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)

Gene transfer into the pancreas would be useful for the treatment of a variety of disorders, including cystic fibrosis, diabetes, cancer, and immunomodulation of pancreatic allografts. A hypothesis that various cell populations in the pancreas could be targeted by recombinant adenoviruses was developed and tested. Gene transfer into the rat ductal epithelium, acinar cells, and islets of Langerhans was accomplished with a recombinant adenovirus containing bacterial beta-galactosidase by retrograde delivery of adenovirus into the pancreaticobiliary duct. Maximal gene expression was observed at 3 days and correlated with DNA blot analysis. Histologic analysis of sections from pancreatic tissue in the adenovirus-treated rats demonstrated severe pancreatitis. Immunophenotyping of the inflammatory infiltrate with rat lymphocyte-specific markers showed CD45-, CD8-, and CD4-positive cells. Tissue injury resolved as gene expression was lost, with both features absent by 21 days. Pancreatic regeneration was documented by the presence of 5-bromo-2'-deoxyuridine-positive staining cells. Pancreatic gene transfer with first-generation recombinant adenoviruses can be accomplished by techniques applicable to clinical situations. The use of first-generation recombinant adenoviruses for pancreas-directed gene transfer is limited by the development of inflammation and transient expression.
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PMID:Adenovirus-mediated in vivo gene transfer and expression in normal rat pancreas. 874 Apr 9

Direct multi-colour flow cytometric analysis was employed in patients with Graves' disease (n = 10) to determine the immunophenotype in peripheral blood lymphocytes (PBL) at the time of diagnosis without treatment (PBLw) and prior to operation (PBLp) and in thyroid-derived lymphocytes (TL). Additionally, the secretion of anti-thyroperoxidase antibodies (anti-TPO) was measured during culture of isolated peripheral or thyroid-derived B cells. Among TL from patients with high serum levels of anti-TPO (6/10) a significantly (p < 0.01) higher percentage of B cells were detected compared to PBLp (TL: 21.7 +/- 7.2%; PBLp: 13.2 +/- 4.5%). Enriched thyroid-derived B cells only from these patients also showed high spontaneous anti-TPO secretion during culture. The difference between peripheral and thyroid-derived natural killer (NK) cells was highly significant (p < 0.001; TL: 5.6 +/- 6.3%; PBLp: 13.6 +/- 5.5%). Two patients were found with a higher number of NK cells within TL. These patients were among those who had a low number of B cells infiltrating the thyroid gland. Regarding the expression of several other differentiation antigens, i.e. CD4 and CD8, gamma/delta TCR bearing T cells and CD45R0 on CD4+ T cells as a marker for memory cells, on TL no differences could be detected between patients with or without anti-TPO. In TL 31.5 +/- 7.7% of CD3- cells expressed the HLA-DR antigen (vs. 6.1 +/- 2.4% in PBLp; p < 0.001). Half of these cells simultaneously expressed the activation antigen CD69. Surprisingly, the number of CD3+ TL bearing the IL-2 receptor (CD25) and transferrin receptor (CD71) was not increased. Taken together, the proportional distribution of B and NK cells within the thyroid correlates with the anti-TPO secretion in vivo and in vitro, suggesting different immune response regulation processes of TL.
Exp Clin Endocrinol Diabetes 1996
PMID:Different immunophenotype and autoantibody production by peripheral blood and thyroid-derived lymphocytes in patients with Graves' disease. 875 May 71

While it is generally accepted that T cells are critical for the development of diabetes in the non-obese diabetic (NOD) mouse, the precise functions of the CD4+ and CD8+ subsets remain ill-defined. Transfer experiments have provided evidence that CD4+ cells are the disease initiators, provoking massive mononuclear leukocyte infiltration into the pancreatic islets, while CD8+ cells play an effector role, responsible for the final destruction of islet beta cells. It was surprising, then, to find that NOD mice carrying a null mutation at the beta 2-microglobulin (beta 2-mu) locus, and thereby lacking major histocompatibility complex class I molecules and CD8+ T cells, developed neither insulitis nor diabetes. Here, we argue that the absence of insulitis in these animals results from their lack of CD8+ cells because islet infiltration is also absent when NOD mice are treated with an anti-CD8 monoclonal antibody (mAb) at a young age. Interestingly, the anti-CD8 effect is only observed when the mAb is injected during a discrete age window--2 to 5 weeks after birth. Transfer experiments indicate that the lack of CD8+ cells during this period somehow alters the phenotype of CD4+ cells, preventing them from expressing their insulitis potential. This is not because they are generally immuno-incompetent nor because they are generally more prone to differentiating into cells with Th2 characteristics. Given that neither the beta 2-mu mutation nor anti-CD8 treatment affect insulitis in a T cell receptor transgenic (tg) mouse strain with a CD4+ T cell repertoire highly skewed for an anti-islet cell reactivity, the most straight-forward interpretation of these observations is that CD8+ cells are required for effective priming and expansion of autoreactive CD4+ cells.
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PMID:The role of CD8+ T cells in the initiation of insulin-dependent diabetes mellitus. 876 18

Twenty-four patients with moderately controlled insulin dependent diabetes with a duration of diabetes ranging from 2 to 10 years as well as 17 control subjects were vaccinated against hepatitis B virus using Gen Hevac B vaccine. The vaccine was injected 0.5 mL intramuscularly into the deltoid region on three separate occasions at intervals of 1 month. If subjects were still negative for anti-hepatitis B surface antigen (HBs) or had inadequate antibody after the third injection, a fourth administration of vaccine was given 3 months later. The mean anti-HBs titer was 243.3 +/- 97.2 mi.u./mL in control subjects and 39.8 +/- 53.2 in diabetic patients (P < 0.001). In the control group optimal protection was obtained in 100% of subjects, whereas 11 diabetic patients (45.8%) had low anti-HBs titer (< 10 mi.u./mL). All of 11 diabetic patients showed adequate (> 10 mi.u./mL) anti-HBs titer after the fourth dose of vaccine. In diabetic patients the most striking feature was the reduced CD4/CD8 ratio which was significantly lower (P < 0.001) than that of the control group. We conclude that diabetic children have an impaired immune response to hepatitis B vaccine. It is suggested that diabetic children should be vaccinated against hepatitis B virus with four injections instead of three.
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PMID:Reduced immune response to hepatitis B vaccine in children with insulin dependent diabetes. 877 51

Most female NOD mice spontaneously develop insulin-dependent diabetes mellitus (IDDM) after the 4th month of age. We have recently reported that infection of 2-month-old NOD mice with Mycobacterium avium prevents IDDM expression in these mice. We have searched here for changes in splenic lymphocytes that are associated with the effect of M. avium vaccination. Three experimental groups of female NOD mice were studied: (i) animals infected with 10B viable M. avium bacteria (mice that become protected from IDDM); (ii) mice inoculated with 10B heat-killed (HK) M. avium bacilli, and (iii) untreated age-matched NOD mice. Similar treatments were given to mice of the NON strain which are related to NOD mice but do not develop IDDM. Flow cytometry was used to compare M. avium-infected, HK M. avium inoculated and untreated NOD and NON mice with regard to subpopulations of splenic lymphocytes bearing the surface antigens CD3, CD4, CD8, IgM and B220. We found that M. avium infection of NOD mice caused a sustained enhancement in T cells that was due to an early and transient increase in CD8+ T cells (detected at day 7 of infection). This was followed by marked augmentation in the number of CD4+ T cells at days 14 and 30. There was also elevation in B220+ B cells at days 14 and 30, and of IgM+ B cells at day 30 of infection. Inoculation of NOD mice with HK mycobacteria, which did not prevent IDDM, failed to produce significant changes in the number of T and B cells. No significant enhancement in T and B cells was observed in NON mice that were injected with either viable or HK M. avium bacilli. In NOD mice that reached 16 months of age because of being protected from IDDM (due to the M. avium infection) there was an increase in B220+ B cells. We conclude that: (i) M. avium-induced protection of NOD mice from diabetes depends on the viability of the bacteria; (ii) the protective effect of the infection is associated with an early and marked increase in helper T cells and with a smaller elevation in B cells; (iii) elevation in B cells, but not in T cells, is associated with long term mycobacteria-induced protection of NOD mice from IDDM.
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PMID:Changes in B and T lymphocytes associated with mycobacteria-induced protection of NOD mice from diabetes. 886 25

Beta2m-deficient nonobese diabetic (NODbeta2mnull) do not develop insulitis or diabetes. Expression of a beta2m transgene controlled by the rat insulin promoter (RIP-beta2m) in NODbeta2mnull mice resulted in reconstitution of IFN-gamma-inducible cell surface MHC class I protein on pancreatic beta-cells. These mice developed insulitis, but did not develop diabetes. Transfer of T cells from diabetic NOD mice to NODbeta2mnull recipients resulted in insulitis, which took several months to progress to diabetes. In contrast, transgenic RIP-beta2m/NODbeta2mnull mice with islet MHC class I reconstitution developed diabetes rapidly after transfer of diabetic NOD spleen cells. Administration of cyclophosphamide, which accelerates diabetes in NOD mice, resulted in 43% of RIPbeta2m/NODbeta2mnull mice becoming diabetic compared with 75% of wild-type mice and 0% of NODbeta2mnull mice. Acceleration of diabetes by cyclophosphamide was prevented by anti-CD8 mAb treatment. FACS analysis of peripheral blood and lymphoid organs from transgene-bearing animals did not show an increase in the number of CD8+ T cells compared with that in NODbeta2mnull mice. In summary, beta-cell expression of beta2m in NODbeta2mnull mice resulted in a return of insulitis, but not spontaneous diabetes. These studies demonstrate that beta2m and cell surface MHC class I expression on beta-cells are essential for the initiation of diabetes in the NOD mouse and further confirm that efficient progression to diabetes requires both CD4+ and CD8+ T cells.
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PMID:RIP-beta 2-microglobulin transgene expression restores insulitis, but not diabetes, in beta 2-microglobulin null nonobese diabetic mice. 887 71

Cyclosporine (CsA) and FK506 are structurally unrelated immunosuppressants, but function in similar ways. FK506 and rapamycin (RAPA), on the other hand, have structural similarities, but act by different mechanisms to yield immunosuppression. Besides their immunosuppressive action, CsA and FK506 are known to interfere with T-cell development. CsA treatment after lethal X-irradiation and syngeneic bone marrow transplantation results in autoimmune disease, which is referred to as CsA-induced autoimmunity. In this study, we examined the effect of RAPA on T-cell development by flow cytometry and immunohistochemistry in female Lewis and Brown Norway rats. Irradiation and syngeneic bone marrow transplantation were performed before a 4-week course of RAPA administration to determine de novo T-cell development in relation to possible autoimmune phenomena. RAPA interfered with the maturation of thymocytes to the CD4+CD8+ DP stage, which resulted in a relative increase in TCRalphabeta(-) immature thymocytes, localized in a rim along the outer cortex. The thymus of RAPA-treated animals had a thinner cortex, leading to stronger thymic atrophy. In the periphery, only a few T cells were observed at the end of RAPA treatment. In the Lewis rat, a normal CD4/CD8 T-cell ratio and an increased Th1/Th2 ratio was observed within the T-cell population. Six weeks after cessation of RAPA therapy, the T-cell compartment was restored to normal, with respect to number and phenotype. In Brown Norway rats, however, T-cell areas were barely detectable at the end of RAPA treatment. The CD4/CD8 T-cell ratio was decreased as a result of a lower number of CD4 T cells; the Th1/Th2 ratio was increased but Th2 remained higher. Similar to Lewis rats, the situation was almost normalized 6 weeks after cessation of RAPA administration. However, Brown Norway rats, in contrast to Lewis rats, showed T-cell infiltration and concomitant induction of MHC class II in the submandibular salivary gland, as well as insulitis, in the pancreas. Possible relationships to Sjogren's disease and diabetes remain to be established.
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PMID:Effect of in vivo rapamycin treatment on de novo T-cell development in relation to induction of autoimmune-like immunopathology in the rat. 887 95

Allografts of BALB/c (H-2d) fetal proislets facilitated long-term (> 100 days) reversal of streptozotocin-induced diabetes in CBA/H (H-2k) mice treated with a combination of anti-CD4 and anti CD8 mAbs. Anti-CD8 monotherapy was partially effective in restoring normoglycemia but anti-CD4 mAb treatment of host animals failed to promote allograft function. In contrast, allografts of BALB/c adult islets demonstrated indefinite reversal of diabetes in recipient mice treated only with anti-CD8 mAb. Anti-CD4 monotherapy resulted in only transient restoration of normoglycemia. These findings clearly demonstrate (1) a critical role for CD8 T cells in the acute rejection of pancreatic islet tissue allografts and (2) tissue-specific differences in the participation of CD4 T cells as primary effectors in the rejection reaction. Immunohistochemical studies showed that the capacity for CD4 T cells to initiate the rejection of proislet but not adult islet allografts correlates with the presence/absence, respectively, of graft parenchymal cells that constitutively express Class II MHC alloantigens. Proislet grafts, unlike transplants of purified adult islets, contain heterogeneous tissue components including Class II MHC+ve duct epithelium. Thus, the participation of CD8 and CD4 T cells as primary effectors of graft rejection depends on which class or classes of MHC antigens are constitutively expressed on graft parenchymal cells and are available for recognition. Islet tissue in both rejecting proislet and islet allografts showed de novo induction of Class II MHC alloantigens only after severe disruption to islet architecture had been achieved by infiltrating mononuclear cells. Thus, at this stage of advanced allograft injury, CD4 T cells have the potential to act as secondary effectors, possibly by amplifying the inflammatory reaction and thus accelerating graft destruction. The capacity for antirejection mAb therapy to establish transplant tolerance was facilitated in the islet allograft model where it was necessary to target only the CD8 T cell subpopulation.
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PMID:Differences in the contribution of CD4+ T cells to proislet and islet allograft rejection correlate with constitutive class II MHC alloantigen expression. 888 12

Converging data suggest an important role for IL-7 in T lymphocyte maturation as illustrated by the severe T lymphopenia observed in IL-7-deficient mice. We recently reported that IL-7 preferentially promotes the in vitro expansion of a discrete MHC class I-dependent lymphocyte subset comprising both CD4+ and CD4-CD8- TCR alpha beta + cells bearing several NK cells markers such NK1.1 and Ly-49. These T cells, designated as NK1+ T cells, have the unique property among thymocytes of producing large amounts of IL-4 upon primary stimulation via the TCR. We have further demonstrated that thymic NK1+ T cells of non-obese diabetic (NOD) mice, a spontaneous model of autoimmune type I diabetes, are markedly deficient in maturation both quantitatively and functionally (IL-4 production). In the present experiments, the addition of exogenous IL-7 completely restored IL-4 production by anti-TCR alpha beta-stimulated mature (HSA-CD8-) thymocytes in NOD mice. A short 2 h preincubation with IL-7 was sufficient to restore both the expression of IL-4 mRNA and IL-4 production capacity. This was related to a direct effect on NK1+ thymocytes since: (i) the effect of IL-7 was restricted to the non-mainstream MEL-14- 3G11- TCR alpha beta + subset which mostly concentrates the IL-4-producing capacity and (ii) IL-7 did not restore IL-4 production in class I-deficient mice which lack the NK1+ T cell subset. Importantly, this activity of IL-7 on NK1+ T cells was also demonstrated in non-autoimmune strains of mice. These results were extended in vivo by showing that the IL-7 treatment significantly increased the anti-CD3 triggered IL-4 production by NK1+ T spleen cells. These findings confirm the role of IL-7 in NK1+ T cell maturation and suggest that the NK1+ T cell defect in NOD mice could be related to insufficient intrathymic IL-7 bioavailability.
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PMID:IL-7 reverses NK1+ T cell-defective IL-4 production in the non-obese diabetic mouse. 894 70

The NOD mouse is a model for autoimmune diabetes that develops symptoms similar to Type I diabetes. The incidence of diabetes is greater in females but the degree of insulitis is comparable in both sexes. The purpose of this study was to assess the populations of lymphocytes and macrophages in the pancreas and spleen of NOD mice. Comparisons were made between male and female; young (32-40 days old) and old (197-297 days old); diabetic and non-diabetic mice. Using analytical fluorescent cell cytometry we quantitated the percentages of CD4, and CD8 T-cells, B-cells and macrophages and the percentages of these subsets expressing interleukin-2 (IL-2R), prolactin (PRLR) and Hi-intensity PRL (Hi-PRLR) receptors. Evaluation of T-splenocytes indicated a 2:1 ratio of CD4 to CD8 T-lymphocytes in the spleen. The pancreas had higher percentages of all of the subsets in the old male and female groups compared to their young counterparts. Pancreatic immunocompetent cell subsets expressed lower percentages of IL-2R, PRLR and Hi-PRLR compared to splenocytes. The results did not demonstrate any dramatic differences in the immunocompetent cell populations of the spleen or pancreas between male and female animals, however we were able to establish the percentage of immunocompetent cells with IL-2R, PRLR and Hi-PRLR as a reference for future studies.
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PMID:The lymphocyte and macrophage profile in the pancreas and spleen of NOD mice: percentage of interleukin-2 and prolactin receptors on immunocompetent cell subsets. 895 20


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