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)

Protective immunity to the parasitic nematode Onchocerca volvulus (Ov) appears to be directed against molecules of invading L3 larvae. In this study, the cellular immune reaction to such an Ov L3 protein (S1) which is protective in an animal model was analyzed using peripheral blood mononuclear cells (PBMC) of individuals from a hyperendemic area in West Africa who were exposed to Ov but remained free from disease ('putatively immune individuals'). Despite seronegativity of these individuals against S1, proliferation of PBMC was inducible, allowing generation of an S1-specific T cell line which produced IFN-gamma upon stimulation with both Ov lysate and S1. However, S1 induced significantly more IL-5 than Ov lysate. S1-specific, DQ6 (DQA1*0103/DQB1*0603)-restricted T cell clones were generated which reacted against synthetic peptides comprising amino acids 99-111 of S1. These clones, which are the first generated against a recombinant fllarial antigen, produced both IFN-gamma and IL-5 as well as little IL-4, suggestive of a Th0-like phenotype. In conclusion, in putative immunity, reactivity against a particular parasite protein can be detectable on the level of T but not B cells. Induction of both IFN-gamma and IL-5 by S1 suggests that it may trigger macrophage plus eosinophil dependent killing of L3 in vivo. The identification of a likely DQ6 (DQA1*0103/DQB1*0603)-restricted T cell epitope may be of more general relevance, given that allele combinations of DQ6, including DQA1*0103/DQB1*0603, are negatively associated with diabetes mellitus.
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PMID:Production of both IFN-gamma and IL-5 by Onchocerca volvulus S1 antigen-specific CD4+ T cells from putatively immune individuals. 918 17

The diabetes-resistant BioBreeding (DR-BB) rat, derived from diabetes-prone forebears, does not normally develop spontaneous insulitis or diabetes, but when infected with Kilham rat virus (KRV) this animal develops autoimmune diabetes similar to the diabetes-prone BioBreeding (DP-BB) rat. In this study, we attempted to determine whether macrophages and macrophage-derived cytokines play a role in the development of KRV-induced diabetes in DR-BB rats. Seventy-eight percent of DR-BB rats treated with KRV and poly(I:C) develop diabetes, whereas depletion of macrophages with liposome-encapsulated dichloromethylene diphosphonate (lip-Cl2MDP) in KRV and poly(I:C)-treated DR-BB rats results in the near-complete prevention of insulitis and diabetes. Measurement of the macrophage-derived cytokines IL-12, TNF-alpha, and IL-1beta revealed a selective increase of their expression, after KRV infection, in the splenic lymphocytes and the pancreatic islets. Measurement of CD4+ T cell-derived cytokines revealed that IL-2 and IFN-gamma cytokine gene expression closely correlates with an elevation of IL-12, but IL-4 and IL-10 do not change. Depletion of macrophages before the isolation of splenic lymphocytes from DR-BB rats treated with KRV and poly(I:C) resulted in the loss of ability to transfer diabetes to young DP-BB rats. On the basis of these observations, we conclude that macrophages and macrophage-derived cytokines play a critical role in the cascade of events leading to the destruction of pancreatic beta cells, culminating in the development of insulin-dependent diabetes mellitus.
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PMID:Role of macrophages and macrophage-derived cytokines in the pathogenesis of Kilham rat virus-induced autoimmune diabetes in diabetes-resistant BioBreeding rats. 920 Apr 87

Dapsone (4,4'-diaminodiphenyl sulfone) has a large clinical experience due to its antimicrobial effects against Mycobacterium leprae, the causative agent of leprosy, and is used clinically where inflammation mediated by neutrophils is perceived to play a role. We administered dapsone in two concentrations (0.001% and 0.0001% w/w of diet) to 30 female non-obese diabetic (NOD) mice to explore the effect of dapsone on the development of IDDM following either a 1-week pulse or 20 weeks of continuous oral dapsone administration. Those mice receiving either the high or low doses of dapsone in the continuous group had a significantly reduced cumulative percentage of onset of IDDM. One of the seven mice given 0.0001% dapsone became diabetic (age 25 weeks), while none of the eight high dose (0.001%) mice developed the disease. Histological examination of pancreatic sections revealed islet infiltration in all groups of animals. The pulse and continuous experiments showed no statistically significant difference in the frequency or severity of lymphocytic infiltration. Dapsone administration did not inhibit growth, and growth rates were greater in those animals receiving the higher dapsone dose compared with the lower dose comparable to controls. We studied whether dapsone influenced murine lymphocyte function in addition to the published effects of the drug on neutrophils. At doses approximating those achieved in vivo (0.4 and 2 micrograms/ml), dapsone was found to inhibit murine splenocyte IL-2 and IL-4 secretion in response to concanavalin A. In view of the wide clinical experience with dapsone, randomized trials of the drug in new onset diabetes may be warranted.
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PMID:Dapsone decreases the cumulative incidence of diabetes in non-obese diabetic female mice. 920 62

We have previously shown that immunotherapy with complete Freund's adjuvant (CFA) or BCG is highly effective in the prevention of spontaneous insulin-dependent diabetes mellitus (IDDM) and in circumventing the rejection of syngeneic islet grafts in diabetic NOD mice. This protection is reversed by treatment with cyclophosphamide (Cy). The present study was undertaken to determine the effect of BCG vaccination on the progression of Cy-accelerated diabetes in NOD mice and to understand the mechanism of BCG immunotherapy. The time course of Cy and BCG administration showed that the progression of Cy-induced diabetes can only be blocked when BCG vaccination is given within 3 days of Cy administration. Mice given BCG 3 days before (-3 days) or 7 days after Cy treatment were not protected. BCG immunization 1 day after Cy treatment almost completely prevented insulitis in the islets of Cy-treated mice. Cy treatment reduced the endogenous production of anti-GAD67 antibody, whereas BCG vaccination 1 day after Cy treatment restored the production of anti-GAD67 antibody of IgG1 isotype. The comprehensive effect of BCG vaccination on cytokine production in Cy-treated mice was to increase IL-4 production and change the IL-4/IFN-gamma ratio in both serum and supernatant of spleen cell cultures. We found that BCG-induced protection was associated with increased splenic CD4+CD45 RB(high) T cells. Taken together, our results indicate that BCG treatment counteracts the effect of Cy on autoimmune process in IDDM. However, BCG immunotherapy has a narrow window of up to 3 days after Cy treatment to block the progression of Cy-induced diabetes and to allow for the induction of regulatory cells which may effectively downregulate the diabetogenic cells. In summary, our results suggest that BCG vaccination prevents IDDM if given in the prediabetic state. After the induction of diabetes, disease progression can only be prevented within a narrow window of opportunity by this treatment.
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PMID:BCG vaccination prevents insulin-dependent diabetes mellitus (IDDM) in NOD mice after disease acceleration with cyclophosphamide. 921 54

As a result of failed induction of T cell tolerance to pancreatic B cells, non-obese diabetic (NOD) mice develop spontaneous autoimmune insulin-dependent diabetes mellitus (IDDM). The thymic stroma, which plays a crucial role in thymic T cell maturation, undergoes extensive premature disorganization in NOD mice, so it is of interest to examine NOD T cell development. In this study, both major and minor developmental populations of thymocytes of NOD/Lt mice were studied and compared to those of BALB/c, C57BL/6 and CBA mice by multiparameter flow cytometry (FACS). These results are described in detail and reveal that most thymocyte subsets were normally represented, including alphaTcR-CD4-CD8- (triple negative; TN), alphabetaTcR-CD4+CD8- and alphabetaTcR-CD4-CD8+ (immature single positive; ISP), alphabetaTcR-/lowCD4+CD8+ (double positive; DP) and alphabetaTcR+CD4+CD8- and alphabetaTcR+CD4-CD8+ (mature single positive; SP) as well as gammadelta T cells. However, NOD mice exhibited a marked deficiency of thymic alphabetaTcR+CD4-CD8- (alphabeta+DN) T cells. alphabeta+DN T cells, which are included among NK1+ T cells in C57BL/6 mice, produce large amounts of IL-4 on primary stimulation. Given the potential significance of NKT cells in immunoregulation, it is possible that the scarcity of these cells in NOD mice plays a role in the pathogenesis of IDDM.
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PMID:Flow cytometric study of T cell development in NOD mice reveals a deficiency in alphabetaTCR+CDR-CD8- thymocytes. 921 55

Autoimmune diabetes is caused by the CD4(+), T helper 1 (Th1) cell-mediated apoptosis of insulin-producing beta cells. We have previously shown that Th2 T cells bearing the same T cell receptor (TCR) as the diabetogenic Th1 T cells invade islets in neonatal nonobese diabetic (NOD) mice but fail to cause disease. Moreover, when mixed in excess and cotransferred with Th1 T cells, Th2 T cells could not protect NOD neonates from Th1-mediated diabetes. We have now found, to our great surprise, the same Th2 T cells that produced a harmless insulitis in neonatal NOD mice produced intense and generalized pancreatitis and insulitis associated with islet cell necrosis, abscess formation, and subsequent diabetes when transferred into immunocompromised NOD.scid mice. These lesions resembled allergic inflamation and contained a large eosinophilic infiltrate. Moreover, the Th2-mediated destruction of islet cells was mediated by local interleukin-10 (IL-10) production but not by IL-4. These findings indicate that under certain conditions Th2 T cells may not produce a benign or protective insulitis but rather acute pathology and disease. Additionally, these results lead us to question the feasibility of Th2-based therapy in type I diabetes, especially in immunosuppressed recipients of islet cell transplants.
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PMID:T helper 2 (Th2) T cells induce acute pancreatitis and diabetes in immune-compromised nonobese diabetic (NOD) mice. 922 59

Oral administration of antigen leads to systemic immune unresponsiveness. Low dose oral tolerance generates regulatory cells which, when triggered in an antigen-specific manner, suppress inflammatory responses. We have previously shown that oral administration of an organ-specific antigen, porcine insulin, protects against diabetes development in the NOD mouse. In the present study we extend these observations to the B-chain of insulin, a 30-amino-acid peptide which has now been shown by others to contain the immunogenic epitope. Oral administration of the B-chain slowed diabetes development in a co-transfer model in which cells from B-chain-fed animals were co-transferred with diabetogenic cells (P=0.02). Further exposure to antigen via feeding of the co-transfer recipient animals not only slowed diabetes development but prevented diabetes in some animals (P=0.01). In vitro proliferation of popliteal lymph node cells from fed and immunized animals was suppressed in an antigen-specific manner when cells were restimulated with the fed antigen. When those cells were cultured and restimulated in vitro with the B-chain of insulin, we also observed a decrease in IFN-gamma expression and an increase in IL-4, TGF-beta and IL-10 expression. These results demonstrate that an orally protective epitope resides in the B-chain of insulin and that refeeding following adoptive transfer enhances protection. Finally, the orally administered antigen is associated with a decrease in Th1 responses and an increase in Th2 responses to the insulin B-chain.
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PMID:Oral administration of the immunodominant B-chain of insulin reduces diabetes in a co-transfer model of diabetes in the NOD mouse and is associated with a switch from Th1 to Th2 cytokines. 923 97

Cell-mediated tissue destruction, such as that occurring in allograft rejection, is thought to be mediated by Th1 cells and cytokines. We have recently shown that transgenic expression of the Th2 cytokine IL-4 by pancreatic beta cells completely protects nonobese diabetic (NOD) mice from autoimmune diabetes by inducing functional tolerance among autoreactive T cells. To investigate whether local IL-4 production could also induce functional tolerance among alloreactive T cells and thus prevent allograft rejection, we transplanted pancreata from transgenic neonatal mice and their nontransgenic littermates into allogeneic hosts. Within 2 wk, recipient mice had rejected their grafts regardless of the transgene's presence or absence. Considering that the vigorous immune response induced might have prevented any effect by IL-4, we injected recipient mice with anti-CD4 and anti-CD8 mAbs, thereby depleting them of T cells and thus providing the islets with an opportunity to mature and grow. This approach indeed delayed rejection of neonatal pancreata from nontransgenic mice by >1 wk. By that time, however, pancreata from transgenic mice had also been rejected. Our results indicate that the allograft rejection response under these conditions, in contrast to the autoimmune response in NOD mice, cannot be regulated by local IL-4 production, regardless of the cytokine's impact on Th1 cells.
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PMID:IL-4 expression by grafts from transgenic mice fails to prevent allograft rejection. 925 18

The effect of Lactobacillus casei (LC) on the onset of diabetes in an insulin-dependent diabetes mellitus model, nonobese diabetic (NOD) mice, were examined. From the age of 4 weeks, female NOD mice were fed a diet of either standard laboratory chow (n = 12) or the same chow containing 0.05% weight heat-killed cells of LC (n = 12), and the onset of diabetes was thereafter recorded. The incidence of diabetes in the control group (10/12) was significantly higher than that in the LC-treated group (3/12) (p < 0.01). Pathological analysis in the LC-treated group revealed strong inhibition of the disappearance of insulin-secreting beta cells in Langerhans islets caused by autoimmune disease. The proportion of CD45R+ B-cells in the spleen was increased and that of CD8+ T-cells in spleen cells was decreased in the LC-treated group. Analysis of cytokine production revealed lower interferon-gamma production in the LC-treated group compared to the control group, while the interleukin (IL)-2 production was higher. The levels of IL-4, IL-5, IL-6 and IL-10 in the LC-treated group were somewhat higher than in the control group. Taken together, these findings clearly demonstrated that oral feeding of LC to NOD mice effectively inhibited the occurrence of diabetes and regulated the host immune response.
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PMID:Prevention of onset in an insulin-dependent diabetes mellitus model, NOD mice, by oral feeding of Lactobacillus casei. 929 4

Beginning at the time of insulitis, nonobese diabetic (NOD) mice demonstrate a thymocyte and peripheral T cell proliferative hyporesponsiveness induced by TCR cross-linking, which is associated with reduced IL-2 and IL-4 secretion. We previously reported that NOD CD4+ T cell hyporesponsiveness is reversed completely in vitro by exogenous IL-4, and that administration of IL-4 to NOD mice prevents the onset of insulin-dependent diabetes mellitus (IDDM). This result suggested that T cell-mediated destruction of pancreatic islet beta cells may result from a hyporesponsiveness in regulatory Th2 cells favoring a Th1 cell-mediated environment in the pancreas. In the present study, we tested this possibility by analysis of the mechanisms of protection from IDDM afforded by IL-4 treatment in NOD mice. We show that IL-4 protects NOD mice from insulitis and IDDM when administered i.p. three times a week for 10 wk beginning at 2 wk of age. This occurs by the modulation of the homing of autoreactive cells to inflammatory sites and the stabilization of a protective Th2-mediated environment in the thymus, spleen, and pancreatic islets. Thus, IL-4 treatment favors the expansion of regulatory CD4+ Th2 cells in vivo and prevents the onset of insulitis and IDDM mediated by autoreactive Th1 cells.
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PMID:IL-4 prevents insulitis and insulin-dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper-2 cell function. 936 91


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