Passive transfer of diabetes from BB/W to Wistar-Furth rats.

We describe the induction of autoimmune diabetes, insulitis, and thyroiditis in athymic rats following ujections of major histocompatibiity complex compatible spleen cells. Lymphocytes with these capabilities were found in normal rats ofthe YOS, WAG, PVG, and diabetes-resistant BB strains, and in diabetes-prone BB rats. Adoptive transfer was facilitated by prior in vivo depletion of RT6.1+ regulatory T cells and in vitro mitogen activation of donor spleen cells. By RT6 depleting diabetes-resistant donors and nsing nude recipients, transfer of diabetes and thyroiditis was accomplished by using fresh, unstimulated spleen cells. The data suggest that organ-specific autoreactive cells may be present to various degrees but suppressed to a variable extent in many rat strains. The equilibrium between autoreactive and regulatory cells appears to determine the expression of autoimmunity.Clonal deletion of autoreactive lymphocytes during repertoire development and active suppression of autoreactive cells in peripheral tissues contribute to the prevention of autoimmune diseases (1). In mice, T-lymphocyte populations are deleted in the thymus following interaction with a major histocompatibility complex (MHC) class II (I-E) molecule (2). Nonobese diabetic mice do not express I-E and develop autoimmune diabetes (3). These mice harbor T-cell populations normally deleted in I-E-expressing strains (4). In B6AF1 mice, neonatal thymectomy induces organ-specific autoimmunity (5). Thymectomy earlier or later is ineffective, suggesting that a sequence ofintrathymic events culminates in an immunological definition of self.Evidence for suppression of autoreactive T cells in peripheral tissues is also accumulating. Transplantation of Lyt-1-depleted spleen cells from nu/+ mice (6) or thymuses from cyclosporin-treated nu/+ mice (7) into nu/nu recipients results in autoimmune endocrinopathy. This can be prevented by cotransplantation of a nu/+ thymus or unfrictionated spleen cells together with the cyclosporin-treated thymus.An imbalance between autoreactive and regulatory (RT6+) cells may in part determine the expression of BB rat autoimmunity (8). Diabetes-prone (DP) BB rats are lymphopenic and deficient in T cells that express the RT6 alloantigen (9). They spontaneously develop insulitis, hyperglycemia, and thyroiditis (8,10 ITo whom reprint requests should be addressed. 7618The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.Proc. Natl. Acad. Sci. USA 87 (1990) 7619 isolated splenocytes were injected into recipients (108 cells in 0.5 ml per rat).Flow Microfluorimetry. To determine the number of native T cells present in athymic rats and to assay for chimerism in adoptive recipients, lymph node cell suspensions were labeled with 0X19 mouse anti-rat CD5 (pan-T cell) monoclonal antibody (mAb), with the rat anti-RT6.1 mAb DS4.23, or with the rat anti-RT6.2 mAb 6A5 (9). Cell...

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“…This requires mitogen activation of donor cells (12,13). Diabetes-resistant (DR) BB rats have normal numbers of RT6+T cells.…”

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confidence: 99%

Adoptive transfer of autoimmune diabetes and thyroiditis to athymic rats.

McKeever

Mordes

Greiner

et al. 1990

Proc. Natl. Acad. Sci. U.S.A.

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“…lymphocytes (an inflammatory lesion termed insulitis), and adoptive transfer diabetes has been demonstrated (10,11). The DP-BB rat also has severe T cell lymphopenia (12) with reduced numbers of CD4' and CD8' T cells and complete absence of RT6' T cells (13,14).…”

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confidence: 99%

Prevention of diabetes in the BB rat by essential fatty acid deficiency. Relationship between physiological and biochemical changes.

Lefkowith

Schreiner

Cormier

et al. 1990

The Journal of Experimental Medicine

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Essential fatty acid (EFA) deficiency exerts a striking protective effect in several animal models of autoimmune disease. We now report that EFA deprivation prevents diabetes in the BB rat, an animal model of human insulin-dependent diabetes mellitus. In diabetes-prone (DP)-BB rats, the incidences of spontaneous diabetes and insulitis (the pathological substrate of autoimmune diabetes) were greatly reduced by EFA deficiency. This beneficial effect of the deficiency state was also seen in diabetes-resistant (DR)-BB rats that, after treatment with antibody to eliminate RT6+ T cells, would otherwise have become diabetic. The susceptibility of EFA-deprived DP-BB rats to spontaneous diabetes was restored when they were given dietary supplements of linoleate at 70 d of age (during the usual period of susceptibility), but not when they were repleted beginning at 120 d (after the peak incidence of diabetes). EFA deficiency did lead to growth retardation, but calorically restricted control rats demonstrated that the protective effect of the deficiency state was not a function of decreased weight. To examine the relationship between the biochemical changes of EFA deficiency and its physiological effects in this system, we compared the fatty acid changes that occurred in EFA-deficient animals that did and did not develop diabetes. Nondiabetic animals had significantly lower levels of (n-6) fatty acids (i.e., linoleate and arachidonate) and higher levels of oleate, an (n-9) fatty acid, than did diabetic animals. Levels of 20:3(n-9), the fatty acid that uniquely characterizes EFA deficiency, were similar in both groups, however. Among diabetic EFA-deficient rats, the age at onset of diabetes was found to correlate inversely with the level of (n-6) fatty acids, the least depleted animals becoming diabetic earliest, whereas there was no correlation with levels of 20:3(n-9). Among animals repleted with linoleate beginning at 70 d, restoration of susceptibility to diabetes correlated with normalization of the level of arachidonate. In summary, EFA deprivation reduced the frequency of diabetes in both DP and RT6-depleted DR-BB rats. This protective effect was strongly associated with depletion of (n-6) fatty acids, particularly arachidonate, but not with accumulation of the abnormal 20:3(n-9). Conjecturally, arachidonate and/or a metabolite may play a key role in mediating inflammatory injury in this animal model of autoimmune diabetes.

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“…Lymphocytes from diabetic BB rats can transfer IDDM into resistant rats (14) and BB rats. IDDM can be inhibited by procedures directly interfering with lymphocyte functions or numbers, e.g., neonatal thymectomy (15) and treatment with lymphocyte antiserum (16) …”

Section: Discussionmentioning

confidence: 99%

Inhibition of diabetes in BB rats by virus infection.

Dyrberg¹,

Schwimmbeck²,

Oldstone³

1988

J. Clin. Invest.

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BB rats serve as a model for human insulin-dependent diabetes mellitus (IDDM), since without insulin treatment, most 60-140-d-old animals die within 1 to 2 wk of developing polyuria, polydypsia, hyperglycemia, and hypoinsulinemia. Lymphoid cells accumulate in the islets of Langerhans and beta cells undergo destruction. We report that inoculation of such BB rats with lymphocytic choriomeningitis virus (Armstrong strain, clone 13) reduces over a prolonged period the incidence of IDDM, normalizes the concentration of blood sugar and pancreatic insulin, prevents the mononuclear cell infiltration in the islets of Langerhans, and for a short time after inoculation alters T lymphocyte subsets. Thus, a virus might be programmed to carry out useful functions.

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Passive transfer of diabetes from BB/W to Wistar-Furth rats.

Abstract: Autoimmune diabetes can be transferred to young, diabetes prone BB/W rats by injecting them intravenously with conca-

Cited by 44 publications

References 17 publications

Adoptive transfer of autoimmune diabetes and thyroiditis to athymic rats.

Adoptive transfer of autoimmune diabetes and thyroiditis to athymic rats.

Prevention of diabetes in the BB rat by essential fatty acid deficiency. Relationship between physiological and biochemical changes.

Inhibition of diabetes in BB rats by virus infection.

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