Anti-V beta 8 antibody therapy prevents disease recurrence in fetal pancreas isografts in spontaneously diabetic nonobese diabetic mice.
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Animals↗
Biomedical subjects
T E Mandel
Publications and source records attributed to T E Mandel.
The effect of recipient strain and sex on pig pancreas xenograft survival in mice.
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Transplantation of the segmental pancreas in STZ-treated diabetic mice.
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Hemolytic anemia in non-obese diabetic mice.
The non-obese diabetic mouse (NOD mouse) is widely used as a model of organ-specific autoimmunity because it develops specific autoimmune destruction of pancreatic beta cells mediated by T cells and culminating in insulin-dependent diabetes mellitus. Here, we report that the NOD mouse also develops Coombs'-positive hemolytic anemia, a B cell-mediated autoimmune disease. Aged NOD mice were found to have splenomegaly and jaundice predominantly due to raised unconjugated serum bilirubin. Their hematocrits were markedly lowered, and there was a reciprocal increase in the reticulocyte count. Red blood cells (RBC) from anemic mice showed a normal lytic response to hypotonicity. RBC from non-anemic mice had normal half lives in non-anemic, non-diabetic NOD mice by 51Cr labeling but, dramatically shortened half lives in anemic mice. Similar results were obtained with RBC from anemic mice. Hemolysis could be transferred with serum from anemic mice resulting in reticulocytosis. The antibody-mediated nature of the anemia was confirmed with the direct Coombs' test. Anemia was found only in mice aged greater than 200 days and was more common in diabetic (4/8) than non-diabetic (1/16) mice at 300 days. However, by 550 days, 14/17 non-diabetic mice were affected.
Anemia, Hemolytic↗
Intercellular adhesion molecule (ICAM-1) inhibition can induce tolerance in vivo.
Antigen specific unresponsiveness can be induced in vivo by administration of antibody against CD4, major histocompatibility complex (MHC) Class II or LFA-1 at the time of antigen exposure. Since target cell depletion is not necessary for this effect it was hypothesized that interference with intercellular interaction was responsible. To test this hypothesis, antibody against the ligand for LFA-1, ICAM-1, was administered during primary immunization with human gamma-globulin (HGG) and long-term secondary antibody responses monitored. It was found that HGG specific unresponsiveness resulted from this treatment (less than 10% of normal secondary antibody response). Delayed-type hypersensitivity responses to HGG were also suppressed suggesting unresponsiveness in some T cell subsets. These findings suggest a role for ICAM-1/LFA-1 interaction in determining the long-term outcome of contact with antigen.
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Accelerated diabetes in non-obese diabetic (NOD) mice differing in incidence of spontaneous disease.
The NOD mouse is an established model of autoimmune diabetes mellitus. Various lines of NOD mice differ in their incidence of spontaneous diabetes, e.g. 93% of female NOD/Lt mice compared with 46% of female NOD/Wehi mice develop diabetes by 250 days. These two lines were studied under conditions which greatly accelerate the onset of hyperglycaemia. It was hoped that their responses to these manipulations would reveal characteristic differences which would increase our understanding of diabetes resistance in the low incidence NOD/Wehi line. One dose of 300 mg/kg of cyclophosphamide (CP) produced hyperglycaemia in 50% of NOD mice within 2 weeks in both lines. They were also equally susceptible to diabetes induced by splenocyte transfer at 21 days of age from prediabetic 150-day-old NOD/Lt or NOD/Wehi females. Five daily 40 mg/kg doses of streptozotocin (STZ) resulted in a severity of diabetes in the NOD mice greater than in C57BL or SJL/mice. While the incidence and severity of diabetes induced in the two NOD lines were similar, this appeared to be principally due to sensitivity to the toxic effects of STZ rather than its ability to exacerbate autoimmune beta cell destruction. It has previously been shown that it is possible to prevent diabetes in susceptible NOD mice with simple, relatively benign therapies and here we show that it is possible to induce diabetes in resistant animals at a rate indistinguishable from fully predisposed individuals. It therefore appears that the prediabetic NOD mouse is poised in an immunologically precarious state with the onset of disease being highly dependent on factors which exacerbate or moderate autoimmune destruction.
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Monoclonal antibody to ICAM-1 prolongs murine heterotopic corneal allograft survival.
Graft rejection requires an initial interaction between donor antigen presenting cells (APC) and recipient T cells; an interaction known to involve a variety of cell surface molecules. We have been investigating an interaction involving two of these molecules: lymphocyte function associated antigen-1 (LFA-1) on the T cell and its ligand, intercellular adhesion molecule-1 (ICAM-1) on the APC, in an effort to assess the effect its interruption would have on the ability of the recipient to reject an allograft. A monoclonal antibody (MAb) against ICAM-1 was given peritransplant to mice with heterotopically grafted corneas. Mice were killed at various time points and the grafts taken for histological assessment of rejection. Mice treated with Mab have a delayed influx of cells into the graft site and marginally better graft viability to day 50 after transplantation compared to controls. These results suggest that it is possible to decrease rejection even with brief peritransplant treatment. This provides encouragement for further experiments using more extensive therapy.
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The expression of adhesion molecules in the human retina and choroid.
This study examines the expression of some selected adhesion molecules likely to be important in the migration of leucocytes across the blood-retinal and blood-aqueous barriers in samples of normal human retina and choroid by immunoperoxidase staining. ICAM-1, LFA-3 and ELAM-1 were expressed on retinal endothelium and ICAM-1, ELAM-1 and CD44 in the region of the external limiting membrane. VLA-2 was found around the retinal ganglion cells and in the inner and outer fibre layers and is likely to be important in maintaining the structural integrity of the retina. The endothelium on the choriocapillaris showed moderate staining of ICAM-1, and slight staining of LFA-3 and ELAM-1. These molecules may have an important functional role in the pathogenesis of many immunological ocular conditions, including uveoretinitis and corneal allograft rejection.
Antibodies, Monoclonal↗
Inherent beta-cell dysfunction induced by transgenic expression of allogeneic major histocompatibility complex class I antigen in islet cells.
Insulin-dependent diabetes mellitus (IDDM) is generally believed to be an autoimmune disease resulting from T-cell dysfunction that produces beta-cell damage, but it is conceivable that some forms of IDDM are not immunologically mediated. The effect of the expression of a foreign transgenic MHC class I antigen (H-2Kb), restricted to pancreatic islet beta-cells, was tested in vitro and in nude (athymic) mice to determine whether beta-cell dysfunction was due to non-immune mechanisms. The models used clearly excluded immune involvement in beta-cell damage. Fetal pancreas from transgenic and littermate control mice was maintained in organ culture for up to 18 days and insulin secretion into the medium assessed. For the initial 3-4 days in vitro, fetal control and transgenic pancreas secreted similar amounts of insulin, but thereafter insulin secretion by the transgenic tissue decreased in comparison with the controls. When the cultured pancreas was transplanted into nude mice, the transgenic issue produced smaller grafts than the control pancreas, but there was wide variation in graft size. Expression of H-2Kb antigens in beta-cells of nude transgenic mice also resulted in early-onset diabetes. The insulin content in the pancreas of young H-2Kb transgenic euthymic mice, (previously shown not to have insulitis), was reduced but glucagon content was normal. The reduction in in vivo insulin production was similar chronologically to the reduced insulin production by transgenic islets in vitro. These data confirm the non-immune loss of beta-cell function in MHC-transgenic mice and they may be a model for atypical Type I diabetes.
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High and low diabetes incidence nonobese diabetic (NOD) mice: origins and characterisation.
The Nonobese Diabetic mouse (NOD mouse) is an established model of autoimmune diabetes mellitus. While all colonies of NOD mice are derived from a single diabetic female detected during the breeding of a cataract-prone strain of mice, some of the dispersed colonies have been separated for many generations and express varying levels of diabetes. It is unclear to what extent this is due to environmental factors such as diet factor or a result of the varied origins of the colonies. Here we compare the incidence of diabetes and severity of insulitis in two divergent lines of NOD mice that differ in incidence of disease, but are maintained in the same environment. F1 crosses were performed and the progeny found to express the disease incidence of the low incidence line. This finding is consistent with either a dominant resistance gene(s) being responsible for reduced penetrance of disease or a transmissible environmental agent reducing the severity of the autoimmune process.
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Prevention of cyclophosphamide-induced and spontaneous diabetes in NOD mice by syngeneic splenocytes treated with cytotoxic drugs.
Infusions of syngeneic T-cells, lethally damaged with ultraviolet A light (UVA) and 8-methoxypsoralen (8-MOP), have been reported to prevent or ameliorate a number of autoimmune diseases in humans and in animal models of autoimmune disease. We previously demonstrated that the combination of UVA/8-MOP, or deoxycoformycin and deoxyadenosine (dCF/dAdo), damaged human lymphoid cells by inducing DNA strand breakage and stimulating poly (ADP-ribosyl)ation. These cells subsequently underwent programmed cell death ("apoptosis"). These findings suggested a common mechanism of lymphocyte damage, and that in vitro treatment of T-cells with cCF/dAdo might substitute for UVA/8-MOP. This hypothesis was tested in a model of autoimmune diabetes in the NOD mouse. Young adult female NOD/Wehi mice were given 350 mg/kg cyclophosphamide (CP) on day 1 to induce rapid-onset diabetes and divided into five treatment groups. Four groups received approximately 50 x 10(6) syngeneic mouse splenocytes that had been treated with various cytotoxic agents. 27/40 (68%) of the CP-only control group and 14/30 (48%) of the group given untreated splenocytes developed diabetes. By contrast, only 2/20 (10%) mice of UVA/8-MOP and 3/23 (14%) of dCF/dAdo-treated splenocyte groups developed diabetes (P < 0.01). Diabetes in high spontaneous-diabetes incidence NOD/Lt female mice was also greatly reduced (4/8 untreated vs 1/7 treated; (< 0.05). We postulate that cytotoxic damage to activated splenic T-cells allows their recognition by host T-cells and results in a protective response against autoreactive cells as a form of T-cell vaccination.(ABSTRACT TRUNCATED AT 250 WORDS)
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Islet transplantation in Type-I diabetes: current state and prospects.
Islet transplantation in Type I diabetes mellitus is appealing because of its potential for curing the disease, its relative simplicity and the potential for immunomodification of the graft so that immunosuppression may be avoided. Transplantation of isolated islets is widely used in experimental animals but has had little impact clinically. In contrast, vascularised pancreas grafts in patients are increasingly successful and this success will inevitably result in an even greater shortage of donor organs for islet isolation. Islet grafts can cure diabetes in animal models and prevent the development of diabetic complications, and in some situations even allografts can be accepted and function without immunosuppression. In contrast, vascularised grafts require a major operative procedure and continuing immunosuppression. Recurrence of autoimmune disease in the grafted islets may also be a problem. The shortage of donor tissue may be overcome by the use of xenogeneic islets, perhaps from the pig pancreas. The induction of immunological tolerance has been reported for pig islet xenografts in mice, and xenogeneic islets also appear to be relatively resistant to disease recurrence in a murine model of spontaneous autoimmune diabetes. Thus, vascularised pancreas allografts may be most suitable for and perhaps be restricted to patients who also need a renal transplant and immunosuppression for this, while isolated islet grafts of perhaps xenogeneic origin may become a more suitable treatment for patients early in the course of their disease if adequate immunosuppressive protocols, ideally resulting in immunological tolerance, can be developed.
Autoimmune Diseases↗
Fetal pig pancreas xenografts in non-obese diabetic mice treated with continuous anti-CD4 monoclonal antibody.
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Prevention of diabetes in non-obese diabetic I-Ak transgenic mice.
The non-obese diabetic (NOD) mouse develops insulin-dependent diabetes mellitus (IDDM) with mononuclear cell infiltration of the islets of Langerhans and selective destruction of the insulin-producing beta-cells, as in humans. Most infiltrating cells are T lymphocytes, and most of these carry the CD4 antigen. Adoptive transfer of T cells from diabetic NOD mice into irradiated NOD or athymic nude NOD mice induces diabetes. Susceptibility to IDDM in NOD mice is polygenic, with one gene linked to the major histocompatibility complex class II locus, which in NOD mice expresses a unique I-A molecule but no I-E. Speculation exists as to the role of the I-A molecule in the diabetes susceptibility of NOD mice, especially regarding the significance of specific unique residues. To examine the role of the NOD I-A molecule in IDDM pathogenesis, we made NOD/Lt mice transgenic for I-Ak by microinjecting I-Ak alpha- and beta-genes into fertilized NOD/Lt eggs. Insulitis was markedly reduced and diabetes prevented in NOD/Lt mice expressing I-Ak.
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The evolution of function and response to arginine challenge and pregnancy of portally and systemically placed islet cell grafts in streptozotocin diabetic mice.
Mice made diabetic with streptozotocin received organ cultured fetal islet cell grafts in the portal (PG) or systemic (SG) vascular beds in order to determine whether portal delivery of insulin is an important consideration in graft placement. Grafts were established more quickly in SG mice as shown by body weight and blood glucose estimations. Intraperitoneal arginine was found to be a stronger insulin secretagogue than intravenous glucose with the doses used when serum insulin was measured 5 minutes after injection. Glucose response to an arginine challenge was initially abnormal in both groups of mice, but was identical to normal controls 4 months after transplantation, showing that engraftment is a gradual process. Mice were then mated and their response to the chronic glycemic stress of pregnancy was noted. PG and SG mice had normal fertility rates in contrast to untreated diabetics, none of which became pregnant. Offspring were normal with respect to litter size, body weight, malformation rate, and pancreatic insulin content compared with historical controls. PG and SG mothers behaved normally during pregnancy, with the exception of a raised glycosylated hemoglobin level at day 19.5 gestation (5.5% and 5.5% v 3.7%, P less than .01). We were, therefore, unable to detect any difference between portally and systemically placed islet grafts.
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Chronic diabetes harms islet-cell transplants by inhibiting graft vascularisation.
Pancreatic islet-cell transplantation is very effective in treating insulin-dependent diabetes in animals but has had no success in humans. Most animals have received islet-cell grafts after short periods of diabetes, while patients have been grafted after years of disease. We have shown a detrimental effect of chronic diabetes on islet-cell grafts in animals, which is at least partially ameliorated by peritransplant insulin infusion. We suggest that this detrimental effect may be mediated by poor vascularisation. There is further evidence from wound healing and tumour grafting experiments, and from the recent insulin pump studies in humans to support our hypothesis. To be successful, islet-cell grafts in humans may have to be performed earlier in the course of the disease and be preceded by a period of accurate diabetic control.
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Fetal pig pancreas. Preparation and assessment of tissue for transplantation, and its in vivo development and function in athymic (nude) mice.
The possibility of using xenogeneic islets for transplantation in insulin-dependent diabetes mellitus (IDDM) necessitates characterization of their potential for growth and functional differentiation. Fetal pig pancreas (FPP) of various gestational ages was examined with respect to morphology, ability to produce insulin before and during culture, and development and function in nude mice. Insulin-containing beta cells were present, but distinct islets were not apparent in FPP even in late gestation, and did not develop during culture. FPP remained viable and produced insulin for up to 30 days in vitro. Mitotic figures were seen in cultured tissue. Culture on a gelfoam raft resulted in more viable tissue than free-floating culture. Culture in a high concentration of O2 (90% O2/10% CO2) was detrimental compared with culture in 10% CO2 in air. Responses to static incubation in secretagogues showed that IMBX, theophylline, and tolbutamide all stimulated insulin secretion, but high glucose concentration (5 g/L), arginine, and leucine did not. The potential of this tissue for growth and its ability to regulate blood glucose levels appropriately were tested in athymic (nu/nu) mice. Pancreatic tissue from fetuses as young as 4 weeks gestation showed growth after transplantation into athymic mice, with representation of the major pancreatic endocrine cells demonstrated by selective immunochemical staining. The increase in the size of the grafts showed an impressive proliferative capacity, and histology confirmed mitotic activity and islet structure in the graft. The amount of endocrine tissue in grafts reflected the condition of the explants at the time of grafting, and prolonged culture times were detrimental to eventual graft size. Functional capability of the grafted FPP to release insulin in response to hyperglycemia was tested by transplantation into mice made diabetic with streptozotocin. Blood glucose levels, animal weights and survival, and the histological appearance of the tissue after graft nephrectomy indicated that either fresh tissue or tissue cultured for up to 8 days (Gelfoam; 10% CO2 in air) had better eventual graft function then FPP grown in 90% O2 or transplanted as a secondary graft following an interim period to allow gestational maturation in a nondiabetic nu/nu host. Return to euglycemia took 3-4 months after transplantation of FPP. The in vitro characteristics of FPP are similar to those reported for human fetal tissue, and since FPP is capable of growth and proliferation in vivo and has the ability to normalize hyperglycemia, further investigation of FPP to establish its suitability as a source of xenogeneic insulin-secreting tissue for human transplantation is warranted.
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The prevention of diabetic retinal and renal basement membrane thickening in mice by islet cell allografts.
The effect of fetal islet cell allografts on retinal capillary (RCBMT) and glomerular (GBMT) basement membrane thickening in diabetic mice was studied, as well as the effect of diabetes on the anterior lens capsule and the inner lamina of Descemet's membrane. CBA mice rendered diabetic with streptozotocin received fetal pancreatic islet cell grafts from C3H and BALB/c donors four weeks after induction of diabetes with an additional late transplant group receiving C3H grafts after six months of diabetes. After 12 months animals with successful grafts were examined for RCBMT along with untreated diabetics (UD, n = 4) and normals (N, n = 9). Untreated diabetics had significantly increased RCBMT (167.1 +/- 12.1 vs 129.2 +/- 24.3 nm, p = 0.05) and GBMT (278 +/- 11 vs 248 +/- 6 nm, p = 0.004) compared to normals. All graft recipients had RCBMT similar to normal and significantly less than untreated diabetics: BALB/c (n = 7), 123.8 +/- 21.0, p = 0.02; C3h early (n = 5), 126.6 +/- 21.7, p = 0.05; C3H late (n = 4), 134.4 +/- 16.9, p = 0.03. The same was true for GBMT; 250 +/- 10 nm, p = 0.02 for BALB/c recipients, 250 +/- 8 nm, p = 0.04 for early and 255 +/- 9 nm, p = 0.02 for late C3H recipients. GMBT in six month biopsies of normals and prospective late graft recipients were well below these levels.(ABSTRACT TRUNCATED AT 250 WORDS)
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