Short-term dietary adjustment with a hydrolyzed casein–based diet postpones diabetes development in the diabetes-prone BB rat
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Insulitis
In an effort to study the pathophysiological events in the development of insulitis in NOD mice, we have developed ILI- and NOD-nu/nu mice. ILI mice are a nondiabetic inbred strain but are derived from the same Jcl:ICR mouse as NOD mice and share the same H-2 allotype with NOD mice. Splenocytes and CD4+ cells from diabetic NOD mice appeared to transfer insulitis to ILI-nu/nu mice, suggesting that ILI mice already express autoantigen(s) responsible for insulitis. But reciprocal thymic grafts from NOD mice into ILI-nu/nu mice and those from ILI mice into NOD-nu/nu mice failed to allow the development of insulitis, implying that ILI mice possess neither precursor T cells nor the thymic environment responsible for the development of insulitis. In addition, splenocytes from ILI mice appeared to contain regulatory cells which suppress the development of diabetes but not that of insulitis in NOD mice. The use of these nude mice should provide more information on the products of insulitis-susceptibility genes of NOD mice.
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Multiple injections of subdiabetogenic doses of streptozotodn (SZ) to CD-I male mice produce a diabetic syndrome that includes a cell-mediated immune reaction against the pancreatic islet. The importance of the host genetic background in the pathogenesis of this model of diabetes was studied by comparing various inbred strains of mice. Of eight strains of mice studied, only C57BL/KsJ developed insulitis and hyperglycemie comparable to that observed in CD-I mice. In two mouse strains (DBA/2J and BALB/cJ) having an haplotype similar to the C57BL/KsJ, only mild insulitis and glucose intolerance were observed. These data suggest that major histocompatibility complex genes, as presently defined, cannot be the only determinant of the severity of hyperglycemia and insulitis in this model.
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Insulitis, an inflammatory process restricted to the pancreatic islets, can experimentally be induced by active immunization with insulin or passive transfer of anti insulin serum. --Mice and rats injected with anti insulin serum from guinea pigs develop a polymorphcellular islet infiltration composed of many eosinophiles and neutrophiles. This inflammatory reaction is caused by the occurrence of immune complexes within the islet area produced by the injected insulin antibodies and the endogenous insulin. Thus polymorphcellular immune complex insulitis represents a type III immune response, respectively a local Arthus phenomenen. --Cattle, sheep and rabbits immunized with crystalline insulin preparations and Freund's adjuvant were found to develop a lymphoidcellular insulitis. As far as specific localization, histologic features, ultrastructure and an occasional manifestation of a diabetes mellitus-like syndrome are concerned lymphoidcellular immune insulitis suggests an immune response of the cell mediated type with temporary autoimmune characteristics to endogenous insulin evoked by the immunization with exogenous crystalline insulin. Insulin derivatives are the most probable candidates for the assumed insulitis-inducing antigen. --Whether immune reactions may also play a role in the pathomechanisms leading to human insulitis is until now an unsolved question.
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Summary. Rabbits were immunized in different ways with bovine insulin in order to study the influence of duration and mode of immunization on the course of experimental immune insulitis and on the induction of diabetes mellitus. 2 groups (II, III) of 10 animals each received four insulin immunizations within four weeks either with predominantly Freund's adjuvant incomplete (FAI) or with exlusively Freund's adjuvant complete (FAC). 3 groups of 10 to 12 animals each were immunized with insulin for a period of 16 weeks. Within this time group IV received four immunizations with predominantly FAI, group V received seven immunization with predominantly FAC, and group VI sixteen immunizations with predominantly FAI. In groups II and III, 50% of the animals showed insulitis after 4 weeks independent of the mode of immunization. In groups IV, V and VI, a different frequency of insulitis was found after 16 weeks dependent on the mode of immunization (IV 10%, V and VI 50% to 70%). The extent of insulitis was, in general, smaller than in groups II and III. At the third, respectively fourth week two animals, also showing the most severe insulitis observed, developed an acute diabetes mellitus. After the fourth week no other animal showed diabetes mellitus. The B cells of the diabetic animals were heavily degranulated and exhibited poorly developed endoplasmic structures. Analogous B cell changes were not observed in animals with insulitis but without diabetes mellitus. The data suggest that immune insulitis does not run a chronic progressive course but represent a temporary immunity phenomenon. The occurrence of diabetes mellitus at an early phase of immunization may possibly be due to transient autoaggressive mechanisms to B cells at the climax of immune insulitis. Zusammen]assung. Kaninchen wurden auf verschiedene Weise mit Insulin immunisiert, um den EinfluB der Dauer und des Modus der Immunisierung auf den Verlauf der experimentellen Immun-Insulitis und auf die Induzierung eines Diabetes mellitus zu untersuchen. 2 Gruppen (II, III) von je f0 Tieren wurden viermal innerhalb yon 4 Wochen entweder mit fiberwiegend Freunds Adjuvans incomplete (FAI) oder ausschlieglich mit Freunds Adjuvans complete (FAC) und Insulin immunisiert. 3 Gruppen yon je 10 bis 12 Tieren wurden fiber 16 Wochen mit Insulin immunisiert. Innerhalb dieser Zeit wurde 'die Gruppe IV viermM mit fiberwiegend FAI, die Gruppe V siebenmal mit fiberwiegend FAC und die Gruppe VI sechszehnmal mit fiberwiegend FAI immunisiert. In den Gruppen II und III land sich nach 4 Wochen unabh~ngig vom Immunisierungsmodus bei 50% der Tiere eine Insulitis. In den Gruppen IV, V und VI fand sich nach 16 Wochen in Abh/ingigkeit vom Immunisierungsmo dus eine unterschiedliche H/~ufigkeit tier Insulitis (IV 10%, V und VI 50% bis 70%). Das AusmaB der Insulitis war dabei generell geringer als in der Gruppe II und III. In der dritten, bzw. vierten Woche entwickelte sich bei zwei Tieren, welche aueh di e stgrkste Insulitis zeigten, ein akuter Diabetes mellitus. Zu spgteren Zeitpunkten wurde keine weitere Manifestation eines Diabetes mellitus beobachtet. Die
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This article is concerned with the role of thymic immunity in the development of diabetes experimentally induced by multiple injections of subdiabetogenic doses of streptozocin (STZ). Euthymic + / +, + /nu, and athymic nu/nu mice of CD-1 and BALB/cAJcl origin were studied. Daily intraperitoneal (i.p.) injections of 30 mg /kg body wt of STZ for 5 consecutive days in CD-1 + / + and + /nu mice resulted in hyperglycemia and mononuclear cell infiltrations of islets (insulitis). The CD-1 nu/nu mice developed neither insulitis nor hyperglycemia after the same treatment. In the nu/nu mice, when thymic immunity was restored by thymus grafting, both insulitis and hyperglycemia developed, thus demonstrating that thymic immunity was a prerequisite for the development of insulitis and hyperglycemia. There was a positive correlation among the degrees of thymic immunity, insulitis, and hyperglycemia in CD-1 + /nu,nu/nu with thymus grafts, and nu/nu mice, indicating that thymic immunity may amplify the diabetogenic effect of STZ by eliciting insulitis. In contrast, in BALB/cAJcl mice, a nonsusceptible strain to insulitis, no significant differences in plasma glucose levels were observed between the + /nu and nu/nu or between the nu/nu and thymus-grafted nu/nu mice. Furthermore, no significant difference was found in plasma testosterone levels between the + /nu and nu/nu mice of both CD-1 and BALB/cAJcI origin. In conclusion, our data indicate that thymic immunity enhances the diabetogenic effect of STZ by eliciting insulitis in susceptible mice.
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The “BB” rat spontaneously develops insulitis, and an insuli in-dependent diabetic syndrome like that in man. Lymphocytes were isolated from blood and spleen of newly-detected “BB” diabetic rats and injected intraperitoneally (IP) into athymic nude mice. Of 72 mice receiving single injections 37% showed insulitis, with 13% of islets examined being affected, and mean intensity of 1.9±0.3 (on a scale of 0 to 3). In 12 mice receiving 3 separate injections of pooled blood and spleen lymphocytes, 58% showed insulitis, with 17% of islects affected, and mean intensity 2.5±0.3 of 45 contorl mice either untreated, injected IP with saline, or injected with cells from nondiabetic contorl rats, only one showed mild insulitis. No random or post IP glucose hyperglycemia was observed. Thus, 1) passive transfer of insulitis has been achieved; 2) insulitis may be present without glucorequlatory disturbances; 3) the pancreatic B cell need not display abnormal membrane structure for it to be susceptible to involvement in the cell-mediated immune process; and 4) detailed studies are required to define the relationship of administered lymphocytes to the observed pathology.
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