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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several immunological responses of the spontaneously diabetic BB rat colony in Edinburgh designated (BB/E) have been studied. The proliferative responses to Con A and LPS, ability to make IL-2 and to show NK activity have been studied using diabetic and non-diabetic BB/E rats and normal Wistar rats. Our data suggest that the diabetic animals in the BB/E colony do not have marked deficiencies in any of these parameters. Lymphopenia and depressed T-cell responses do not appear to be a prerequisite for the development of diabetes in the BB/E colony.
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PMID:Immunological responses of the BB rat colony in Edinburgh. 349 4

BBUF rats, derived from BB rats, spontaneously develop a form of insulin-dependent diabetes mellitus (IDDM) associated with infiltration of the islets of Langerhans by lymphocytes (insulitis). BBUF rats bear the RT1u major histocompatibility complex (MHC) haplotype that we have shown to be necessary for the expression of this form of IDDM. A T-lymphocyte line obtained from the pancreas of a diabetic rat (UPCC.5) and three T-lymphocyte hybridomas derived by fusing T-lymphocytes of BBUF rats (MUS1.2, MUS1.13, and MUP3.21) respond to islet cell antigens in an MHC-restricted way. UPCC.5 responds to a combination of islet cell antigens (ICAg) and antigen-presenting cells by proliferation, whereas the T-hybridoma responses are detected on the basis of IL-2 production in a similar assay. This study reveals that an antiserum against mu-haplotype MHC antigens or a monoclonal antibody against the product of the D class II subregion of the rat MHC could inhibit ICAg recognition. A monoclonal antibody against the product of the B class II MHC subregion of the rat was not inhibitory. These results suggest that RT1.D antigens (analogous to human DR and mouse I-E) restrict islet cell recognition in this rat model of spontaneous IDDM.
Diabetes 1987 Feb
PMID:Major histocompatibility complex restriction of T-lymphocyte responses to islet cell antigens in IDDM rats. 354 48

Oral administration of autoantigens suppresses development of autoimmunity in several animal models, and is being tested in clinical trials in patients with autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent diabetes mellitus at 15 to 20 weeks of age, after mononuclear cell (MNC) infiltration of the pancreatic islets of Langerhans and destruction of insulin-producing beta cells. We have previously shown that oral administration of insulin suppresses insulitis and development of diabetes in the NOD mouse. Oral insulin has no metabolic effect on blood glucose. Oral insulin mediates its effect through a T cell-dependent mechanism as shown by adoptive transfer and T cell depletion experiments, but the mechanisms responsible have not been fully explored. We now report a serial analysis of the cells and cytokines associated with development of diabetes in NOD mice, and contrast this with the findings in animals fed equine insulin or a control protein (ovalbumin). Animals were fed 1 mg twice a week for 5 weeks, beginning at 5 weeks of age. Marked insulitis in naive or ovalbumin-fed NOD mice occurred at 10 weeks, at which time a dense peri-islet and intra-islet MNC infiltration was observed. Immunohistological studies using monoclonal antibodies showed that infiltrating MNC consisted mainly of CD4+ T cells ( > 75% of leukocytes) plus smaller numbers of macrophages and CD8+ T cells. These cells displayed evidence of immune activation with expression of receptors for interleukin-2 (IL-2R) plus Th1 cytokines; dense labeling for IFN-gamma and tumor necrosis factor-alpha, plus lesser amounts of IL-2, was observed. MNC lacked labeling for IL-4, IL-10, prostaglandin-E, or transforming growth factor-beta. By contrast, at 10 weeks, pancreatic tissues from NOD mice fed insulin showed considerably less insulitis, and the residual MNC, although still largely CD4+ T cells plus macrophages, showed dense labeling for IL-4, IL-10, prostaglandin-E, and transforming growth factor-beta and an absence of IL-2, IFN-gamma or tumor necrosis factor-alpha Taken together with our previous findings, these data indicate that oral administration of insulin affects the development of diabetes in NOD mice through the generation of cells that elaborate immunoregulatory cytokines within the target organ and shift the balance from a Th1 to a Th2 pattern of cytokine expression.
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PMID:Suppression of insulitis in non-obese diabetic (NOD) mice by oral insulin administration is associated with selective expression of interleukin-4 and -10, transforming growth factor-beta, and prostaglandin-E. 748 82

We determined the percentage of circulating natural killer (NK) cells, using the monoclonal antibodies anti-CD57 and anti-CD16, NK cytotoxic activity (lytic units/10(6)) and lymphokine-activated killer (LAK) activity in 25 IDDM patients aged 3-23 years, 12 with disease for < 1 year (Group I) and 13 with disease for > 3 years (Group II). Nine age-matched healthy subjects served as controls. The percentage of CD57+ cells was similar in IDDM patients and controls, while the percentage of CD16+ cells was lower in IDDM patients (P < 0.05) than in controls. NK cell cytotoxic activity was lower in IDDM patients than in controls (P < 0.01), in Group I and II compared with controls (P < 0.005). LAK activity was similar in IDDM patients and in controls. No correlation was found between NK cytotoxic activity and metabolic control, HLA typing, while a negative correlation was found between NK cytotoxic activity and insulin requirement (P < 0.05). The decreased NK cytotoxic activity observed in our patients, in particular in long-standing diabetics, with normal NK cell number, could be due to a qualitative defect of the NK cells, or to a deficient IL-2 and/or TNF-alpha production, or to a immunomodulatory or immunosuppressing effect of insulin.
Diabetes Res Clin Pract 1994 Feb
PMID:Cytotoxic activity in children with insulin-dependent diabetes mellitus. 751 51

We have used a reverse transcriptase-polymerase chain reaction (RT-PCR) protocol to examine the expression of cytokines in the pancreases and islets of patients with type I diabetes. We detect a significant increase in the level of expression of interferon (IFN)-alpha in the pancreases of the diabetic patients as compared with the control pancreases. In contrast, IFN-beta was detected at comparable levels in both groups, while IFN-gamma was detected in three of four control pancreases and one of four pancreases from the diabetic individuals. The IFN-alpha cDNAs generated by the RT-PCR were cloned and sequenced to determine which alpha-subtypes were being expressed. We found that the repertoire of subtypes was quite limited in any one individual (diabetic or not), although each individual was different with respect to the pattern of subtypes expressed. We also examined these pancreases for the expression of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, IL-2, IL-4, and IL-6. We found no detectable expression of TNF-alpha or IL-2 in any pancreases, and the expression of the other cytokines was variable, with no pattern emerging from the comparison of the diabetic and nondiabetic individuals. We conclude that, of the cytokines examined, only IFN-alpha was significantly increased in the diabetic patients, a result that is consistent with the possibility that this cytokine is directly involved in the development of type I diabetes.
Diabetes 1995 Jun
PMID:Interferon expression in the pancreases of patients with type I diabetes. 754 May 71

T cells are involved in the induction and suppression of autoimmune diabetes in nonobese diabetic (NOD) mice. Because the incidence of diabetes is 13-fold greater in NOD/Smrf females, we searched for T cell phenotypes that showed sexual dimorphism and associated with diabetes in backcross segregants. The percentage of CD4+PBL was higher in NOD/Smrf females than males, was intermediate in [NOD X NON] F1 mice and approximated a 1:1 distribution in F1 mice backcrossed to either NOD or NON parental strains, suggesting primary control of the phenotype by an incompletely dominant gene, but not excluding additional effects by other genes. We term this primary gene Tlf(T lymphocyte frequency) because it also influenced the percentage of CD8+ T cells, although to lesser extent and independently from the MHC previously shown to lower the CD8+ T cell fraction in NON mice. Tlf segregated with diabetes in BC1 females, suggesting linkage with at least one diabetic locus. Genotyping of markers for Idd1, Idd2, and Idd3/10 revealed that Tlf mapped with Idd2 on chromosome 9. Dihydrotestosterone simultaneously lowered CD4+ PBL levels and prevented diabetes in NOD females while, in vitro, it had a differential effect on Con A elicited cytokines, increasing IL-2 22% and decreasing IL-4 39% (p < 0.0001). Thus the Tlf phenotype in NOD females, like diabetes, can be modulated by androgens.
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PMID:Association of an androgen-responsive T cell phenotype with murine diabetes and Idd2. 757 87

Peripheral blood mononuclear cells from patients with non-insulin-dependent diabetes mellitus (NIDDM) show reduced proliferative response to phytohemagglutinin (PHA) and other mitogens. This study was undertaken to determine whether this reduced lymphocyte proliferation is mediated by a decreased production of cytokine or decreased expression of interleukin-2 receptor (IL-2R). Mononuclear cells from NIDDM patients (n = 34) and healthy controls (n = 22) were cultured in RPMI-1640 media containing PHA, concanavalin-A and phorbol myristate acetate. NIDDM patients showed reduced [3H]thymidine uptake (57% of controls, P < 0.01), reduced percentage of IL-2R-positive cells (61% of controls, P < 0.02) and increased level of tumor necrosis factor (TNF)-alpha (200% of controls, P < 0.05). The percentage of complement receptor (CR) 3-positive monocytes from NIDDM patients was also decreased (72% of controls, P < 0.05). However, the production of IL-1 beta, IL-2 and interferon-gamma, the percentages of pan T cells (CD3), T helper cells (CD4), T suppressor cells (CD8), the ratio of CD4/CD8 and the expression of CR1 and Fc receptors for immunoglobulin G (Fc gamma RII and Fc gamma RIII) were not significantly different between NIDDM patients and healthy subjects. Human recombinant IL-2 was unable to restore the [3H]thymidine uptake by PHA-stimulated mononuclear cells from NIDDM patients. Elevation of glucose concentration up to 27.8 mmol/l in the culture medium did not suppress the [3H]thymidine uptake and IL-2R expression by activated lymphocytes from healthy subjects. The decreased expression of IL-2R on activated lymphocytes might be responsible for the insufficient lymphocyte proliferation in NIDDM patients. These findings suggest that decreased expression of CR3 on monocytes, decreased lymphocyte proliferation and decreased IL-2R expression despite a higher production of TNF-alpha may explain the impaired cell-mediated immunity seen in NIDDM patients.
Diabetes Res Clin Pract 1995 May
PMID:Decreased cell-mediated immunity in patients with non-insulin-dependent diabetes mellitus. 758 21

Markers of cell-mediated immune activation were studied in 32 Chinese patients with recent-onset insulin-dependent diabetes mellitus (IDDM) as compared with 12 patients with recent-onset non-insulin-dependent diabetes mellitus (NIDDM) and 34 normal subjects. Sera were assessed for soluble markers of T-cell activation (sCD4, sCD8, sIL-2R); the cytokines (IL-1 beta, TNF-alpha, IL-2, IL-6), and T-cell subsets were also determined. Only 1 of the 32 IDDM patients had increased sCD4 levels, 5 had increased sCD8, and 3 had increased sIL-2R. None of the sera from NIDDM patients and control subjects showed such increased levels of soluble markers. Three IDDM patients had detectable IL-1 beta and this weakly so (< 3.5 pg/ml). However, the other cytokine data and the frequency of activated T-cells, CD4+, CD8+ T-cell subsets and CD4:CD8 ratio showed no significant differences among the IDDM, NIDDM and normal subjects. Our data suggest that in addition to a low frequency of islet cell antibodies, Chinese patients with recent onset IDDM also showed a lack of serum markers of cellular activation.
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PMID:Soluble T-cell markers and serum cytokines in type I (insulin-dependent) diabetes mellitus. 764 84

Syngeneic pancreatic islet grafts in nonobese diabetic (NOD) mice elicit a cell-mediated autoimmune response that destroys the insulin-producing beta cells in the islet graft. IL-4 and IL-10 are cytokines that inhibit cell-mediated immunity. In this study, we evaluated the effects of IL-4 and IL-10 on the survival of syngeneic pancreatic islets transplanted into diabetic NOD mice. Islet grafts survived beyond 18 days and normoglycemia was maintained in 67% (10 of 15) of mice treated with IL-4 plus IL-10, but in none (0 of 20) of vehicle-injected (control) mice. Also, 40% (6 of 15) of the mice treated with IL-4 plus IL-10 were normoglycemic at 30 days after transplantation, compared with 14% (1 of 7) of the mice treated with IL-4 alone, 8% (1 of 13) of the mice treated with IL-10 alone, and none (0 of 20) of the control mice. Histological examination of grafts at 10 days after transplantation revealed peri-islet accumulations of mononuclear leukocytes and intact islet beta cells in grafts from IL-4 plus IL-10-treated mice, whereas islets were infiltrated by leukocytes and the beta cell mass was greatly reduced in grafts from control mice. Polymerase chain reaction (PCR) analysis of cytokine mRNA expression in the grafts revealed higher levels of IL-2, IFN gamma, and IL-10 mRNA in grafts of diabetic compared with normoglycemic control mice, whereas IFN gamma and TNF alpha mRNA levels were significantly decreased in grafts of IL-4 plus IL-10-treated mice compared with either normoglycemic or diabetic control mice. These results suggest that T helper (Th)1 cells and their cytokine products (IL-2, IFN gamma, and TNF alpha) may promote islet beta cell destructive insulitis and autoimmune diabetes recurrence in syngeneic islet-transplanted NOD mice, and that administration of IL-4 plus IL-10 may inhibit diabetes recurrence by suppressing Th1 cytokine production in the islet grafts.
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PMID:Combined therapy with interleukin-4 and interleukin-10 inhibits autoimmune diabetes recurrence in syngeneic islet-transplanted nonobese diabetic mice. Analysis of cytokine mRNA expression in the graft. 765 67

Previously we reported that the administration of human (h) lymphotoxin (h-LT) markedly protected NOD mice from insulin-dependent diabetes mellitus (IDDM) partly by affecting the generation phase of anti-islet effector cells, probably in the thymus. In this study, we investigated the effect of h-LT on the signal transduction of the mouse thymocytes by observing c-Fos expression in the thymocytes by using a flow cytometer. The intensity of c-Fos expression in whole thymocytes was significantly lower in the female NOD with a high incidence of diabetes than that in the male NOD mice with a low incidence of diabetes and than that in normal mice (P < 0.0001). The low c-Fos expression in the female NOD thymocytes was most prominent in CD3low thymocytes. c-Jun expression of the CD3low thymocytes was also lower in the female NOD mice. Administrations of h-LT, h-TNF, and h-IL-2, which has been reported to prevent IDDM in NOD mice by systemic administration, significantly up-regulated c-Fos expression in CD3low thymocytes. From these results, it is assumed that a relationship may exist between the high diabetes incidence and the defective c-Fos expression in female NOD mice and between the prevention of IDDM and the amelioration of the defective c-Fos expression with h-LT in female NOD mice.
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PMID:Reduced expression of c-Fos in female NOD mouse thymocytes and up-regulation with human lymphotoxin. 765 36


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