Diabetes in the Bio-Breeding/Worcester rat. Induction and acceleration by spleen cell-conditioned media.

Handler, Eugene S.; Mordes, John P.; Seals, Jonathan R.; Koevary, Steven B.; Like, Arthur A.; Nakano, Koji; Rossini, A A

doi:10.1172/jci112156

Cited by 16 publications

(4 citation statements)

References 10 publications

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“…However, there have been spontaneous outbreaks of diabetes in DR colonies (21,22). Diabetes can also be induced in DR rats by low-dose irradiation (23), cyclophosphamide (24), media conditioned by spleen cells cultured in the presence of lectin (25), and in vivo depletion of RT6 + T lymphocytes with a cytotoxic monoclonal antibody (MoAb) (20). About 50% of RT6-depleted DR rats develop diabetes within 4 wk.…”

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confidence: 99%

T-Lymphocyte Requirement for Diabetes in RT6-Depleted Diabetes-Resistant BB rats

Woda

Handler²,

Greiner³

et al. 1991

Diabetes

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Diabetes-prone (DP) BB rats develop spontaneous autoimmune insulin-dependent diabetes mellitus (IDDM). The cell populations involved in the expression of diabetes are not precisely known but probably include natural killer (NK) cells, macrophages, and T lymphocytes. Because the DP rat has few lymphocytes of the CD5+/CD+ phenotype, cytotoxic T lymphocytes (Tc) are not believed to be important in the process. Diabetes-resistant (DR) BB rats that are depleted of RT6+ T lymphocytes also become diabetic and provide an additional model of IDDM. We report that diabetes in DR rats depleted of RT6+ T lymphocytes is prevented by the concomitant depletion of either the CD5+ or the CD8+ population. In contrast, coadministration of anti-asialogangliosideM1 (alpha-ASGM1), an antiserum that principally recognizes NK cells, failed to prevent hyperglycemia in RT6-depleted rats. We propose that the initiation of diabetes in both DP and RT6-depleted DR rats is T-lymphocyte dependent. However, the final common pathway leading to autoimmune beta-cell destruction in IDDM may be different in these models. The RT6-depleted DR rat requires a cell that is sensitive to anti-CD8 (possibly a Tc), whereas the DP rat requires an anti-ASGM1-sensitive cell.

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confidence: 99%

T-Lymphocyte Requirement for Diabetes in RT6-Depleted Diabetes-Resistant BB rats

Woda

Handler²,

Greiner³

et al. 1991

Diabetes

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“…Injection of IL-1 into rats increases the peripheral insulin level and causes sustained hypoglycemia (26). Furthermore, in terleukin-1 -containing supernatants from concanavalin-A-activated spleen cells accelerate the appearance of diabetes in diabetes-prone BB rats (15).…”

Section: Discussionmentioning

confidence: 93%

Interleukins increase surface ganglioside expression of pancreatic islet cells in vitro

Kjær¹,

Rygaard²,

Bendtzen³

et al. 1992

APMIS

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increase surface ganglioside expression of pancreatic islet cells in vitro. APMIS 100: 509-514, 1992. This experiment was conducted in order to investigate whether expression of gangliosides on islet cell surface in vitro is influenced by cytokines, especially interleukin 1. Islets from adult Lewis rats were incubated with different concentrations of recombinant-derived human cytokines. Following dispase treatment, the single cells were labeled with monoclonal antiganglioside antibodies A2B5 or R2D6, and conjugate. Both are directed against j 3 cells; A2B5 is recognized to bind specifically to pancreatic islet cells, while R2D6 is shown to bind no other pancreatic cells than P cells. Surface labeling was evaluated in blind trials using a fluorescence microscope and a fluorescence-activated cell sorter (FACS). A2B5 staining demonstrated a significantly higher number of labeled cells after incubation with interleukin la (14.9%_+2.8; p<0.005), interleukin l p (23.2%+4.2; p<0.0005) or TNFa (16.l%f 4.0; p =0.005) compared to endotoxin controls (4.1% _+ 1.1). Interleukin 1 P (9.5%f 1.5; p < 0.005) showed a significantly increased number of R2D6-stained cells (control: 2.3%+ 1.3). A similar but not significant effect was seen with interleukin la and TNFa. Interleukin 6 had no effect on the antigen expression. The intensity of labeling was elevated among interleukin 1 P-incubated cells compared to control samples. Thus, treatment of islets with different cytokines, especially interleukin 1 P, increases surface antigen expression. We suggest that this mechanism of action in vitro may be of importance for the putative diabetogenic effect of interleukin 1.

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“…It should be emphasized, however, that non-cellular immune effector mechanisms may also contribute to the pathogenesis of the disease. The successful passive transfer of diabetes with spleen cell-conditioned media [6] and the detection of IgG deposits in inflamed islet [7] point to a role for soluble lymphocyte-derived factors and circulating islet cell surface antibodies (ICSA) [8, 91 in the @ cell destructive process. With respect to the humoral component directed against islet cell surface constituents, C-dependent antibody-mediated cytotoxicity (C'AMC) has been shown to precede and to coincide with the onset of overt diabetes [lo-121.…”

Section: Introductionmentioning

confidence: 99%

Complement‐dependent antibody‐mediated cytotoxicity in the spontaneously diabetic BB/OK rat: association with β cell volume density

et al. 1990

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The present study examined in the spontaneously diabetic BB/OK rat whether a relationship exists between the appearance of complement-dependent antibody-mediated cytotoxicity (C'AMC) in serum and the relative beta cell volume density determined in pancreatic biopsies. C'AMC was estimated by 51Cr release from prelabeled major histocompatibility complex-compatible neonatal rat islet cells after exposure to rat serum and rabbit complement. Fifty-one percent (72/141) of sera from BB/OK rats with newly diagnosed diabetes were positive for C'AMC. At onset of hyperglycemia, insulin-immunoreactive beta cells were only detectable in pancreas biopsies of 25% (10/40) of the BB/OK rats who displayed mild hyperglycemia (plasma glucose 8.3-13.0 mmol/l) and low serum C'AMC. A twofold increase (p less than 0.01) of C'AMC and loss of the remaining beta cells was evident in untreated animals upon their reexamination within 1 week after diagnosis of hyperglycemia. Initiation of insulin therapy prevented neither the increase in C'AMC activity nor the decrease in the beta cell volume density. In contrast, three out of four mildly hyperglycemic BB/OK rats treated with cyclosporin A maintained both their initial C'AMC levels and relative beta cell volume density not only throughout the treatment period (4 weeks) but also for at least 4 weeks thereafter. In one additional animal receiving cyclosporin A no protection of the remaining beta cells could be achieved and C'AMC levels were markedly increased. It is concluded that the appearance of increased C'AMC in serum may reflect autoimmune reactions against the islet beta cells of spontaneously diabetic BB/OK rats. The increase of C'AMC seen in untreated as well as insulin-treated BB/OK rats, which were even devoid of beta cells, suggests that C'AMC activity appears secondary to the loss of beta cells. These results do not support the hypothesis of a direct beta cell destruction via intrainsular complement activation.

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Diabetes in the Bio-Breeding/Worcester rat. Induction and acceleration by spleen cell-conditioned media.

Cited by 16 publications

References 10 publications

T-Lymphocyte Requirement for Diabetes in RT6-Depleted Diabetes-Resistant BB rats

T-Lymphocyte Requirement for Diabetes in RT6-Depleted Diabetes-Resistant BB rats

Interleukins increase surface ganglioside expression of pancreatic islet cells in vitro

Complement‐dependent antibody‐mediated cytotoxicity in the spontaneously diabetic BB/OK rat: association with β cell volume density

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