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The BB rat strain was derived from a colony of outbred Wistar rats that developed spontaneous diabetes mellitus at the BioBreeding Laboratories, Ottawa, Canada, in the 1970s. Affected animals became the founders of the inbred diabetes-prone (DP)-BB/Wor rat strain used in the majority of published studies. At the sixth generation of inbreeding, a subpopulation of nondiabetic DP-BB/Wor rats was selected to start a control line. Now designated as diabetes-resistant (DR)-BB/Wor rats, these coiso-genic descendants of DP-BB/Wor forbearers do not develop spontaneous diabetes. Both BB/Wor rat lines are now fully inbred. BB/Wor and all other BB rat strains express the RT1u rat major histocompatibility complex (MHC) haplotype. As is the case with human insulin-dependent diabetes mellitus (IDDM), predisposition to the disease is strongly linked genetically to MHC genes. The onset of hypergly-cemia is preceded by mononuclear cell infiltration of the islets (insulitis) and the appearance of various autoantibodies directed against islet cells, insulin, and other tissues. Onset of hyperglycemia is associated with weight loss, glycosuria, and ketosis. Exogenous insulin therapy is required from the time of disease onset, or death ensues rapidly from ketoacidosis.

Although both lines of BB/Wor rats are used to model human IDDM, there are important differences between DP and DR-BB/Wor rats. DP-BB/Wor rats have severe T cell lym-phopenia associated with the lyp gene. The lymphopenia results in a deficiency in RT6.1+ T cells in the peripheral lymphoid tissues (Greiner et al., 1986), although the RT6.1 gene is structurally intact (Crisa et al., 1990). Prevention of IDDM in DP-BB/Wor rats by RT6+ T cell engraftment, and induction of IDDM in DR-BB/Wor rats by RT6+ T cell depletion (Gre-

iner et al., 1987), led to the hypothesis that IDDM outcome is determined by a balance between RT6- autoreactive T cells and RT6+ regulatory T cells (Mordes et al., 1987; Greiner et al., 1988). Both lines of BB/Wor rats are also susceptible to autoimmune lymphocytic thy-roiditis, which is not discussed further in this unit. Table 15.3.1 compares the salient features of IDDM in DP- and DR-BB/Wor rats.

Efficient induction of IDDM in both lines requires both CD4+ and CD8+ cells (Metroz-Dayer et al., 1990; Edouard et al., 1993; Whalen et al., 1994). Genes for interferon y (IFN-y) and interleukin 12 (IL-12) are expressed in BB/Wor rat islets of both lines before and during IDDM onset, with little or no IL-4 or IL-10 observed (Zipris et al., 1996). The balance between autoreactive and regulatory T cells in DR-BB/Wor rats may therefore reflect a balance between TH1 and TH2 cell populations. The inciting autoantigen(s) for T cells have not been identified, but the onset of hyperglyce-mia is preceded by the appearance of autoan-tibodies directed against a variety of tissue antigens (antigens expressed on the surface of islet cells, insulin, thyroid colloid, endo-thelial cells, smooth muscle, and gastric parietal cells). Thymic epithelial cell defects have been described in BB rats (Rozing et al., 1989; Doukas et al., 1994), and it has been hypothesized that these defects may result in faulty intrathymic selection processes and subsequent release of autoreactive T cells from BB rat thymus.

Adoptive transfer of IDDM into histocom-patible WAG nude recipients can be achieved with a diabetogenic inoculum administered at an appropriate cell dose. Fresh T cells from acutely diabetic DP-BB/Wor rats fail to adoptively transfer insulitis or diabetes, even at a dose of 1 x 108 spleen cells. IDDM transfer is possible if DP-BB/Wor spleen cells are acti

Table 15.3.1 Characteristics of DP- and DR-BB/Wor Ratsa-fc




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