The BB Rat as a Model of Human Insulin Dependent Diabetes Mellitus

Insulin-dependent diabetes mellitus (IDDM) in humans is a disorder characterized by severe hyperglycemia, weight loss, glycosuria, and ketoacidosis. These signs and symptoms are the result of severe insulin deficiency. IDDM results from selective destruction of the insulin-producing P cells in the pancreatic islets of Langerhans in the context of an inflammatory infiltrate. Its pathogenesis is believed to be autoimmune in origin. Affected individuals require chronic treatment with exogenous insulin for survival. Knowledge of IDDM advances steadily, but the disorder remains difficult to study in humans. The diseased organ is inaccessible, and ethical considerations limit procurement of biological samples and testing of treatment modalities. Use of the BioBreeding (BB) rat to model human IDDM offers numerous advantages. Characteristics of diabetes in the BB rat closely parallel those observed in human IDDM. Diabetic animals can be biopsied, autopsied, and bred to study the genetic basis of IDDM. The genetic, immunological, and environmental components of the disease can all be investigated under controlled conditions.

Two inbred lines of BB have been used in the majority of published studies using this model system; these rats are designated as diabetes prone (DP-BB/Wor) and diabetes resistant (DR-BB/Wor). DP-BB/Wor rats of both sexes spontaneously develop IDDM between 55 and 110 days of age. They are severely deficient in circulating T lymphocytes that express the maturational alloantigen RT6. Transfusion of histocompatible normal rat T cells to young DP recipients prevents spontaneous disease provided that RT6+ T cells become engrafted. In contrast, DR-BB/Wor rats have normal levels of circulating RT6+ T cells and do not develop spontaneous autoimmunity. Several intervention strategies can be used to induce the disease in DR-BB/Wor rats. In vivo depletion of RT6+ T cells using a cytotoxic monoclonal antibody, together with certain immunostimulatory agents, induces IDDM in >90% of treated animals.

The two basic protocols describe diagnosis (see Basic Protocol 1) and prevention (see Basic Protocol 2) of spontaneous IDDM in DP-BB/Wor rats. Two alternate protocols are given for the induction of autoimmune disease in DR-BB/Wor rats (see Alternate Protocol 1) and for the adoptive transfer of autoimmunity into histocompatible athymic WAG nu/nu recipient rats (see Alternate Protocol 2). Support protocols are also given for diagnosis of insulitis (see Support Protocol 1), treatment of diabetic rats with insulin (see Support Protocol 2), and serological analysis of blood samples from sentinel rats (see Support Protocol 3) to monitor the pathogen status of the colony.

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