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

Early intensive insulin treatment is thought to improve subsequent Beta-cell function in Type 1 (insulin-dependent) diabetic patients. Prophylactic insulin administration also reduced diabetes incidence in diabetes-prone animals. To study the mechanisms by which these effects occur, we tested the ability of insulin therapy in the model of non-obese-diabetic mice, to prevent the penetration of committed T cells into the islets and subsequent Beta-cell destruction. Sublethally irradiated non-obese-diabetic males of 8 weeks of age were adoptively transferred with splenocytes from diabetic donors and treated with the maximum tolerable dosage of fast-acting insulin (0.5 U, twice daily) until 30 days after cell transfer. Diabetes incidence was compared to control animals injected with the same concentration of insulin diluent. After one month of treatment, the cumulative diabetes frequency was significantly less within the insulin-treated group (4 of 15, 26.6%) than in the control group (15 of 18, 83.3%; p less than 0.01). Pancreatic histological analysis of insulin-treated animals revealed a lower severity of insulitis and Beta-cell necrosis and a higher percentage of normal islets (46.6 +/- 10% vs 2.3 +/- 2%, p less than 0.01), including five (33%) mice with no lesions. Immunoperoxydase staining of pancreatic sections indicated similar insulin and ganglioside staining of Beta cells from insulin-treated mice and control animals. Insulin-treated mice had comparable pancreatic insulin content to normal mice. Flow cytometry analysis of spleen cell populations indicated that insulin increased the number of Thy1,2+ and Lyt-2+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Insulin prevents adoptive cell transfer of diabetes in the autoimmune non-obese diabetic mouse. 186 85

It is generally accepted that T lymphocyte-mediated autoimmunity contributes to the pathogenesis of Type 1 diabetes in humans and animals. Using spleen cells from nonobese diabetic (NOD) mice, a model of human Type 1 diabetes, we have analyzed the subset of T lymphocytes by flow cytometry and investigated concanavalin A (Con A)-induced interleukin 2 (IL-2) production and cell proliferation. NOD mice showed a higher percentage of Thy1.2+, L3T4+, and Lyt2+ T lymphocytes than did control ICR mice through the whole age examined. Spleen cells from a large majority of NOD mice were found to generate very low IL-2 production and cell proliferation in response to Con A. However, a few mice preserved their responsiveness to Con A. The following reasons may indicate that macrophage-mediated suppression participates in the deficient function of NOD spleen cells. (a) Macrophage depletion from NOD spleen cells retrieved Con A-induced IL-2 production. (b) Thioglycollate-induced peritoneal exudate cells containing many activated macrophages could completely suppress cell proliferation. (c) Prostaglandin synthetase inhibitor indomethacin reversed the suppression of IL-2 production by macrophages. (d) Conversely, exogenous prostaglandins could show the partial suppression of IL-2 production. These results suggest that activated macrophages suppress the response of NOD spleen cells to Con A mostly through prostaglandins. This impairment may contribute to the pathogenesis of Type 1 diabetes in NOD mice.
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PMID:[Cellular immune dysfunction in the NOD mouse: suppression of concanavalin A-induced responses in spleen cells by activated macrophages]. 258 13

The diabetic db/db mice of the C57 BL/KsJ strain display anti-islet immunity, thymic dysfunction, and lymphopenia. In the present work, lymphocytes, T-cells, and T-cell subsets were enumerated in thymus and spleen from diabetic db/db mice and their db/ + heterozygote littermates from the 10th day to the 10th month of life. A significant lymphopenia was detected in thymus and spleen from the second month on, involving specifically the T-cell compartment, as assessed by use of a monoclonal anti-Thy1 antibody in indirect fluorescence. The study of T-cell subsets by monoclonal anti-Lyt1 and anti-Lyt2 antibodies revealed a significant increase in Lyt1+ cells and a decrease in Lyt2+ cells, with a corresponding increase of the Lyt1+/Lyt2+ ratio. These anomalies appeared early in life, and were apparently linked neither with the degree of hyperglycemia nor with weight loss or infection. The T-cell depletion in thymus was more pronounced in young male (less than 3 mo) than in young female db/db mice. These alterations may correspond to an increase in the helper/suppressor-cytotoxic ratio and could be linked with the thymic anomalies present in these mice, contributing to the development of anti-islet autoimmunity.
Diabetes 1986 Feb
PMID:T-lymphopenia and T-cell imbalance in diabetic db/db mice. 351 Sep 25

The importance of T-lymphocytes in the induction of insulitis and hyperglycemia in certain strains of mice treated with multiple subdiabetogenic doses of streptozocin has been a matter of controversy. To understand the role of T-lymphocytes, we treated thymectomized BALB/c ByJ mice with five daily doses of streptozocin (45 mg/kg) and determined the effect of treatment with monoclonal antibodies against T-lymphocyte subsets on the development of diabetes and insulitis. Hyperglycemia (mean glucose of 321 +/- 29 vs. 167 +/- 15 mg/dl in controls) and insulitis were induced in BALB/c ByJ mice given streptozocin. Thy1.2+, L3T4, and Lyt2+ cells were all identified within the islets of diabetic mice. There was a relative paucity of L3T4+ cells and an overabundance of Lyt2+ cells compared with the frequency of these cells found in lymphatic tissues or peripheral blood. Treatment with anti-L3T4 or anti-Lyt2 monoclonal antibodies caused a reduction in splenic T-lymphocyte subsets and attenuated the hyperglycemia to 212 +/- 14 and 197 +/- 16 mg/dl (P less than .001 and .01), respectively, compared with controls and prevented the insulitis induced by streptozocin. Our studies support the hypothesis that an immune response is important to the development of multi-low-dose streptozocin diabetes and indicate that treatment with monoclonal antibodies against the L3T4+ or Lyt2+ T-lymphocyte subsets can attenuate this process.
Diabetes 1987 Jul
PMID:Treatment with anti-T-lymphocyte antibodies prevents induction of insulitis in mice given multiple doses of streptozocin. 355 79

The circulation pathway of diabetogenic T lymphocytes prior to insulitis was investigated using adoptive transfer of diabetes in the non-obese diabetic (NOD) mouse model. Transferred T cells were distinguished from recipient T cells using two strains of mice congenic at the Thy1 locus. They were monitored in the pancreas and in several lymphoid organs including thymus, spleen, and lymph nodes from pancreatic, mesenteric, axillary, inguinal and lomboaortic areas, from Day 0 to Day 15 after the adoptive lymphocytic transfer. Immunohistochemical studies showed that at Day 2 post-transfer the pancreatic lymph nodes (PLN) and to a lesser extent the spleen, are the first two organs to be infiltrated. The amount of T cells of donor origin using quantitative flow cytometric analysis was 4% and 2.6% respectively. This percentage increased to 19% in the PLN at Day 15 and did not exceed 7% in the spleen. Analysis of the expression of IL-2 receptor present at the surface of activated T lymphocytes showed that 73% of donor T cells were activated in the PLN within 3 days post-transfer in contrast to 0% in the spleen. The accumulation and activation of T cells in the PLN may imply a role of these lymphoid organs in harbouring the diabetogenic T cells during the early steps of the disease.
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PMID:Pancreatic lymph nodes are early targets of T cells during adoptive transfer of diabetes in NOD mice. 757 94

Since the modulation of the immune system at birth may influence the course of insulin-dependent (type 1) diabetes, we investigated whether neonatal injections of cyclosporin (CsA) to newborn non-obese diabetic (NOD) mice influence diabetes during later life. Two groups of 90 mice (45 female, 45 male) were injected intraperitoneally for the first 6 days of life with CsA (10 mg/kg per day) or with vehicle. In female NOD mice, the onset of diabetes was earlier and cumulative incidence was higher after neonatal treatment with CsA (P < 0.01). The incidence of diabetes was also dramatically enhanced in male NOD mice (P < 0.01), which normally display a very low disease incidence. Concomitantly, the severity of lymphocytic infiltration of the pancreatic islets was higher in female NOD mice neonatally treated by CsA (P < 0.02), and to a lesser extent in males, than in control mice. After administration of CsA to newborn NOD mice, there was a reduction (P < 0.01) of both CD4+CD8- and CD4-CD8+ thymocytes, whereas the number of double positive CD4+CD8+ thymocytes was increased. Concomitantly, Thy1-2+ cells in spleen were decreased (P < 0.01), and spleen cells expressing either CD3 molecule or alpha beta TCR complex were diminished (P < 0.01). Both CD4+ and CD8+ spleen T cells were depleted. By contrast, the low percentage of gamma delta TCR-expressing splenocytes was not modified. Numbers of MHC class 1+ or MHC class 2+ spleen cells were also depressed (P < 0.01). After neonatal injections of CsA, spleen cells showed a reduced response to concanavalin A (Con A) (P < 0.01). On the contrary, stimulation indices of splenocytes incubated with xenogeneic insulin-producing cell extracts were enhanced (P < 0.03). Proliferation indices of splenocytes to self class 2 antigens, generating suppressor cell activity, during syngeneic mixed lymphocyte reaction (SMLR) were significantly reduced (P < 0.01). Irradiated NOD mice were used as recipients for spleen cells from CsA-neonatally treated NOD mice. They displayed enhanced insulitis 2 weeks after transfer, and diabetes was successfully produced by 1 month after transfer in 50% of the recipients. By contrast, NOD mice which received control syngeneic spleen cells remained normoglycaemic, with only moderate islet infiltration which would be expected of NOD mice of this age. Thus, neonatal injections of CsA markedly enhance diabetes in both female and male NOD mice.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neonatal injections of cyclosporin enhance autoimmune diabetes in non-obese diabetic mice. 803 11

Precise definition of the role of both CD4 and CD8 T-cell subsets from NOD mice in the adoptive transfer of diabetes has been complicated by the possibility that endogenous T-cells may be recruited. Two newly created NOD congenic stocks, NOD.NON-Thy-1a and NOD/LtSz-scid, have been used as T-cell donors and recipients, respectively, to eliminate contributions from endogenous T-cells and thus to define the requirement for transferred T-cell subsets as a function of underlying diabetes development in the NOD donor. Total T-cells and T-cell subsets prepared from either prediabetic or diabetic NOD.NON-Thy-1a donors were adoptively transferred into 6-wk-old NOD-scid/scid recipients that were monitored for diabetes development. Both flow cytometric and histological analysis of recipient spleen and pancreas after adoptive transfer showed lymphocytes of donor (Thy1.1+) origin exclusively. Total T-cell and enriched CD4+ T-cell preparations from both diabetic and young prediabetic donors transferred diabetes to NOD-scid/scid recipients. However, the mean time to diabetes onset was doubled when CD4+ lymphocytes were isolated from prediabetic versus diabetic donors, and these transfers were complicated by the generation of small but significant numbers of CD8+ cells over time. Enriched CD8+ populations alone were unable to transfer disease. More rigorous exclusion of CD8+ cells by means of anti-CD8 MoAb treatment in vivo of the recipients of enriched CD4+ cells demonstrated a significant difference in the diabetogenic potency of CD4+ lymphocytes from diabetic versus nondiabetic donors. Diabetes was adoptively transferred to 58% of the recipients of enriched CD4+ lymphocytes from diabetic donors. In contrast, none of the recipients of enriched CD4+ lymphocytes from young prediabetic donors developed diabetes after MoAb treatment in vivo. The ability of a T-cell population to produce severe insulitis and sialitis in NOD-scid/scid recipients of T-cells closely paralleled its ability to induce diabetes. In an effort to suppress insulitis by suppression of macrophage migration to the islets, NOD-scid/scid mice were treated with silica in conjunction with adoptive transfer of T-cells from diabetic donors. Chronic silica treatment failed to deplete tissue macrophages and did not prevent diabetes development after transfer of unfractionated T-cells. Evidence is discussed indicating that the age-associated differences in ability of CD4+ T-cells to adoptively transfer diabetes in the absence of the CD8+ T-cells subset is a function of prior, chronic exposure of the CD4+ lymphocytes to beta-cell antigens in the donor.(ABSTRACT TRUNCATED AT 400 WORDS)
Diabetes 1993 Jan
PMID:Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. 809 6

Abnormalities in postthymic T cell development in the BB/W rat model of autoimmune insulin-dependent diabetes mellitus (IDDM) result in part from a lymphopenia (lyp) gene defect. To better characterize these abnormalities, the phenotypes of T cells from diabetes-prone (DP) and diabetes-resistant (DR) coisogenic rats were analyzed by multiparameter flow immunocytometry (FCM). Marked decreases in the numbers of Thy1- RT6+ T cells, most of which are CD8+, were documented in DP rats by live-gating. Conversely, an approximately 3-fold increase was observed in the percentage of Thy1+ RT6- T cells, which normally serve as the precursors of both Thy1- RT6+ and Thy1- RT6- T cell subsets in rats. These results suggested that, at a minimum, an arrest in maturation of the Thy1+ precursors of RT6+ T cells occurs postthymically in DP rats. To determine more precisely the stage(s) in T cell development at which lymphopenia occurs, the export and fate of recent thymic emigrants (RTE's) and their immediate descendants in DP rats was traced after intrathymic (i.t.) labelling with fluorescein isothiocyanate (FITC). The results showed that in DP, as compared with DR, rats: 1) 5-fold fewer RTE's are exported from the thymus per 24 hr; 2) more than 80% of the RTE's are CD4+; 3) most of the immediate descendants of RTE's disappear from the peripheral lymphoid tissues within one week after export from the thymus; and 4) few of the descendants of the RTE's that do survive differentiate into RT6+ T cells. Staining with propidium iodide revealed that a significantly higher proportion of Thy1+ T cells in DP than in DR rats are in cycle (S/G2/M), thereby accounting for their disproportionately high numbers relative to RTE's. These results indicate that, in addition to defective thymic export, most of the immediate descendants of RTE's in DP rats undergo non-productive proliferation and death at the time (3-7 days postthymic) at which their counterparts in DR rats differentiate into Thy1- RT6+ T cells. The resulting deficiency of immunoregulatory T cells, acting in concert with defective intrathymic selection of effector T cell precursors, appears to conspire to markedly enhance the predisposition of DP rats to autoimmunity.
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PMID:Abnormalities in the export and fate of recent thymic emigrants in diabetes-prone BB/W rats. 893 86

Oral administration of antigens has been proposed in the prevention and treatment of autoimmune diseases. We reported that oral administration of 0.8 mg of recombinant human insulin to 6-week-old NOD mice every other day for a month generated regulatory T-cells that were able to reduce the severity of insulitis and the percentage of clinical diabetes in naive irradiated recipients when co-injected with diabetogenic T-cells. In the present study, immunohistochemical analysis of the pancreatic glands revealed that injection of T-cells from insulin-fed mice upregulated the number of interleukin (IL)-4-secreting cells within the islets. Using two strains of NOD mice congenic at the Tbeta, or Thy1, locus, we observed a higher proportion of T-cells from insulin-fed mice in both the spleen (7.73 +/- 0.3 vs. 5.57 +/- 0.2%; P < 0.001) and the pancreatic lymph nodes (10.1 +/- 0.8 vs. 7.2 +/- 0.7%; P < 0.05) of cotransferred mice. By reverse transcription-polymerase chain reaction (RT-PCR) analysis, mice reconstituted with T-cells from insulin-fed animals had detectable amounts of IL-4 mRNA, specifically in the pancreatic lymph nodes (8 of 9 experimental mice vs. 1 of 9 control mice) and the pancreas (3 of 3 experimental mice vs. 0 of 3 control mice). Gamma-interferon mRNA was detectable in all cotransferred animals, but IL-10 mRNA and transforming growth factor beta mRNA were undetectable. These results suggested a shift from a T-helper 1 (Th1) to a Th2 pattern of cytokine expression and underlined the role of pancreatic lymph nodes in the protection. Repeated injections of 500 microg s.c. of anti-IL-4 monoclonal antibody led to an accentuation of the severity of islet infiltration and to the development of clinical diabetes. We concluded that oral administration of insulin can induce the presence of regulatory T-cells in the pancreas and the corresponding draining lymph nodes, initiate the secretion of IL-4 in this microenvironment sufficiently to suppress the activity of Th1 autoreactive T-cell clones, and ultimately provide protection against autoimmune diabetes.
Diabetes 1998 Jan
PMID:Protection against autoimmune diabetes with oral insulin is associated with the presence of IL-4 type 2 T-cells in the pancreas and pancreatic lymph nodes. 942 72

Restoration of peripheral tolerance to target autoantigens during autoimmune diseases has met with several limitations because of the limited efficacy of this approach in an already immune host. To optimize the induction of tolerance, we have shown that feeding insulin conjugated to cholera toxin B-subunit (CTB), a potent mucosal adjuvant, reduced by 5,000 the amounts of antigen necessary for delaying diabetes onset in NOD mice. To analyze these protective mechanisms, we have performed cotransfer experiments using splenocytes from young females fed once with 10 microg of CTB-insulin, mixed with diabetogenic T-cells, and intravenously injected into irradiated syngeneic male recipients. We demonstrated that the delayed onset of diabetes relied on CD4+ T-cells. We studied the cytokine production from plate-bound anti-CD3-stimulated cells. Higher interleukin (IL)-4 amounts were observed in both splenocytes and pancreatic lymph node (PLN) cell cultures from CTB-insulin-fed mice as soon as 4 h after the feeding. An increase in the levels of transforming growth factor-beta was seen after 24 h only in the mesenteric lymph nodes (MLN). In both of these organs, a reduction of gamma-interferon (IFN-gamma) production occurred after CTB-insulin treatment, at 24 h in the PLN and at 7 days in the MLN. Reverse transcription-polymerase chain reaction analysis indicated an increase in the level of IL-4 and a reduction in IFN-gamma transcripts in the PLN of mice treated orally with CTB-insulin and of the recipients of regulatory T-cells. Using different strains of congenic NOD mice at the Thy1 locus, we showed that protection was associated with the accumulation of T-cells from CTB-insulin-fed mice in the lymph nodes from draining sites containing functional islets, i.e., the PLN in normal mice and the renal lymph nodes after a syngeneic islet graft under the kidney capsule of streptozotocin-treated mice. Taken together, our results clearly indicate that oral administration of CTB-insulin conjugates in NOD mice produced a shift from a T-helper type 1 to a type 2 profile with the induction of antigen-specific regulatory CD4+ T-cells in the vicinity of the mucosal barrier and close to the inflamed islets.
Diabetes 1999 Nov
PMID:Oral administration of cholera toxin B-insulin conjugates protects NOD mice from autoimmune diabetes by inducing CD4+ regulatory T-cells. 1053 48


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