Islet cell surface and lymphocyte antibodies often precede the spontaneous diabetes in the BB rat

Abstract

Summary. The diabetic syndrome of the BB rat shows many homologies with that of human insulin-dependent diabetes and evidence that the onset of the disease is associated with the presence of autoantibodies, including islet cell surface antibodies. In this study, sera were sampled serially from weaning to 157 days of age from 26 BB rats in two low-incidence litters, and 22 rats of three high-incidence litters. Clinical and metabolic variables were monitored concurrently with blood lymphocyte counts. Islet morphology was correlated at sacrifice. In the high-incidence litters, eight rats developed insulin-dependent diabetes, five impaired glucose tolerance, and the remaining nine all showed insulitis. In the low-incidence litters, only one animal showed impaired glucose tolerance and another insulitis. In the high-incidence litters 16 rats (73%) had islet cell surface antibodies compared with 4 out of 26 (15%) low-incidence controls (p< 0.002). Antibodies reactive with Wistar rat spleen lymphocytes were present in all high-incidence rats compared with 19% (5 out of 26) among the control litters (p< 0.002). Time courses of islet cell surface and lymphocyte antibody appearance and their peak values varied, but already at weaning the levels of both antibodies were increased among the high-incidence litter rats (p< 0.001). Islet cell surface and/or lymphocyte antibodies were therefore present in the majority of animals at an age where neither morphological nor metabolic evidence of the diabetic syndrome were yet detected. All rats that showed any form of the syndrome were lymphopenic. These findings suggest that BB rats have an abnormal immune response which predisposes to later development of insulin-dependent diabetes, often preceded by the presence of islet cell surface and/or lymphocyte antibodies.Key words: BB rats, islet cell surface antibodies, lymphocyte antibodies.The BB rat develops insulitis and insulin-dependent diabetes mellitus with many features analogous to that of the human disease [1][2][3] including the possibility that cell-mediated and humoral immunological mechanisms are associated with development of the diabetic syndrome [3]. Evidence for altered cell-mediated immunity includes (a) mononuclear cell infiltrates in the islets [1-3], (b) marked lymphocytopenia in blood as well as in lymphoid organs [4,5] associated with an abnormal mitogenic response of remaining T lymphocytes [6,7], (c) possible prevention of the syndrome by either neonatal thymectomy [8], antilymphocyte serum [9], cyclosporin [10]; bone marrow transplantation [11] or by transfusion of blood from normal rats [7], and (d) passive transfer of insulitis by lymphocytes from diabetic rats to nude mice [12]. Evidence for an altered humoral immune function in diabetic BB rats includes the presence of circulating islet cell surface antibodies (ICSA) and antibodies to splenic lymphocytes [13] as well as antibodies to thyroid, smooth muscle, and gastric parietal cells [14][15][16]. The above investigations suggest that diabetes develops in ...

Molecular biology of Type 1 (insulin-dependent) diabetes mellitus

“…Similar observations have been made in the spontaneously diabetic BB rat (Table 3) which develops insulin-dependent diabetes with many similarities to that in man [45]. In some animals which later developed insulin-dependent diabetes, both ICSA and autoantibodies against an Mr 64000 component were present even at the time of weaning [46,47]. Protein II/lIlI 230aa Sig 7 D1 D2 TMCT 3'NONn a I CODI N G C DNA 32p 790bp Fig.6.…”

In vivo prevention of thyroid and pancreatic autoimmunity in the BB rat by antibody to class II major histocompatibility complex gene products.

“…An animal model for spontaneous IDDM and thyroiditis has been developed in the BB rat (2). As in humans, the rat disease is controlled in part by the genes encoding the major histocompatibility complex (MHC) (3,4), is characterized by islet infiltration (5), and is associated with the presence of anti-islet cell antibodies (6,7). Class II MHC genes and gene products act to regulate immune responses in the rat (8) as well as in the mouse and man (9,10).…”

Experimental Models of Type-I Diabetes

“…Anti-islet cell autoantibodies are detected in the serum of BB rats at an early age, before the onset of diabetes. Paradoxically, the islet cell cyto plasmic antibodies (ICA) that are the hall mark of human IDDM are not found in BB rats [34,36,37], Anti-islet cell autoantibod ies can however be detected against surface determinants using different techniques: in direct immunofluorescence [38][39][40], radiola beled protein-A-binding assay [36,41,42], immunoenzymology (ELISA), cytotoxicity in the presence of complement on 5,Crlabeled islet cells [43] or inhibition of insulin release by glucose-stimulated islets [43]. Anti-islet antibodies are usually found in a majority of diabetic rats with peak values at the time of diabetes onset (titers tending to decrease thereafter).…”