Spontaneous Diabetes Mellitus: Reversal and Prevention in the BB/W Rat with Antiserum to Rat Lymphocytes

Like, A A; Rossini, A A; Guberski, Dennis L.; Appel, M. C.; Williams, Rachel

doi:10.1126/science.388619

Cited by 203 publications

(97 citation statements)

References 9 publications

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“…By comparison with the normal mouse, the athymic (nude) mouse either does not become diabetic, or becomes much less severely diabetic, when exposed to the encephalomyocarditis virus [1][2][3] or low dose streptozotocin [4][5][6]. If anti-lymphocyte serum is given to spontaneously diabetic BB/W rats, these animals do not develop diabetes [7]. In patients with Type 1 diabetes, different antibodies against islet cells and/or beta cells have been found [8,9], as have abnormal K cell levels [10], and abnormal suppressor cell activities [11].…”

mentioning

confidence: 99%

T lymphocyte subsets in patients with newly diagnosed Type 1 (insulin-dependent) diabetes: A prospective study

Buschard¹,

Røpke

Madsbad³

et al. 1983

Diabetologia

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Summary. T lymphocyte subsets in peripheral blood from 11 newly diagnosed Type 1 (insulin-dependent) diabetic patients were studied prospectively at three time intervals: as soon as possible after diagnosis, 3 weeks and 5 months later. Lymphocytes were marked with monoclonal OKT antibodies and examined in a fluorescence-activated cell sorter. The percentage of T lymphocytes (OKT 3) did not change significantly at the three study times. The percentage of helper/inducer T cells (OKT 4) was high the first week after diagnosis, but decreased at the 5-month examination (p< 0.05). The percentage of suppressor/cytotoxic T cells (OKT 8) was low at diagnosis but increased at 3 weeks (p< 0.02) and 5 months (p< 0.01). The ratio OKT 4/OKT 8 lymphocytes was 2.28 at diagnosis, decreasing to 1.77 at 3 weeks and 1.87 at 5 months, compared with 1.46 for 16 age-matched control subjects. There was no significant change in the absolute number of lymphocytes. It is concluded that the distribution of T cell subsets was abnormal at the time of diagnosis, but changed towards normal within a few weeks, after which there was no significant change at 5 months. It is as yet unknown whether the high proportion of helper/inducer T cells and/or the low percentage of suppressor/cytotoxic T cells at diagnosis favour immune reactions involved in the pathogenesis of Type 1 diabetes.

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mentioning

confidence: 99%

T lymphocyte subsets in patients with newly diagnosed Type 1 (insulin-dependent) diabetes: A prospective study

Buschard¹,

Røpke

Madsbad³

et al. 1983

Diabetologia

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“…In earlier studies, whole-body irradiation of BB rats was reported to cause decreased incidence of diabetes [22]; however, irradiation was not followed in that study by immunologic reconstitution, and the high morbidity and mortality observed in the animals make interpretation of the results difficult. In contrast, Rossini, et al [35] found that total lymphoid irradiation of BB rats at a dose of 1600 rads did not decrease frequency of diabetes.…”

Section: Discussionmentioning

confidence: 93%

“…In our study [6], mixed lymphocyte cultures and ConA stimulation assays performed with lymphocytes from the recipient BB rats demonstrated that they had been immunologically reconstituted. Diabetes in the BB rat can be prevented or reversed by various immunosuppressive procedures, such as administration of antilymphocyte globulin [22], glucocorticoids [23], or cyclosporin [23-251. A series of bone marrow irradiation chimeras were constructed [26,27], using various combinations of normal or BB rat recipients and bone marrow donors, in an attempt to determine the site of the defect(s) leading to diabetes and/or T-cell lymphopoenia in the BB rat. If the defect(s) in BB rats leading to diabetes and/or T-cell lymphopoenia resides in the lymphoid stem cells, then transplanting these stem cells from diabetes-prone animals into irradiated diabetes-resistant (normal) animals should induce diabetes and/or lymphopoenia.…”

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confidence: 99%

Bone marrow irradiation chimeras in the BB rat: evidence suggesting two defects leading to diabetes and lymphopoenia

1987

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Summary. A series of bone marrow irradiation chimeras were constructed in an attempt to determine the site of the defect(s) leading to diabetes and/or lymphopoenia in the BB rat. In BB rats that were lethally irradiated and reconstituted with T-cell-depleted Wistar-Furth (WF) rat bone marrow, the incidence of diabetes was reduced, and in animals treated with WF bone marrow at < 44 days of age, the disease was completely prevented. Such animals demonstrated normal lymphocyte counts in peripheral blood, and normal lymphocyte function (as indicated by mixed lymphocyte response), but retained an abnormal T-cell subset distribution only partially improved above that of diabetes-prone BB rats. The incidence of diabetes in these irradiated chimeras was significantly reduced compared to the indicence in BB rats irradiated at the same age but reconstituted with bone marrow from BB rats. In WF rats that were lethally irradiated and reconstituted with T-cell-depleted bone marrow from overtly diabetic BB rats, no diabetes was induced. Such animals demonstrated normal lymphocyte counts in peripheral blood, normal lymphocyte function, and normal T-cell subset distributions. Overall, these results suggest two defects leading to diabetes and/or lymphopoenia in the BB rat. One of these occurs at the level of the bone marrow stem cell while the other resides in the T-cell differentiative environment.Key words: Insulin-dependent diabetes, BB rat, immunology, chimeras, bone marrow, lymphopoenia.The spontaneously diabetic BB rat is currently the best-studied animal model of Type 1 (insulin-dependent) diabetes mellitus. The salient features of the disease in BB rats include an abrupt onset of severe hyperglycaemia, insulinopoenia, glycosuria, and acute ketoacidosis [1]. Histologic study of acutely diabetic animals reveals an intense mononuclear infiltration of the pancreatic islets (insulitis) [2,3], involving mostly activated lymphocytes and macrophages [4]. Obesity is absent, and both sexes are affected equally. The syndrome develops in approximately 70 percent of diabetes-prone rats between 60 and 120 days of age [1,5,6].There is considerable evidence that diabetes in BB rats, like human Type 1 diabetes, has an autoimmune aetiology. The BB rat is characterised by multiple abnormalities of humoral and cell-mediated immunity. The insulitis is accompanied by rapid, selective destruction of virtually all pancreatic B cells [2,3]. Nonspecies-specific but organ-specific antibodies directed against surface determinants of rat islet cells have been detected in the serum of BB rats [7,8]. In addition, approximately 50% of these rats develop antibodies to gastric parietal cells and smooth muscle, with concomitant lymphocytic gastritis [9]. Diabetes-prone BB rats are profoundly T-lymphocytopoenic with reductions of both T-helper/inducer (Th/Ti) and T-cytotoxic/suppressor (To/Ts) cell populations [10][11][12]. As is typical of autoimmunity in other animals, the BB rat shows depressed responsiveness to concanavalin A (ConA) and to allogeneic s...

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“…In the present study, on the analogy of the report that spontaneous diabetes in the BB rat is suppressed by multiple injections of anti-lymphocyte serum [2] we studied the suppressive effects of anti-thymocyte serum (ATS) and anti-Thy 1, 2 monoclonal antibody prepartion on spontaneous diabetes in NOD mice.…”

mentioning

confidence: 99%

“…Although hyperglycemia and elevated plasma glucose concentration have been reported to return to normal levels after treatment with anti-lymphocyte serum (ALS) in approximately 38,90 of diabetic BB rats [2], ATS treatment after the onset of diabetes failed to exert such a curative effect in five out of six NOD mice. The discrepancy between the findings in the BB rat and the NOD mouse might be due to the difference in the frequency of the treatment (ALS was injected to the rats three times weekly for 30 days).…”

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Suppression of Overt Diabetes in NOD Mice by Anti-thymocyte Serum or Anti-Thy 1, 2 Antibody

Harada

Makino

1986

Experimental Animals

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Effects of anti-thymocyte serum (ATS) and anti-Thy 1, 2 monoclonal antibody on the spontaneously occurring diabetes in NOD mice were examined.Spontaneous diabetes in female mice was markedly suppressed by intravenous injection of rabbit antimouse thymocyte serum diluted to 1:4 on three consecutive days during the time period from 70 to 100 days after birth; the cumulative incidence of overt diabetes upto 195 days of age was greatly reduced and the onset of diabetes was delayed.Similar effect was observed with anti-Thy 1, 2 antibody treatment.These findings suggest that T lymphocytes play a role in the production of spontaneous diabetes in this mouse strain.

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Spontaneous Diabetes Mellitus: Reversal and Prevention in the BB/W Rat with Antiserum to Rat Lymphocytes

Cited by 203 publications

References 9 publications

T lymphocyte subsets in patients with newly diagnosed Type 1 (insulin-dependent) diabetes: A prospective study

T lymphocyte subsets in patients with newly diagnosed Type 1 (insulin-dependent) diabetes: A prospective study

Bone marrow irradiation chimeras in the BB rat: evidence suggesting two defects leading to diabetes and lymphopoenia

Suppression of Overt Diabetes in NOD Mice by Anti-thymocyte Serum or Anti-Thy 1, 2 Antibody

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