Bone marrow irradiation chimeras in the BB rat: evidence suggesting two defects leading to diabetes and lymphopoenia

Abstract

Summary. A series of bone marrow irradiation chimeras were constructed in an attempt to determine the site of the defect(s) leading to diabetes and/or lymphopoenia in the BB rat. In BB rats that were lethally irradiated and reconstituted with T-cell-depleted Wistar-Furth (WF) rat bone marrow, the incidence of diabetes was reduced, and in animals treated with WF bone marrow at < 44 days of age, the disease was completely prevented. Such animals demonstrated normal lymphocyte counts in peripheral blood, and normal lymphocyte function (as indicated by mixed lymphocyte response), but retained an abnormal T-cell subset distribution only partially improved above that of diabetes-prone BB rats. The incidence of diabetes in these irradiated chimeras was significantly reduced compared to the indicence in BB rats irradiated at the same age but reconstituted with bone marrow from BB rats. In WF rats that were lethally irradiated and reconstituted with T-cell-depleted bone marrow from overtly diabetic BB rats, no diabetes was induced. Such animals demonstrated normal lymphocyte counts in peripheral blood, normal lymphocyte function, and normal T-cell subset distributions. Overall, these results suggest two defects leading to diabetes and/or lymphopoenia in the BB rat. One of these occurs at the level of the bone marrow stem cell while the other resides in the T-cell differentiative environment.Key words: Insulin-dependent diabetes, BB rat, immunology, chimeras, bone marrow, lymphopoenia.The spontaneously diabetic BB rat is currently the best-studied animal model of Type 1 (insulin-dependent) diabetes mellitus. The salient features of the disease in BB rats include an abrupt onset of severe hyperglycaemia, insulinopoenia, glycosuria, and acute ketoacidosis [1]. Histologic study of acutely diabetic animals reveals an intense mononuclear infiltration of the pancreatic islets (insulitis) [2,3], involving mostly activated lymphocytes and macrophages [4]. Obesity is absent, and both sexes are affected equally. The syndrome develops in approximately 70 percent of diabetes-prone rats between 60 and 120 days of age [1,5,6].There is considerable evidence that diabetes in BB rats, like human Type 1 diabetes, has an autoimmune aetiology. The BB rat is characterised by multiple abnormalities of humoral and cell-mediated immunity. The insulitis is accompanied by rapid, selective destruction of virtually all pancreatic B cells [2,3]. Nonspecies-specific but organ-specific antibodies directed against surface determinants of rat islet cells have been detected in the serum of BB rats [7,8]. In addition, approximately 50% of these rats develop antibodies to gastric parietal cells and smooth muscle, with concomitant lymphocytic gastritis [9]. Diabetes-prone BB rats are profoundly T-lymphocytopoenic with reductions of both T-helper/inducer (Th/Ti) and T-cytotoxic/suppressor (To/Ts) cell populations [10][11][12]. As is typical of autoimmunity in other animals, the BB rat shows depressed responsiveness to concanavalin A (ConA) and to allogeneic s...

Renin and angiotensinogen expression during the evolution of diabetes.

“…as previously described. 7 - 8 Individual rats were classified as diabetic on the basis of positive, sustained glycosuria as described previously. 78 Each diabetic rat was subsequently maintained on a single daily dose of PZI insulin (Eli Lilly and Co., Indianapolis, Ind.…”

DR.lyp/lyp bone marrow maintains lymphopenia and promotes diabetes in lyp/lyp but not in +/+ recipient DR.lyp BB rats

“…2A and C, respectively. normal lymphocyte counts in peripheral blood, normal lymphocyte function, and normal T cell subset distributions [18]. The recipient WF rats transplanted with BBDP T cell-depleted bone marrow cells did not differ from control WF to WF rats and WF to BB rats, suggesting that both a lymphoid stem cell as well as differentiating environment influenced the lymphopenia phenotype and diabetes [30].…”

“…The same authors suggested from bone marrow transplantation experiments between RT1 B u/u compatible BB and WistareFurth rats that there were two defects leading to lymphopenia and diabetes. One of these would occur in the bone marrow stem cells while the other resides in the T cell differentiating environment since lethally irradiated WistareFurth recipient rats did not develop lymphopenia or diabetes when receiving bone marrow cells from diabetic BB rats [18]. Other investigators suggested that bone marrow stem cells [19,20] or a combination of thymic and bone marrow defects [21] were responsible for the altered immune state of the bone marrow recipient rat.…”