A role for macrophages in the pathogenesis of type 1 diabetes.
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Animals↗
Biomedical subjects
H Kolb
Publications and source records attributed to H Kolb.
The time course of insulin autoantibodies (IAA) in the diabetes prone BB rat.
The BB rat is a widely used animal model for the study of insulin dependent diabetes. An enzyme linked immunosorbent assay, using purified rat insulin, was used to measure serial insulin autoantibodies (IAA) levels in coded sera from the BB/W/D rat colony in order to establish the time course of IAA. The animals included 26 diabetes-prone BB rats, six diabetes-resistant BB rats and six Wistar controls. There was an increase in both IAA frequency and titre with time in the diabetes-prone group: none were positive at 45 days, 17/19 (89%) were positive by day 90 and all were positive thereafter. Similar results were observed in the diabetes-resistant BB group (0/6 positive at day 51, 6/6 positive at day 90). None of the Wistar controls were positive at 105 days, although occasional positive sera were observed at 120 days. IAA seem to be acquired early on in the majority of BB rats, both diabetes-prone and diabetes-resistant, and much later, if at all, in controls. A clear homology of the MHC genes exists in both BB rat sublines, thus IAA appear to be a strain related phenomenon rather than a marker for IDDM.
Animals↗
Bone marrow transplantation in childhood leukaemia--experience and strategies in the Federal Republic of Germany.
BMT has gained its place in the treatment of childhood leukaemia. Nevertheless, there are still many questions open. In acute lymphoblastic leukaemia children should normally be grafted in 2nd remission (CR). Some high risk cases, however, should probably be grafted in 1st CR. It is not clear whether children with late relapses benefit more from BMT than from renewed chemotherapy. Children with a relapse during maintenance therapy, however, have a better survival rate with BMT. In acute nonlymphoblastic leukaemia certain high risk patients should be grafted in 1st CR but it has still to be shown that BMT is superior to chemotherapy in such cases. It is not clear whether children with a relapse following intensive chemotherapy (such as the BFM-protocols) will benefit from BMT at all. In chronic myelocytic leukaemia, BMT in chronic phase should be performed. Thus, for the first time cure has become possible for this disease. Waiting for acceleration or even the occurrence of a blast crisis decreases the chance of survival after BMT dramatically. Since complications of BMT such as graft-versus-host reaction or severe infections are less frequent in children, relapses remain the main problem after BMT in childhood leukaemia.
Bone Marrow Transplantation↗
Analysis of the major histocompatibility genes that control susceptibility to diabetes mellitus in the BB rat.
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Animals↗
Modulation of arachidonic acid metabolism has limited effects on the development of type I diabetes in animal models.
The therapeutic potential of modulators of arachidonic acid metabolism was probed in two animal models of type I (insulin-dependent) diabetes. Sulphasalazine treatment (50 and 400 mg/kg) did not affect diabetes development in the low dose streptozotocin model in male CD-1 mice nor in diabetes prone BB/WorD rats (100 mg/kg). Administration of acetyl salicylic acid (50 mg/kg) or BW755C (60 mg/kg) caused partial suppression of hyperglycaemia in male C57BL/6 mice after low dose streptozotocin. Twice daily treatment of BB rats with acetyl salicylic acid (5 mg/kg) did not significantly alter the course of diabetes development. We conclude that modulation of arachidonic acid metabolism has limited effects on immune-mediated diabetes.
4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
[Anorectal abnormalities--incontinence and abnormalities].
The quality of life of incontinent patients was analysed in a group of 494 children treated over 20 years. The ratio of incontinent children was constant above an age of 10 years. Incontinence correlates with social status of the family; it is better in single children and worse in single-parent families. School outcome and professional status is significantly better for continent patients. The main problems of the children and adults were analysed. Compensatory mechanisms and the importance of early care of incontinent patients are mentioned.
Adolescent↗
The hepatic asialoglycoprotein receptor selectively binds to some endogenous tissues.
The hepatic asialoglycoprotein receptor (ASGP-R) was isolated from various rat tissues or freshly prepared single cell suspensions and tested for the binding to endogenous tissues or specific cell types by indirect immunofluorescence. Inhibition with N-acetyl-D-galactosamine demonstrated specificity of binding. ASGP-R binds to mesodermal tissues and to selected cells of the majority of glandular tissues but not to lining epithelia. ASGP-R stains heart muscle but not skeletal muscle. In addition, ASGP-R stains spleen cells (52%), bone marrow cells (55%), thymocytes (62%), and a fraction of peripheral blood lymphocytes (29%), which was identified as B-lymphocytes. Five different rat tumors also showed binding of ASGP-R. The binding pattern and staining intensity of peanut agglutinin and soybean agglutinin were strikingly different although the binding specificity of these lectins is related to the ASPG-R. It is concluded that considerable numbers of endogenous binding sites for the hepatic ASGP-R exist in normal tissue, even on cells which pass the liver on circulation.
Animals↗
Prospective analysis of eosinophilia in spontaneously diabetic BB rats: correlation with islet inflammation but not with diabetes development.
A prospective analysis of eosinophil counts in diabetes prone BB rats showed that eosinophilia (greater than 5%) occurred between 70-100 days of age. The presence of eosinophilia did not predict diabetes onset because persistently normoglycaemic animals developed eosinophilia as well. Nevertheless a correlation with the disease process in BB rats was found. Eosinophilia decreases a few weeks after diabetes onset but persists in non diabetic rats. Histological analyzes showed that eosinophilia correlates with eosinophil infiltration of islets (p less than 0.005) and the latter correlates with severe insulitis (p less than 0.005). These findings indicate that eosinophilia is associated with a late stage of islet inflammation in diabetes prone BB rats independent of whether the animals develop diabetes or not.
Animals↗
Allogeneic bone marrow transplantation for secondary leukaemia and myelodysplastic syndromes. Leukaemia Working Party of the European Bone Marrow Transplantation Group (EBMTG).
This retrospective survey of the EBMT Leukaemia Working Parking describes 78 patients with myelodysplasia (MDS) or secondary acute myelogenous leukaemia (sAML) who were given an allogeneic bone marrow transplant (BMT). The status of underlying disease at the time of transplantation was prognostic for the two-year disease-free survival which was 60% for patients transplanted in complete remission. Similar results were obtained for those with less advanced MDS (50-64%) who had not received any prior intensive chemotherapy. The results were significantly less favourable for those with more advanced disease who only partially responded to prior intensive chemotherapy (18%) while none of those who either relapsed or were resistant to chemotherapy survived. Allogeneic BMT can therefore be considered as curative treatment for patients with MDS. Patients with sAML who have a histocompatible donor should be given chemotherapy intensive enough to induce complete remission. If this is achieved these individuals have a prognosis comparable to those with de novo AML in first remission after BMT.
Adolescent↗
Organization of the inner plexiform layer of the turtle retina: an electron microscopic study.
We have performed a serial-section electron microscopic study of the inner plexiform layer (IPL) of the retina of the turtle Pseudemys scripta elegans. A qualitative and quantitative assessment of the neuropil of the IPL has been done from photomontages taken from the linear visual streak area and peripheral retina. Counts of conventional, ribbon, serial, and reciprocal synapses, of ganglion cell dendrites, and of profiles containing large, dense-cored vesicles were made in five equal-thickness strata in each montage. Averages of these different features were plotted for each stratum in the linear visual streak and compared with peripheral retina. The trend was for stratum 2 to have the highest overall absolute number of amacrine and bipolar interactions, and also of serial synapses, both in the linear visual streak and in peripheral regions. Stratum 4 tended to have the second-highest number of synapses. The total number of synapses for the entire thickness of the IPL, regardless of stratification, is higher in the streak than in the periphery. The total amacrine-to-bipolar-synapse ratio in the IPL is the highest of any vertebrate studied to date (11.0 in the streak and 14.5 in the periphery) but the number of synapses/micron 2 was found to be similar to that reported for other vertebrates. Amacrine-to-amacrine synaptic contacts greatly outnumber other types of synapses; amacrines constitute the principal input to ganglion cells, whereas bipolar output is mainly onto amacrines. The trend for higher numbers of synaptic interactions in strata 2 and 4 of the streak region of the turtle IPL can be correlated with the branching of small-field amacrine and ganglion cells described in Golgi studies (Kolb: Philos. Trans. R. Soc. Lond. B 298:355-393, '82). In peripheral retina, branching of large-field amacrines and a lower number of bipolar pathways may account for the trend for larger numbers of amacrine synapses in strata 2 and 4. Profiles having large, dense-cored vesicles tend to occur most frequently in strata 1 and 5, which correlates well with the stratification in the IPL of the processes of immunoreactive amacrine cells described in other studies.
Animals↗
No evidence for increased variation in first phase insulin response to intravenous glucose.
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Glucose↗
Prospective analysis of islet cell antibodies in children with type 1 (insulin-dependent) diabetes.
The prevalence of islet cell antibodies in children with Type 1 (insulin-dependent) diabetes was determined in a cohort of 678 children. The natural course of islet cell antibodies was followed in 375 children at 1 year, 252 and 135 children after 2 and 3 years respectively. Islet cell antibodies were determined by indirect immunofluorescence on cryostat sections of human pancreas. At diagnosis of diabetes 85% of the children had detectable islet cell antibodies (mean titre 10.4). After 3 years 62% of the children were still islet cell antibody positive (mean titre 2.9) indicating a greater persistence of islet cell antibodies than described in earlier studies. In this large cohort a significant correlation between islet cell antibody prevalence or persistence and sex, age or HLA-DR type was not observed except for a faster loss of islet cell antibodies in very young boys and in patients lacking HLA-DR types 3 and 4. Complement fixing islet cell antibodies correlated with high titre islet cell antibodies. Greater persistence of islet cell antibodies was seen for cases with high antibody titre and in children with diagnosis of diabetes during the first half of the year.
Adolescent↗
Administration of a 600 kD molecular fraction from pancreatic islets suppresses immune mediated diabetes in mice.
Treatment of male C57BL6/J mice with low doses of streptozotocin causes the development of diabetes. Infiltration of pancreatic islets by immune cells and the concomitant loss of beta islet cells can be prevented by immunosuppression. We now report that i.v. administration of islet homogenate 13 d prior to low dose streptozotocin treatment largely protects from development diabetes. Homogenates from liver, kidney or exocrine pancreas were without effect. The suppressive activity was isolated partially from mouse islets as well as from a rat insulinoma cell line. After gelchromatography the suppressive activity was found in the 600 kD fraction. The relevant substance appears negatively charged and does not bind to lentil lectin or concanavalin A.
Animals↗
Neural organization of the retina of the turtle Mauremys caspica: a light microscope and Golgi study.
The organization of the retina of the turtle species Mauremys caspica, found in fresh water ponds of Israel, has been examined by light microscopical techniques including examination of fresh wholemount retina, one micron blue-stained vertical sections and Golgi-stained material. The anatomical findings on Mauremys retina have been compared with those of the Pseudemys retina (Kolb, 1982) which is more commonly used for electrophysiological and neurochemical studies in the USA. The photoreceptors of Mauremys are similar in type and oil droplet content to Pseudemys photoreceptors except for the double cone in Mauremys. This cone type appears more abundant than in Pseudemys and the principal member contains a yellow oil droplet instead of an orange oil droplet. Golgi staining reveals that the cell types that have been seen in Pseudemys are found in Mauremys with identical morphology. In addition, two amacrine cell types that were not before described for Pseudemys have been added to the classification. One of these is the tristratified dopaminergic amacrine cell described in immunocytochemical studies (Witkovsky et al., 1984; Nguyen-Legros et al., 1985; Kolb et al., 1987). We have used these anatomical studies on Pseudemys and Mauremys retina to form a catalogue of neural types for the turtle retina in general. We conclude with an attempt to combine findings from anatomy, electrophysiology, and neurochemistry to form an overview of the organization of this reptilian retina.
Animals↗
Evidence of IgG autoantibodies against human proinsulin in patients with IDDM before insulin treatment.
IgG proinsulin autoantibodies (IgG-PAAs) have been found in a fraction of sera from patients with newly diagnosed insulin-dependent diabetes mellitus (IDDM) before onset of insulin treatment. Only sera lacking insulin antibodies have been analyzed, to avoid interference. Competitive inhibition studies provide specificity for human proinsulin but not for insulin. IgG-PAAs largely cross-react with human C-peptide. Precursors of insulin thus are involved in the immune process of IDDM.
Adolescent↗
Low-dose streptozocin-induced diabetes in mice. Electron microscopy reveals single-cell insulitis before diabetes onset.
We investigated the morphology of mouse islets 5 days after completion of low-dose streptozocin treatment of C57BL/6 mice by electron microscopy. At this stage, mice were still normoglycemic and light microscopy did not reveal massive islet infiltration. The electron-microscopic investigation revealed two characteristics indicative of ongoing islet cell destruction. In all islets investigated, lysed islet beta-cells were recognized by disrupted plasma membranes and concomitantly decreased plasma contrast. Many of the lysed islet beta-cells still contained numerous insulin granules. We also found immunocytes scattered throughout the islets, most of which could be identified as macrophages. Some were found engaged in phagocytosis of islet beta-cell debris. This early stage of islet lesion termed single-cell insulitis is followed by the well-known later stage of massive infiltration easily recognized in light microscopy. Administration of silica particles to mice treated with low-dose streptozocin inhibited macrophage infiltration of islets as shown by immunocytochemistry with macrophage-specific monoclonal antibody F4/80. In parallel, the development of hyperglycemia was suppressed. The observations favor a pathogenic role of macrophages in islet destruction.
Animals↗
[Eye manifestations in multihandicapped children with cerebral disorders].
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Brain Damage, Chronic↗
IL-1 and IFN-gamma increase vascular permeability.
We examined the effect of cytokines on vascular permeability in vivo. Wistar rats received intradermal injections of various cytokine preparations and the permeability index (delta PI) was calculated from the difference between the absorption values of cytokine- and vehicle-treated skin sections after the extraction of accumulated Evans blue vital dye. Injections of a mixture of recombinant interleukin-1 alpha and beta (Il-1 alpha, IL-1 beta) and interferon-gamma (IFN-gamma) caused a maximal increase of permeability after 30 min (delta PI = 2). The administration of single recombinant cytokines revealed that the increase of permeability is mainly due to the action of IL-1 beta (delta PI = 1.4) and IFN-gamma (delta PI = 2.9) (P less than 0.001) at doses of 1-20 microU per injection site. IL-1 alpha slightly increased vascular permeability, whereas recombinant IL-2 and recombinant tumour necrosis factor alpha had no significant effects. Histological observations revealed significantly increased numbers of degranulated mast cells in skin sections pretreated with IL-1 beta (P less than 0.005) or IFN-gamma (P less than 0.001). The cytokine-mediated rise of vascular permeability could be suppressed by pretreatment of the animals with the vasoactive amine antagonizing drugs methysergide, pizotifen and cyproheptadine. Our experiments indicate an important role of IL-1 beta and IFN-gamma as vasoactive substances besides their function as hormone-like messengers between leucocytes.
Animals↗