SummaryThe development of autoimmune diabetes in the nonobese diabetic (NOD) mouse is controlled by multiple genes. At least one diabetogenic gene is linked to the major histocompatibility complex (MHC) of the NOD and is most likely represented by the two genes encoding the c~ and chains of the unique NOD class II molecule. Three other diabetogenic loci have recently been identified in the NOD mouse and are located on chromosomes 1, 3, and 11. In addition to the autoimmune diabetes which is caused by destruction of the insulin-producing B cells in the pancreas, other manifestations of autoimmunity are seen in the NOD mouse. These include mononuclear cell inflammation of the submandibular and lacrimal glands, as well as the presence of circulating autoantibodies. To determine the effect of the non-MHC diabetogenic genes on the development of autoimmunity, we constructed the NOD.B10-H-2 b (NOD.H-2 b) strain, which possesses the non-MHC diabetogenic genes from the NOD mouse, but derives its MHC from the C57BL/10 (B10) strain. The NOD.H-2 ~ strain does not develop insulitis, cyclophosphamide-induced diabetes, or spontaneous diabetes. It does, however, develop extensive lymphocytic infiltrates in the pancreas and the submandibular glands that are primarily composed of Thy 1.2 + T cells and B220 + B cells. In addition, autoantibodies are present in NOD.H-2 ~ mice which recognize the "polar antigen" on the insulin-secreting rat tumor line RINm38. These observations demonstrate that the non-MHC genes in the NOD strain, in the absence of the NOD MHC, significantly contribute to the development of autoimmunity. The contribution of a single dose of the NOD MHC to autoimmunity was assessed with a (NOD x NOD.H-2b)F1 cross. Although only '~3% of F1 females developed spontaneous diabetes, approximately 50% of both female and male F1 mice developed insulitis, and 25% of females and 17% of males became diabetic after treatment with cyclophosphamide. These data demonstrate that the MHC-linked diabetogenic genes of the NOD mouse are dominant with decreasing levels of penetrance for the following phenotypes: insulitis > cyclophosphamide-induced diabetes > spontaneous diabetes.T he nonobese diabetic (NOD) 1 mouse spontaneously develops autoimmune diabetes and is an experimental model of human type I diabetes. We previously determined in out-1 Abbreviation used in this paper: NOD, nonobese diabetic. crosses to the C57BL/10 (B10) strain, that at least one gene linked to the MHC of the NOD and three non-MHC-linked recessive diabetogenic genes present in the NOD mouse were required for the development of diabetes (1). Recently, using an outcross with the B10.NOD-H-2g 7 (B10.H-2g 7) strain (a B10 congenic mouse whose MHC was derived from the NOD
Autoimmune, insulin-dependent diabetes mellitus in man is an inherited disease . Many studies have demonstrated (reviewed in references 1, 2) that genes linked to the MHC of man contribute to the genetic susceptibility to diabetes . >90% of Caucasian patients suffering from type 1 diabetes express the DR3 and/or DR4 antigens as compared with a 60% expression in the total population . Interestingly, DR3/DR4 heterozygotes are particularly susceptible to the development of diabetes since up to 50% of type 1 diabetics possess this genotype as compared with only 5% of the general population . The fine specificity of the association of DR3 and DR4 with diabetes has recently been defined using HLA restriction endonuclease fragment length polymorphisms (3-5) and human T lymphocyte clones that define DR subtypes (6, 7).The autoimmune response in type 1 diabetes is characterized by insulitis, which is an inflammatory infiltrate affecting the islets of Langerhans . In a study of 60 recent-onset type 1 diabetics, insulitis was present in 78% of patients (8).A persistence of memory cells specific for insulin-producing a cells is suggested by the observation that long-term insulin-dependent patients receiving a pancreas transplant from an identical twin will still reject the islet tissue even though the original antigenic stimulus has been absent for years (9).Recently, two animal models exhibiting spontaneous diabetes mellitus have been identified . The BB rat (10, 11) and the nonobese diabetic (NOD)' mouse (12-16) both evidence the destructive autoimmune pancreatic insulitis that is characteristic of human type 1 diabetes . In the BB rat model, diabetes can be adoptively transferred with Con A-activated splenic lymphocytes obtained from diabetic BB rats (17,18). Further evidence supporting the autoimmune etiology of diabetes in the BB rat is that treatment of BB rats with a combination of immunosuppressive agents, which included cyclosporine A, glucocorticoids, and
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.
We report that transfusions of RT1 Wistar-Furth (WF) spleen cells prevented spontaneous diabetes in the RT1" BB/W rat while RT1b Buffalo rat spleen cells did not. In addition, donor origin WF T lymphocytes were detected in nondiabetic-susceptible BB/ W recipients 5 mo after transfusion. Survival of donor-origin lymphocytes may provide the cellular mechanism by which major histocompatibility complex-compatible WF spleen cell transfusions prevent BB rat diabetes.
Prophylactic insulin administration is known to prevent hyperglycaemia in diabetes prone BB rats and non-obese diabetic mice. This study investigated the effect of insulin treatment on the development of overt diabetes, clinically inapparent anti-islet autoreactivity, and thyroiditis in RT6-depleted diabetes resistant BB rats. Fewer than 1% of these animals develop spontaneous diabetes, but if depleted of RT6- T cells greater than 50% become hyperglycaemic. We treated 30-day-old diabetes resistant rats with anti-RT6.1 monoclonal antibody, exogenous insulin, or both. Up to 60 days of age, 16 of 20 rats given antibody alone became diabetic, compared with 1 of 20 also treated with antibody plus insulin. Up to 110 days of age, only 1 of 10 rats treated with both insulin and antibody between 30 and 60 days became diabetic. Histologic study of non-diabetic insulin plus anti-RT6 antibody treated rats revealed insulitis in 3 of 9 at 60 days old, and insulitis in 3 of 8 and thyroiditis in 6 of 7 at 110 days of age. Non-diabetic animals were also found to harbour autoreactive spleen cells that adoptively transferred diabetes. Splenocytes from 60 or 110-day-old non-diabetic donors that had been treated with insulin and antibody between 30 and 60 days of age induced diabetes in 7 of 13 and 6 of 8 adoptive recipients respectively. We conclude that insulin treatment prevents clinical diabetes in the RT6-depleted diabetes resistant BB rat, but this treatment does not prevent the development of autoreactive cell populations that cause thyroiditis and adoptively transfer diabetes.
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