Type I diabetes mellitus is an autoimmune disease resulting from the interaction of genetic and environmental factors. A virus that was identified serologically as Kilham's rat virus (KRV) was isolated from a spontaneously diabetic rat and reproducibly induced diabetes in naive diabetes-resistant (DR) BB/Wor rats. Viral antigen was not identified in pancreatic islet cells, and beta cell cytolysis was not observed until after the appearance of lymphocytic insulitis. KRV did not induce diabetes in major histocompatibility complex-concordant and discordant non-BB rats and did not accelerate diabetes in diabetes-prone BB/Wor rats unless the rats had been reconstituted with DR spleen cells. This model of diabetes may provide insight regarding the interaction of viruses and autoimmune disease [corrected]

Complete neonatal thymectomy reduced the frequency of spontaneous diabetes mellitus in BioBreeding/Worcester rats from 27 to 3 percent. Incomplete thymectomy also significantly reduced the frequency of diabetes (to 9 percent). These findings strengthen the hypothesis that thymus-dependent, cell-mediated autoimmune destruction of pancreatic B cells is responsible for the pathogenesis of diabetes in this experimental animal.

Injections of rabbit antiserum to rat lymphocytes reversed hyperglycemia in 36 percent of spontaneously diabetic rats (Bio Breeding/Worcester) and prevented diabetes in susceptible nondiabetic controls. These findings strengthen the hypothesis that cell-mediated autoimmunity plays a role in the pathogenesis of diabetes in this animal model that mimics many morpholigic and physiologic characteristics of human insulin-dependent diabetes mellitus.

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A bstract. The Bio-Breeding/Worcester (BB/W) rat develops spontaneous autoimmune diabetes similar to human insulin-dependent diabetes mellitus. Transfusions of whole blood from the nondiabetic W-line of BB/W rats prevent the syndrome in diabetes-prone recipients. We report three experiments designed to determine which blood component is protective. In all experiments, diabetes-prone BB/W rats 23 to 35 d of age were given four or six weekly intravenous injections. In the first experiment, animals received either saline or transfusions of erythrocytes, white blood cells, or plasma from W-line donors. Diabetes occurred in 7/22 (32%) erythrocyte, 2/27 (7%) white cell, 14/24 (58%) plasma, and 15/27 (56%) saline recipients (P < 0.001). At 120 d of age, peripheral blood was obtained from nondiabetic rats. Fluorescence-activated cell sorter analysis of OX 19 tagged leucocytes revealed 35% T lymphocytes in white cell recipients (n = 13), compared with 9% in saline recipients (n = 7; P < 0.001). Responsiveness to concanavalin A was also increased in the white cell group, whereas the frequency of both insulitis and thyroiditis was decreased. In the second experiment, 1/19 (5%) rats transfused with W-line spleen cells developed diabetes, as contrasted with 12/18 (67%) recipients of diabetesprone spleen cells and 19/31 (61%) noninjected controls (P < 0.001). In the third experiment, diabetes-prone rats A preliminary account of this work has been presented in abstract form (Mordes, J. P., B. A. Woda, A. A. Like, D. Faustman, and A. A. Rossini. 1983. Lymphocyte transfusions prevent diabetes in Bio-Breeding/ Worcester rats. Diabetologia. 25:182.)

D-glucose in the pyranose (ring) form exists as two anomers. The alpha-anomer is more effective than the beta-anomer in promoting insulin secretion, suppressing that of glucagon, and protecting beta-cells against alloxan toxicity. Streptozotocin (SZ), a beta cell toxin, is composed of a cytotoxic moiety, 1-methyl 1-nitrosourea, attached to carbon-2 of glucose and exists as either of two anomers in the pyranose form. In 24-hour-fasted male rats, predominantly alpha- or predominantly beta-SZ was injected intravenously and plasma glucose levels were obtained 48 hours later. The alpha-anomer produced significantly greater beta-cell necrosis at doses of 30, 35, and 40 mg./kg. body weight. At higher doses, no differences between the alpha and beta anomers were observed. 3-O-Methyl glucose (3-OMG) protected against both SZ anomers; however, the alpha-SZ remained more toxic. Larger doses of glucose protected against the lower doses of SZ and, under such conditions, the individual glucose anomers appeared equally potent. Finally, mannitol at comparable molar concentrations was ineffective in protecting against the SZ toxicity. This study suggests that streptozotocin's beta cell toxicity is mediated through recognition by the beta cell. In addition, 3-OMG and, to a lesser but significant extent, glucose were shown to protect against the streptozotocin toxicity, whereas mannitol did not.

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Treatment of C57BL/6 mice with one transfusion of BALB/c spleen cells and a brief course of anti-CD154(anti-CD40 ligand) antibody permits BALB/c islet grafts to survive indefinitely and BALB/c skin grafts to survive for ~50 days without further intervention. We now report adaptation of this protocol to the transplantation of islet and skin xenografts. We observed prolonged survival of rat islet xenografts in mice treated with donor-specific spleen cell transfusion and anti-CD154 monoclonal antibody (mAb). Challenge islet xenografts placed on these animals indicated that graft acceptance was species-specific but not strain specific. Spleen cells from recipients bearing intact grafts led to rejection of rat islet xenografts in scid mice, suggesting that graft acceptance was not due to complete clonal deletion of xenoreactive cells. We also observed prolonged survival of rat skin xenografts in mice treated with donor-specific transfusion and anti-CD154 mAb. Prolonged survival of skin xenografts was also species specific. We conclude that treatment with appropriately timed donor-specific transfusion and anti-CD154 mAb induces durable survival of both islet and skin xenografts in mice. Because this procedure is targeted directly at CD154, a co-activation molecule expressed predominantly by activated CD4 + T-cells, the results suggest that CD4 + cells have a major role in the cellular immune response to xenografts. Diabetes