Immunology in the early stages of type I diabetes.
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Antibodies↗
Biomedical subjects
P Pozzilli
Publications and source records attributed to P Pozzilli.
Labelling of lymphocytes with indium 111 oxine: effect on cell surface phenotype and antibody-dependent cellular cytotoxicity.
Indium 111 oxine is currently used to label peripheral lymphocytes in order to study the kinetics of these cells in vivo. Since the quantity of radioisotope for labelling is still a matter of controversy, we have investigated in vitro the effect of increasing the concentration of indium 111 oxine on the lymphocyte surface phenotype and the antibody-dependent cellular cytotoxicity (ADCC) using lymphocytes from normal subjects. The cell surface phenotype, as evaluated by 2 monoclonal antibodies, was not affected whereas ADCC, at any of the doses used, was significantly reduced compared to the baseline value. The implications of these results for the use of indium 111 oxine for the in vivo studies are discussed.
Adult↗
Tracking of indium-111-oxine labelled lymphocytes in autoimmune thyroid disease.
Peripheral lymphocytes (approximately 10(8)) from 4 subjects affected by autoimmune thyroid disease (2 Hashimoto's thyroiditis, 1 primary myxoedema, 1 Graves' disease) and 4 normal subjects were labelled in vitro with 40 microCi of indium-111-oxine and, following autologous injection, the distribution of the cells in the body was investigated by gamma camera imaging. Lymphocytes in the thyroid were observed 24 h after injection in both patients with Hashimoto's thyroiditis and in the patient with primary myxoedema, but not in the patient with Graves' disease or in any of the controls. To our knowledge, this is the first report using this method to try and demonstrate lymphocytes in the thyroid gland, and supports the concept that cell-mediated immunity may be playing an important role in the pathogenesis of Hashimoto's thyroiditis and primary myxoedema.
Adult↗
Monoclonal antibodies defined abnormalities of T-lymphocytes in type I (insulin-dependent) diabetes.
Peripheral T-lymphocytes subsets have been investigated in 36 patients with type I (insulin-dependent) diabetes of varying duration, 18 patients with type II (non-insulin-dependent) diabetes, and in 23 healthy subjects, using six different monoclonal antibodies. At the time of diagnosis of type I diabetes, there was evidence of an increase in cytotoxic T-lymphocytes, a decrease in suppressor T-lymphocytes, but a normal proportion of helper/inducer T-lymphocytes. In six of seven newly diagnosed cases studied, there was evidence of an increased number of activated T cells. An increase in activated T-cells was also found in 5 of 10 genetically susceptible islet cell antibody positive unaffected siblings in type I diabetic probands. In type I diabetes of long standing, the total T-cell population was decreased, largely due to a marked decrease in helper/inducer T-lymphocytes. Type II diabetic patients showed no abnormalities in T-lymphocyte subsets, making it unlikely that hyperglycemia was responsible for the changes observed. These results suggest that an imbalance of T-lymphocyte regulation is an important feature of type I diabetes and lend support for an immunologic role in its early pathogenesis.
Adolescent↗
Studies of peripheral blood lymphocytes in Crohn's disease. Circulating activated T cells.
Peripheral blood mononuclear cells have been investigated in 43 patients with Crohn's disease (CD) by means of a panel of 4 monoclonal antibodies (UCHT1, UCHT4, 4F2, 5E9). A decrease of total T cells (UCHT1+) (p less than 0.01) and a slight increase of cytotoxic/suppressor T cells (UCHT4+) were observed. Evidence of T-cell activation, as shown by the highly significant increase of 4F2+ and 5E9+ cells, was also found. The latter finding lends support to the concept that cell-mediated immune phenomena are an important feature in CD.
Adult↗
Increased 'killer' cells in Graves' disease.
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Adult↗
Impaired phagocytic function and increased immune complexes in diabetics with severe microangiopathy.
An increase in circulating immune complexes (AgAb) of medium size has been observed in diabetics with late complications. This increase may be related either to an increased formation or reduced clearance. Alternatively, both mechanisms may be involved. As medium-sized AgAb determined by the C1q solid phase method are mainly removed from circulation by the fixed phagocytes of the reticulo-endothelial system, we investigated the function of these cells using a colloid clearance test in diabetics with various degrees of microangiopathy. Microaggregated iodinated human serum albumin was injected into 30 diabetic volunteers with severe (group 1), moderate (group 2), and absent (group 3) microangiopathy, and into 40 normal volunteers. The colloid clearance was significantly reduced in diabetics with severe microangiopathy in comparison with patients who had no sign of microangiopathy, or with normal subjects. A significant correlation was found between reduced colloid clearance and increased levels of circulating AgAb determined by C1q solid phase method. Results of this study suggest that the increase in circulating AgAb observed in patients with severe microangiopathy may result from an impaired function of mixed phagocytes.
Adult↗
Histology of the islets of Langerhans following administration of human lymphocytes into athymic mice.
Lymphocytes from seven newly diagnosed insulin-dependent (Type 1) diabetics, five islet cell antibody positive unaffected children and five normal subjects were injected i.p. into athymic nude mice. A further six mice were injected with medium and six control mice received no injection. Blood was taken from the tail vein before injection for glucose determination. After 10 days blood was again obtained from the tail vein; the pancreas was removed under deep ether anaesthesia and the mice sacrificed by exsanguination. Routine histological sections of the pancreas were prepared. There was no difference between groups in respect of the initial blood glucose. However, final blood glucose levels were raised in all mice that had received an injection including medium only, the rise being statistically significant both after injection of lymphocytes from normal subjects (P less than 0.05) and from newly diagnosed diabetics (P less than 0.001). Histology did not reveal any evidence of 'insulitis' or islet cell damage although enlarged, hyperplastic islets could be found in each group of treated mice. We conclude that passive transfer of diabetes was not achieved in this animal model. Elevation of blood glucose levels and islet hyperplasia may simply reflect a non-specific 'stress' reaction.
Animals↗
Increased killer cell activity in insulin dependent (type 1) diabetes mellitus.
Antibody dependent cell mediated cytotoxicity in relation to the levels of circulating killer cells was investigated in 16 newly diagnosed classical insulin dependent (Type 1) diabetics, 11 islet cell antibody positive non diabetic children with at least one HLA haplotype in common with their diabetic sibling, and in 15 normal controls. Antibody dependent cell mediated cytotoxicity was evaluated using, as target, 51Cr labelled human 0+ erythrocytes sensitised with an anti-CD antiserum. Killer cells were measured by the low affinity E-rosetting cell technique. Increased killer cell levels (greater than normal mean + 2SD) were accompanied by a significant enhancement in antibody dependent cell mediated cytotoxicity both in newly diagnosed diabetics (p less than 0.05) and in unaffected siblings (p less than 0.01). These preliminary results indicate that raised antibody dependent cell mediated cytotoxicity is a feature of insulin dependent diabetes at diagnosis and suggest that active B cell damage might be occurring some time before the onset of clinical symptoms.
Adolescent↗
Alpha 2 macroglobulin: its variability in diabetes.
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Adolescent↗
Inhibition of allogeneic lymphocyte E-rosettes induced by sera from newly diagnosed type I diabetics.
Sera from 64 juvenile onset insulin-dependent diabetics (Type I diabetics) and 30 normal subjects were tested for their ability to inhibit sheep red blood cell rosette formation (E-rosette) by normal allogeneic lymphocytes. Inhibition of E-rosette formation by greater than 20% was found with 16 (66%) sera from newly diagnosed patients, 3 (16%) sera from patients with duration of disease between 2 and 12 months and with 4 (18%) sera from diabetics with duration of disease between 1 and 7 years. On the other hand, only 2 (6%) control sera showed inhibitory effect. No relationship between E-rosette inhibition and islet-cell antibodies presence, anti-lymphocyte antibodies occurrence, anti-HLA activity, blood glucose levels, respectively, was found. Investigation of the properties of this inhibitory factor suggests that it is different from other substances that reportedly inhibit E-rosette formation.
Adolescent↗
Evidence for raised K-cell levels in type-I diabetes.
The proportion of blood mononuclear cells forming low-affinity rosettes with sheep erythrocytes (K cells) was abnormally high in 13 (57%) of 23 children with classical type-1 diabetes at diagnosis but normal in children who had had diabetes for more than a year. A raised proportion of K cells was also found in 5 out of 10 unaffected siblings with islet-cell antibodies and at least one HLA haplotype in common with the diabetic proband; and in 10 (45%) of 22 subjects with type-1 diabetes and co-existent autoimmune thyroid disease irrespective of the duration of diabetes or the presence of islet-cell antibodies. These findings may be new evidence for lymphocyte-mediated beta-cell destruction and support the idea of immunogenetic heterogeneity within type-1 diabetes.
Adolescent↗
Increased lymphocyte transformation by insulin induced hypoglycaemia in normal subjects.
To study the effect of carbohydrate metabolism on lymphocyte reactivity, we performed phytohaemoagglutinin and pokeweed mitogen induced lymphocyte transformation after insulin induced hypoglycaemia in normal subjects. A statistically significant increase of PHA-LT and a slight increase of PKW-LT were detected 30 minutes following insulin administration. These data suggest a stimulating effect of insulin induced hypoglycaemia on T lymphocyte reactivity and this finding has clinical importance in regard to the management of diabetic patients.
Adult↗
Raised alpha-2-macroglobulin levels in acromegaly.
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Acromegaly↗
Immune complexes and diabetic microangiopathy.
Soluble immune complexes (AgAb) as detected and quantitated by the solid phase Clq assay (Clq-SP) were found to be increased in (a) long-duration diabetics with proliferative retinopathy and (b) short duration diabetics with early onset of retinopathy irrespective of whether they were treated with insulin or oral hypoglycaemic agents (OHA), in comparison to a normal population. No such increases were observed in diabetics of comparable duration without retinopathy. The trend for long-term diabetics to show an increased prevalence of AgAb according to the severity of retinopathy was statistically significant. Detection and quantitation of AgAb by the Raji cell assay (RAJI) gave comparable results although the differences were less pronounced and fell short of statistical significance. AgAb as detected by either method in insulin-treated diabetics could not be correlated with insulin antibodies. These findings suggest that AgAb, not necessarily comprised of insulin and anti-insulin antibodies, may contribute to the pathogenesis of diabetic microangiopathy.
Antibodies↗
Diet can influence the ability of nicotinamide to prevent diabetes in the non-obese diabetic mouse: a preliminary study.
BACKGROUND: The non-obese diabetic (NOD) mouse is a widely used model of Type 1 diabetes mellitus (Type 1 DM), which displays many of the characteristics of the disease found in humans. Nicotinamide (NA) is currently being tested in large-scale, multi-centre human trials for the prevention of Type 1 DM in subjects considered 'at risk' of developing the disease. Human trial populations will certainly differ in their dietary patterns and alterations were made to the diet given to NOD mice to determine if this could alter the effect of NA administration on Type 1 DM incidence. METHODS: The effect of NA in the diet was examined, both with and without carbohydrate in the form of a sucrose supplement, on diabetes incidence and insulitis levels in the NOD mouse. The effects of NA and sucrose were each tested alone as well as in combination. RESULTS: Diabetes was unaltered using a low dose NA-supplemented diet (625 mg/kg diet). Diabetes incidence was also unaltered using unmodified diet together with drinking water supplemented with either 5% or 10% w/v sucrose or plain water for controls. However, with mice given NA-supplemented diet (625 mg/kg diet) together with sucrose-supplemented or plain water as previously, diabetes was reduced in the NA+10% sucrose group (p<0.001). Finally, a higher dose of NA was given in supplemented diet (1000 mg/kg). Again, neither sucrose nor NA alone altered the incidence of diabetes, but NA treatment combined with a 10% w/v sucrose-supplemented drinking water reduced diabetes incidence (p<0.001). No mice showed alterations in insulitis, blood-glucose or insulin levels with respect to controls. CONCLUSION: Altering dietary patterns using sucrose can affect the ability of NA to prevent diabetes in the NOD mouse. This finding may be relevant for human studies with NA aimed at preventing Type 1 DM and suggests that diet may need to be monitored or even controlled in these studies.
Animals↗
Immune markers for monitoring the progression of autoimmune disease.
The incidence of immune-mediated diseases is increasing worldwide. Reliable immune markers for monitoring disease progression and also the effect of therapeutic interventions are urgently needed in order to investigate preventive or therapeutic measures effectively. At a recent workshop held on 5 December 1998 in Copenhagen, the state of research on surrogate markers in Type 1 diabetes was discussed and compared with the experience in multiple sclerosis, inflammatory bowel disease and transplantation.
Autoimmune Diseases↗
A multi-centre randomized trial of two different doses of nicotinamide in patients with recent-onset type 1 diabetes (the IMDIAB VI).
BACKGROUND: Intensive insulin therapy is the gold standard by which Type 1 diabetes is treated. In addition to this therapy, administration of nicotinamide (NA) can be beneficial. This concept is reinforced by the results of a recent meta-analysis of the use of NA in patients with recent-onset Type 1 diabetes. METHODS: In this study we compared two different doses of NA in 74 patients with duration of Type 1 diabetes <4 weeks (mean age 13 years). Patients were randomly allocated in blind to two treatment groups: 38 patients received a dose of 25 mg/kg (b.w.) of NA and 36 patients received a dose of 50 mg/kg (b.w.) of NA. Intensive insulin therapy was carried out in order to optimize metabolic control as soon as possible after diagnosis and to maintain blood glucose level as near to normal as possible. Response to therapy was monitored throughout the study by investigating the occurrence of clinical (complete) remission defined, according to the recommendations of the International Diabetes Immunotherapy Group, as restoration of normal fasting and post-prandial blood glucose without any insulin administration for more than 2 weeks. Moreover, the integrated measures of metabolic control (C-peptide, HbA(1c) and insulin dose) were analysed at 3- month intervals up to 1 year after diagnosis. RESULTS: There were no significant differences in the integrated measures of metabolic control between the two NA treated groups either at onset of the disease or at each 3-month interval up to 1 year after diagnosis, although there was a tendency toward higher insulin dosages in the 50 mg NA group. No significant differences were observed in the rate of clinical remission between the two groups. CONCLUSION: We conclude that patients with recent-onset Type 1 diabetes treated with two different doses of NA, in addition to intensive insulin therapy, show similar residual beta-cell function 1 year later. Since both doses of NA are likely to be effective in reducing beta-cell dysfunction, the smaller dose of 25 mg/kg NA would be sufficient as a higher dose may induce insulin resistance.
Adolescent↗