Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The emergence of monoclonal antibody technology has fostered new therapeutic strategies for people with autoimmune diseases. One of the most promising of these strategies involves the use of CD4 monoclonal antibodies, which are effective in animal models for systemic lupus erythematosus, diabetes mellitus, rheumatoid arthritis, myasthenia gravis, and multiple sclerosis. The appeal of CD4 antibodies is enhanced by several factors: (1) their effectiveness does not depend on depletion of target cells; (2) they may block the host immune response to therapy, and (3) they have been well-tolerated in preliminary human trials. The principal obstacle to the use of CD4 monoclonal antibodies stems from their adverse effects on normal immune function.
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PMID:CD4 antibody therapy in systemic lupus erythematosus. 210 79

In an attempt to characterize insulitis induced by multiple low doses of streptozocin (SZ), we immunohistochemically examined sequential changes of the subsets of lymphocytes infiltrating the pancreatic islets in CD-1 mice. Daily intraperitoneal injections of 30 mg/kg body wt of SZ for five consecutive days led to lymphocytic infiltration around the islets. Most of the infiltrated cells were initially CD4 positive (helper/inducer) T-lymphocytes and no immunoglobulin-bearing cells were detected. The number of helper/inducer T-lymphocytes increased with progression of the insulitis, then surface immunoglobulin-positive cells (B-lymphocytes) accumulated around the area of CD4 positive T-lymphocytes. CD8 positive (suppressor/cytotoxic) T-lymphocytes were seen scattered throughout the study and only a few asialo GM1 positive (natural killer) cells existed in the area of insulitis. Subsequently, the pancreatic insulin contents were considerably decreased and diabetes occurred on day 21. These observations suggest that CD4 positive T-lymphocyte-dependent B-lymphocyte infiltration in and around islet cells may be associated with islet cell destruction and the development of diabetes in CD-1 mice treated with multiple low doses of streptozocin.
Diabetes Res Clin Pract 1990 Apr
PMID:Immunohistochemical study of insulitis induced by multiple low doses of streptozocin in CD-1 mice. 214 Sep 77

The authors have previously described a marker of cell-mediated, called "diabetic rosettes", revealed by the increased binding of CD3 CD4 lymphocytes from type I diabetic patients to beta-cell membrane antigens, as compared to lymphocytes from control subjects. In the present study, they have detected such "diabetic rosettes" in some subjects at risk for type I diabetes. The mean value of lymphocytes adhering to beta (RINm5F)-cells (beta-CL) was statistically higher in those subjects at risk than in control blood bank donors (p = 0.003). When a positive test was arbitrarily defined as a value of beta-CL higher than the 95th percentile of controls, 20 p. cent of the subjects at risk were classified as beta-CL+. No difference was observed between two subgroups of subjects at risk: first degree relatives of type I diabetic patients, and non-diabetic subjects with transient hyperglycaemia. "Diabetic rosettes" were associated with HLA DR 3/4 heterozygosity (p less than 0.04) and with a "low" acute insulin release to IV glucose (p = 0.05). They were not associated with islet-cell antibodies, insulin autoantibodies, or "activated" (HLA DR+) T-lymphocytes. The authors suggest that "diabetic rosettes" represent a marker of cellular immunity in some subjects at risk for type I diabetes.
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PMID:["Diabetic rosettes": a cellular immunity marker in subjects at risk for type I diabetes]. 218 35

Nonobese diabetic (NOD) mice develop an autoimmune form of diabetes, becoming hyperglycemic after 3 months of age. This process was accelerated by injecting young NOD mice with CD4+ islet-specific T cell clones derived from NOD mice. Overt diabetes developed in 10 of 19 experimental animals by 7 weeks of age, with the remaining mice showing marked signs of the disease in progress. Control mice did not become diabetic and had no significant pancreatic infiltration. This work demonstrates that a CD4 T cell clone is sufficient to initiate the disease process in the diabetes-prone NOD mouse.
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PMID:Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. 220 20

Cyclosporine prevents the development of diabetes in spontaneously diabetic BB rats and NOD mice. However, islet transplants have been shown to be subject to immunologic destruction in hosts treated with CsA and anti-CD4 antibody or those rendered tolerant to donor antigens. This study determines whether the minimum dose of CsA necessary to prevent rejection of pancreatic transplants will also prevent recurrent diabetes in pancreas transplants in BB rats. Lewis recipients promptly reject BN (n = 13, MST 9.2 +/- 0.7 days) and Fisher (n = 6, MST = 11.3 +/- 0.8 days) pancreatic transplants. Treatment with CsA 5 mg/kg/day 0-50 days posttransplant and 2 mg/kg/day 51-100 days (low-dose CsA) produced indefinite survival of BN (n = 5) but not Fisher (n = 4) allografts. Fisher allografts were uniformly successful if maintained on 5 mg/kg/day (n = 4). Treatment with CsA 5 mg/kg/day for 14 days had no deleterious effect on glucose tolerance in Lewis isografts (control [K = 1.81 +/- 0.24, n = 8] vs. CsA treated [K = 1.76 +/- 0.20, n = 8, P = NS]). Low-dose CsA ensured permanent survival of MHC-compatible WF (n = 7, MST greater than 115 days) and MHC-incompatible BN (n = 9, MST greater than 117 days, P = NS) pancreatic transplants in spontaneously diabetic BB/Wor hosts. Three of 11 recipients surviving greater than 100 days enjoyed seemingly permanent acceptance of their allografts after discontinuation of CsA. Immunocompetence was demonstrated by rejection of their pancreas transplants when challenged with donor skin. Vascularized pancreatic allografts treated with CsA appear to be less vulnerable to recurrent diabetes than are islet transplants. Low-dose CsA protects vascularized pancreatic allografts in BB rats from both rejection and recurrent diabetes.
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PMID:Evidence that cyclosporine prevents rejection and recurrent diabetes in pancreatic transplants in the BB rat. 233

A potent cytolytic pore-forming protein (perforin or cytolysin) has previously been found to be associated with the cytoplasmic granules of CTL and NK cells. Inasmuch as all previous studies on perforin have been conducted with cultured CTL and NK cell lines, it is not clear whether perforin may play a role in the cytotoxicity mediated by CTL that have been primed in vivo. In this study, we investigated the presence of perforin in pancreata from nonobese diabetic (NOD) mice, which have been studied as a model of autoimmune, insulin-dependent (type I) diabetes mellitus. Whereas adult NOD mice spontaneously develop diabetes, it is possible to induce diabetes in young, irradiated NOD mice by adoptive transfer of splenocytes obtained from diabetic donors. By means of immunohistochemical analysis, we were able to detect perforin Ag in a small subpopulation of CD8+/Thy-1+/asialo GM1-/CD4- lymphocytes in the pancreatic islets of animals undergoing both spontaneous and adoptive transfer-mediated insulitis. Perforin+/CD8+ lymphocytes were found in small clusters and were observed to display the morphology of large granular lymphocytes. These observations show for the first time the presence of perforin-containing CD8+ lymphocytes in tissues of animals undergoing autoimmune disease.
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PMID:In vivo expression of perforin by CD8+ lymphocytes in autoimmune disease. Studies on spontaneous and adoptively transferred diabetes in nonobese diabetic mice. 248 Mar 83

Over a period of 5 years, lymphocyte subpopulations and their markers of activation were studied prospectively in 56 first degree relatives of Type 1 (insulin-dependent) diabetic probands. Lymphocytes were phenotyped using a panel of monoclonal antibodies which recognise CD3, CD4, CD8 lymphocytes, K/NK cells, HLA Class II products and IL-2 receptors (IL-2r). Twenty-six subjects were negative for islet cell antibody (ICA), 18 had complement fixing ICA (CF-ICA) and 12 only conventional ICA (ICA-IgG). The total number of observations (blood samples collected) was 386. Overall, changes in T cell data were observed in the three groups of first degree relatives compared to 70 normal subjects without a family history of diabetes. Six individuals developed Type 1 diabetes in the course of the study. They all possessed CF-ICA and five out of six showed a persistent reduction (less than 1.5) of the CD4/CD8 lymphocyte ratio before the clinical onset of the disease. Activated lymphocytes were found on two occasions in two of these subjects. We conclude that imbalance of lymphocyte immunoregulatory subsets is present before the onset of Type 1 diabetes in susceptible individuals; the persistence of a reduced CD4/CD8 lymphocyte ratio may reflect the ongoing process leading to B-cell destruction.
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PMID:Persistent reduction of CD4/CD8 lymphocyte ratio and cell activation before the onset of type 1 (insulin-dependent) diabetes. 250 62

Over 80% of nonobese diabetic (NOD) mice develop lymphocytic infiltrates of their pancreatic islets (insulitis) by 6 wk of age and 50% of the females are diabetic by 6 mo of age. The incidence of insulitis in NOD mice injected once as neonates with 250 micrograms of the CD3 antibody, 145.2C11, was 8% at 10 wk of age, increasing to 25% at 32 wk of age. Fewer than 10% of these animals developed diabetes by 8 mo of age. Neonatal administration of 145.2C11 reduced the proliferative responses of spleen cells to mitogen stimulation 2 and 4 wk postinjection and expression of TCR was reduced 1 to 5 wk postinjection. The percentage of CD4 and CD8 cells in the spleen was transiently reduced after injection and the frequency of Pgp-1+-high cells (putative memory cells) was increased 2 to 4 wk postinjection, suggesting that in vivo administration of the antibody caused some T cells to divide as well as transiently reducing T cell numbers. IL-2R expression was not detected on spleen cells in the 4 wk after antibody injection. The phenotypic and functional changes after neonatal CD3 antibody injection resolved by 8 wk of age. The control and injected mice grew normally and made equivalent IgG antibody responses to injected human IgG. Neonatally injected 145.2C11 antibody was cleared from the circulation with a terminal half-life approximating to 21 days but greater than 90% of antigen binding activity was lost 6 days after injection. Protection from diabetes did not follow neonatal elimination of T cells with CD4 and CD8 antibodies, nor the injection of a TCR subset antibody, F23.1. Our data suggest that the neonatal T cell repertoire is open to modulation by a single injection of a CD3 antibody and they offer a new experimental approach to immunotherapy in an animal model of type 1 diabetes.
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PMID:Neonatal injection of CD3 antibody into nonobese diabetic mice reduces the incidence of insulitis and diabetes. 252 66

Spontaneous diabetes in the non-obese diabetic (NOD) mice is a CD4 T cell-dependent process. We have suggested that specific beta cell destruction results from free radical production at the site of islet inflammation; oxygen radicals are produced by activated inflammatory cells. We reported here that in vivo treatment of spontaneously diabetic NOD mice with the enzyme superoxide dismutase (2000 U for seven injections) and catalase (40,000 U for seven injections) protects islet tissue from disease recurrence following transplantation into spontaneously diabetic mice. Similar results were obtained when animals were treated with either enzyme alone. This effect was dose-dependent and little protection was observed when the dose of enzyme was reduced four-fold. These results indicate that oxygen metabolites, specially superoxide and hydrogen peroxide, are directly involved in the pathogenesis of immunology mediated diabetes.
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PMID:Involvement of O2 radicals in 'autoimmune' diabetes. 254 56

Patients who had been included in a randomized double-blind placebo-controlled trial on the efficacy of cyclosporin A (CyA) in producing remissions in insulin-dependent diabetes mellitus (IDDM) type I were investigated for humoral and cellular immunologic parameters. Whereas metabolic derangement before the initiation of insulin treatment led to small but significant decreases in the percentage of CD4-positive lymphocytes as well as of the activity of natural killer (NK) cells and antibody-dependent cellular cytotoxicity (ADCC), the administration of CyA did not influence any of the immunologic parameters tested, which included proliferative lymphocyte responses to mitogens and alloantigens and serum concentrations of immunoglobulins G, A and M. Thus NK cell activity, ADCC as well as the percentage of CD4-positive lymphocytes returned to normal levels in parallel with the normalization of glycosylated haemoglobin (HbAlc), but were not further influenced in their course by the administration of CyA, as compared with patients receiving placebo. Interferon-induced augmentation of NK cell activity did not differ between patients with IDDM on placebo and those under CyA therapy. All other investigated parameters also remained unchanged during the time of CyA therapy. We conclude that metabolic derangement leads to a reversible disturbance of certain cellular immune functions, but their normalization achieved by insulin treatment and their further course remains uninfluenced by the administration of CyA.
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PMID:Effects of cyclosporin A upon humoral and cellular immune parameters in insulin-dependent diabetes mellitus type I: a long-term follow-up study. 265 21


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