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

It has been reported that isolated pancreatic islets are functionally viable following cryopreservation using fast cooling and that such conditions should be more efficient for the selective destruction of immunocompetent passenger lymphoid cells than techniques employing slow cooling. This study examines the effect of extended pre-freeze and post-thaw culture (72 hr) on the in vitro function of rapidly cooled (70 degrees C/min) rat islets of Langerhans. The viability of the islets was assessed by their ability to secrete insulin in response to stimulation by glucose and theophylline both statically during batch incubations and dynamically in a perifusion system. Extended tissue culture was found to be essential for the retention of insulin secretory function of rapidly cooled islets which showed slightly suppressed but comparable secretion indices compared with non-frozen cultured islets.
Diabetes Res 1989 Jul
PMID:The effect of rapid cooling and culture on in vitro insulin release in cryopreserved rat islets of Langerhans. 269 86

Spleen cells from acutely diabetic (AD) and non-diabetic but diabetes prone (DP) BB/Wor rats lysed insulinoma target cells to a significantly greater degree than did diabetes resistant (DR) cells as determined using a 51Cr release cytotoxicity assay. There were no differences between the AD and DP groups. Lysis was not target cell specific, since somatostatin secreting RIN 14B cells, Wistar Furth leukemia cells designated LW12, PC12 cells and NK sensitive YAC-1 cells were also lysed. Lysis of all target cells was significantly reduced by pretreatment of the effector lymphocytes with antiserum to NK cells (anti-asialo GM1) and complement suggesting that NK cells mediated destruction of these cells. These data demonstrate a generalized increase in non-specific NK cell activity in BB/Wor rats. Since NK cells have been shown to mediate antibody dependent cell mediated cytotoxicity (ADCC), splenic lymphoid cells from AD rats were tested for their ability to lyse insulinoma target cells in the presence of diabetic rat sera which were demonstrated to contain islet cell surface antibodies. Three different ADCC protocols were tested but in each case the addition of serum dilutions from AD rats reduced the lysis of insulinoma cells by AD spleen cells in a dose dependent manner. This inhibition was also demonstrated when sera and effector cells from control rats were used. As a positive control, DR spleen cells were incubated with 51Cr labelled target cells that were untreated or pre-treated with anti-rat class 1 antibody (OX18). Pre-treatment of the target cells resulted in a marked increase in their subsequent lysis.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes Res 1988 Jun
PMID:In vitro natural killer cell activity in the spontaneously diabetic BB/Wor rat: effects of serum on lysis of insulinoma cells. 285 69

Nonobese diabetic (NOD) is an inbred mouse strain susceptible to development of T cell-mediated autoimmune diabetes. The strain is characterized by high percentages of T lymphocytes in lymphoid organs. The syngeneic mixed lymphocyte reaction (SMLR), a T cell response to self MHC class II Ag, is reportedly involved in the generation of a number of immunoregulatory cells, including suppressor inducers. A severely depressed SMLR characteristic of certain other autoimmune strains was found in NOD but not in nonautoimmune SWR/Bm mice. Moreover, IL-2 produced by NOD T cells at day 6 in an SMLR was at least one hundredfold reduced compared with SWR, and NOD T cells harvested from an SMLR at day 6 were functionally defective when tested for ability to induce suppression of an allogeneic MLR. However, functionally competent suppressor T cells were generated in NOD splenic leukocyte cultures in response to Con A, and IL-2 release from these was equivalent to that released by Con A-stimulated SWR splenocytes. A deficiency in cytokine release was not limited to IL-2, because peritoneal exudate cells from NOD exhibited a greatly diminished sensitivity to LPS-stimulated IL-1 release in comparison to SWR mice. IL-2 supplementation both in vitro and in vivo restored the ability of NOD T cells to respond in a SMLR, with production of cells capable of inducing suppression. Like SMLR-activated T cells from untreated SWR controls, SMLR blasts from IL-2-treated NOD mice were enriched for the L3T4 phenotype. IL-1 supplementation in vitro resulted in partial restoration of T suppressor activation in a SMLR. The depressed SMLR exhibited by NOD mice was apparently a stimulator cell dysfunction, because NOD stimulator cells failed to activate T cells from (SWR x NOD)F1 mice, whereas stimulators from SWR or F1 mice were capable of doing so. Collectively, these results suggest a defect in suppressor cell activation rather than an absence of this immunoregulatory cell population.
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PMID:Defective activation of T suppressor cell function in nonobese diabetic mice. Potential relation to cytokine deficiencies. 289 95

The efficacy of the diabetogenic drugs streptozotocin and alloxan were evaluated as models for the study of immune defects associated with diabetes. Streptozotocin- or alloxan-treated mice, with a stable hyperglycaemia of 25-33 mmol/l plasma glucose, were severely impaired in their ability to mount antibody forming, mitogenic, or delayed-type hypersensitivity responses in vivo. Treatment of alloxan-diabetic mice with insulin in vivo completely reversed all immune defects, while insulin treatment of streptozotocin-diabetic mice restored immune function to only 70-80% of normal levels. Results obtained by viability measurements and in vitro biological assays of lymphoid function, including proliferation in response to T- and B-cell mitogens, the production of interleukin-2 by T cells, and the production of interleukin-1 by macrophages indicated that direct exposure to alloxan for 48 h (at concentrations less than or equal to 14 mmol/l) had no adverse effects on lymphoid activity, while exposure to streptozotocin was routinely toxic at concentrations greater than or equal to 1 mmol/l. Both alloxan and streptozotocin exhibited strong toxicity in vitro for isolated pancreatic islet cells. Finally, lymphocytes from streptozotocin-diabetic mice, or cells incubated in vitro with streptozotocin, contained numerous chromosomal abnormalities indicative of DNA strand breakage. Such abnormalities were absent in alloxan-diabetic mice and in cells incubated with alloxan in vitro. These results indicate that immune dysfunction associated with streptozotocin is attributable to direct and irreversible impairment of lymphoid cell function and viability. In contrast, immune dysfunction associated with alloxan-diabetes appears to be a consequence of the diabetic state.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Assessment of the diabetogenic drugs alloxan and streptozotocin as models for the study of immune defects in diabetic mice. 293 86

Insulin-dependent diabetes is caused by the loss of insulin-producing beta cells in pancreatic islets. It has been proposed that aberrant expression of Class II Major Histocompatibility Complex (MHC) molecules on beta cells stimulates an autoimmune attack against beta cell antigens. To test this hypothesis, we generated transgenic mice that express Class II MHC molecules (E alpha d/E beta b, or I-Eb) on beta cells. Diabetes was found in 100% of transgenic progeny from three expressing transgenic mouse lines, but without evidence for lymphocytic infiltrates. Furthermore, T lymphocytes appeared to be tolerant to the transgene I-Eb molecule, despite the absence of expression of I-Eb in the thymus or any other lymphoid tissue. The results suggest that novel expression of Class II MHC molecules on nonlymphoid cells is by itself insufficient to initiate autoimmune responses against tissue-specific antigens.
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PMID:Diabetes and tolerance in transgenic mice expressing class II MHC molecules in pancreatic beta cells. 296 8

Between 12 and 26 wk of age, approximately 80% of female nonobese diabetic (NOD) mice from the inbred Sansum colony develop lymphocytic insulitis and become overtly diabetic. The disease in this animal model is similar to human insulin-dependent diabetes mellitus (IDDM) in both genetics and autoimmune pathogenesis. Cyclosporin A (CsA) has been used for immunosuppression in IDDM of recent onset in humans but has several limiting side effects. Therefore, a different regimen for CsA immunosuppression was investigated. Autologous splenic lymphoid cells from 12-wk-old not-yet-diabetic female NOD mice were cultured for 72 h with CsA plus interleukin 2 (IL-2) before reinfusion into the animal from which they were isolated. After this treatment, only 2 (18%) of 11 mice became overtly diabetic during an observation period of 19 wk, while 18 (86%) of 21 age-matched control mice developed diabetes during the same observation period (P less than .001). These data suggest an ex vivo preferential IL-2 activation of specific suppressor cells for the autoimmune process with CsA blockade of cytolytic/helper activities. Because the in vivo concentrations of CsA with this procedure would be negligible, these findings have implications for the potential nontoxic use of CsA in human protocols as well.
Diabetes 1988 Sep
PMID:Adoptive immunotherapy of diabetes in autologous nonobese diabetic mice with lymphoid cells ex vivo exposed to cyclosporin plus interleukin 2. 304 95

The effect of cyclosporin-A, low-temperature culture, and anti-Ia antibodies on prevention of rejection of rat islet allografts was determined. Wistar-Furth islets were isolated by the collagenase technique and transplanted via the portal vein into diabetic Lewis recipients. Cyclosporin-A (30 mg/kg) injected at 0, 1, and 2 days after transplantation produced a significant prolongation of survival of the islet allografts (MST greater than 35.7 +/- 7.0 days) when hand-picked donor islets were used, whereas only a modest prolongation of survival (14.0 +/- 1.6 days) was obtained using donor islets removed directly from Ficoll gradients. This difference in survival was apparently due to the large number of lymphoid, antigen-presenting cells that were present in the islet fraction removed directly from the Ficoll gradients. Treatment of donor, hand-picked islets with a mixture of cross-reactive anti-Ia antibodies and complement without cyclosporin-A therapy did not prolong the survival of islet allografts (MST, 6.5 +/- 0.4 days versus 7.0 +/- 0.5 days in controls). In contrast, treatment of the donor islets with the mixture of anti-Ia antibodies and complement in conjunction with the 3-day course of cyclosporin-A therapy produced an 83% survival of the islet allografts at 60 days after transplantation. In vitro culture of hand-picked donor islets at 24 degrees C for 7 days and the 3-day course of cyclosporin-A therapy produced a 100% survival of the allografts at 60 days after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1986 Jan
PMID:The effect of cyclosporin-A, low-temperature culture, and anti-Ia antibodies on prevention of rejection of rat islet allografts. 307 14

Recent developments in transplantation immunobiology, concerning the mechanism of tissue rejection, clearly indicate that antigen recognition alone is not sufficient for lymphocyte activation. "Passenger" leucocytes (antigen presenting cells) carried in the donor tissue are now recognized as the major immunogenic stimulus, such that removal of these contaminating leucocytes, using a variety of procedures, has enabled the immunogenicity of allografts to be reduced and the survival of the graft to be significantly extended. Remarkable advances have been made in recent years in preventing rejection of islet allografts, and even xenografts, in experimental animals by using procedures which do not involve continuous immunosuppressive therapy. Cryopreservation offers not only the means by which donor tissue can be stored effectively during such procedures but also the possibility that, under appropriate conditions, the freezing and thawing process itself could modulate tissue immunogenicity by allowing the selective killing of immunocompetent leucocytes whilst preserving the function of parenchymal cells in the graft. In this preliminary study we have characterized the survival of leucocytes and islets from the same species (rat) after cryopreservation by the same technique using dimethyl sulphoxide (Me2SO) as the cryoprotectant. Optimum survival of rat lymphocytes and macrophages was found at cooling rates in the range of 0.3-5 degrees C/min, after cooling at rates greater than 75 degrees C/min, survival was reduced to a negligible level. On the other hand, recovery of islets was 73 +/- 9% at 75 degrees C/min, indicating that depletion of lymphoid cells, with satisfactory preservation of endocrine cells, should be obtainable at this cooling rate.
Diabetes Res 1987 Jun
PMID:Selective killing of leucocytes by freezing: potential for reducing the immunogenicity of pancreatic islets. 311 61

BB rats are prone to develop an autoimmune form of insulin-dependent diabetes mellitus (IDDM) and thyroiditis. Development of autoimmunity is thymus dependent. Previous studies have shown that BB rats lack a population of T cells bearing the RT6 antigen and have very low numbers of suppressor/cytotoxic T cells. In this study, we confirm that BB rats have decreased numbers of phenotypic T suppressor/cytotoxic (Ts/c) cells (OX19+, OX8+ cells) in their lymphoid organs. Moreover, we find that the phenotypic Ts/c cells of BB rats lack apparent cytotoxic activity. These T cells fail to kill allogeneic target cells in a cell-mediated lympholysis assay and fail to generate lectin-dependent cytotoxicity. The addition of interleukin 2, gamma-interferon, and other lymphokines to cultures of BB T cells does not induce functional cytotoxic T lymphocytes. We find that the activated T cells of newly diabetic rats are incapable of killing major-histocompatibility-complex-matched islet cells, despite the ability of these cells to cause IDDM in passive transfer experiments. We conclude that autoimmune disease occurs in BB rats in the absence of functional cytotoxic T cells.
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PMID:Autoimmunity-prone BB rats lack functional cytotoxic T cells. 313 Oct 22

Sera from 80 subjects with IDDM and NIDDM, together with sera from 20 patients with miscellaneous autoimmune conditions and 20 healthy adult subjects were tested for insulin receptor antibodies by (1) inhibition of 125I-insulin binding to EBV-transformed lymphoid cells, and by (2) immunoprecipitation of solubilized insulin receptors in the presence of an excess of mono-specific anti-human IgG or IgM; this test allowed the assessment of the class of antibody activity. Anti-insulin antibodies in the sera were also measured using a double antibody technique. Anti-insulin receptor antibodies were found in 13 of 33 subjects with IDDM and six of 47 with NIDDM. These were principally in the IgM class, and in both groups of diabetics there was a good correlation between % inhibition of insulin binding to intact cells, and % of antibody precipitated by IgM (P less than 0.001), but not by IgG (P greater than 0.1). There was also a good correlation between the % inhibition of insulin binding to intact cells and the daily dose of insulin used in treatment (P less than 0.001). Insulin antibodies were found in seven of 33 subjects with IDDM and six of 12 with NIDDM, all of whom were on insulin treatment. These six subjects were the only ones with NIDDM who also had anti-insulin receptor antibody activity, suggesting that such antibodies may represent auto-anti-idiotype activity. This study shows that autoimmunity in insulin dependent (Type I) diabetes is not limited to islet cells and that such patients also develop antibodies to the insulin receptor. While three out of five patients with relative insulin resistance (requirement greater than 90 u/day) also showed evidence of insulin receptor antibody activity, the clinical significance of these antibodies has yet to be determined.
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PMID:Insulin receptor antibodies in diabetes mellitus. 328 Jan 81


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