by means of isoelectric focusing. This method proved to be relatively simple and reproducible. Approximately 24 samples can be examined simultaneously after capillary withdrawal. The following correlations were found: 1. with the average urinary glucose excretion - a) measured by the clinitest method, measurement being effected several times daily over a period of 4 weeks (R = 0.5063), as well as b) with the 24-hour urinary glucose excretion of the day of withdrawal, 4 weeks, 8 weeks and 12 weeks previously. Best agreement was found between the HbA1c value and the sum of urinary glucose excretion on the day of withdrawal, 4 weeks and 8 weeks previously (correlation coefficient R = 0.6022). 2. a relationship was also found in the current blood sugar levels (correlation coefficient R = 0.5061). The results are discussed with regard to the significance of the HbA1c measurement.

[The influence of metabolic control on chemotactic activity in insulin-dependent diabetes mellitus (author's transl)]. / Der Einfluss der Stoffwechsellage auf die chemotaktische Aktivität beim insulinabhängigen Diabetes mellitus.

An increased incidence of infections, especially during periods of poor metabolic control is well known in patients with insulin-dependent diabetes mellitus. Therefore, we studied polymorphonuclear chemotaxis and its dependence on the degree of diabetic control in 49 patients with insulin-dependent diabetes mellitus in 46 controls. A modification of the chemotaxis assay described by Frei et al. was used as test system. The mean chemotactic activity observed in the total group of insulin-dependent diabetics did not differ from the values obtained in the controls. However, in patients with poor diabetic control and glucosuria exceeding 60 g/24h, a significantly reduced chemotactic leucoyte migration was found. These data indicate that normalization of leucotaxis can be achieved in insulin-dependent diabetes by means of adequate diabetes control.

Prevalence of pathogenic yeasts and humoral antibodies to candida in diabetic patients.

The prevalence of oral yeasts and humoral precipitating antibodies to candida was estimated in 204 unselected diabetic patients (172 outpatients and 32 inpatients). Yeasts, mainly Candida albicans, were isolated from the mouths of 41% of the outpatients and precipitins were found in 17.5% although none of the patients had clinically overt candidiasis. The extent of oral yeast colonisation and incidence of antibodies was not related to their antidiabetic treatment or to the duration of their diabetes. It was, however, related to the blood glucose and urine sugar levels at the time they were sampled, the highest incidence being among the diabetic inpatients with high blood glucose levels at the time of sampling and the lowest among outpatients with normal blood glucose levels at the time of sampling. There was no such correlation when diabetic control over the previous 12-month period was considered.