Prevention of Diabetes in BB Rats: I. Evidence Suggesting a Requirement for Mature T Cells in Bone Marrow Inoculum of Neonatally Injected Rats

Abstract

Injection of major histocompatibility complex (MHC)-compatible bone marrow cells from normal animals into neonatal BB rats resulted in a striking decrease in incidence of diabetes and restoration of concanavalin A (ConA) and mixed lymphocyte responses. However, injection of bone marrow cells pretreated with anti-rat thymocyte antiserum plus complement to remove mature T cells had no effect on incidence of disease, suggesting that mature T cells in the bone marrow inoculum were responsible for prevention of diabetes. Because the decreased incidence of diabetes in rats injected with untreated bone marrow appeared to be unrelated to the extent of lymphopenia in these animals, the involvement of T cells in the onset of diabetes must reflect a defect in the normal function of these cells rather than their absolute number. Approximately 50% of the W3/13+ cells in the spleens of BB rats lacked the OX-8 and W3/25 T cell subset markers. The identity of this W3/13+, OX-8-, W3/25- blank subset remains to be established. Our results, interpreted in light of studies from the other laboratories, suggest the existence of multiple abnormalities in the BB rat, including the presence of T cells as effector or helper cells that augment onset of disease and the absence of a regulatory T cell circuit that could prevent the disease.

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

“…Neonatal inoculation of diabetes-prone BB rats with bone marrow cells from a normal strain of rat (creating chimeras) prevents diabetes [6,12,[19][20][21]. In our study [6], mixed lymphocyte cultures and ConA stimulation assays performed with lymphocytes from the recipient BB rats demonstrated that they had been immunologically reconstituted. Diabetes in the BB rat can be prevented or reversed by various immunosuppressive procedures, such as administration of antilymphocyte globulin [22], glucocorticoids [23], or cyclosporin [23-251. A series of bone marrow irradiation chimeras were constructed [26,27], using various combinations of normal or BB rat recipients and bone marrow donors, in an attempt to determine the site of the defect(s) leading to diabetes and/or T-cell lymphopoenia in the BB rat.…”

“…Neonatal inoculation of diabetes-prone BB rats with bone marrow cells from a normal strain of rat (creating chimeras) prevents diabetes [6,12,[19][20][21]. In our study [6], mixed lymphocyte cultures and ConA stimulation assays performed with lymphocytes from the recipient …”

“…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.…”

“…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].…”

“…Injection of ConA-activated splenic lymphocytes has been shown to adoptively transfer insulitis and diabetes in young diabetes-prone BB rats [17], or in lines of diabetes-resistant BB rats and Wistar-Furth (WF) rats that have been pretreated with cyclophosphamide [18]. Neonatal inoculation of diabetes-prone BB rats with bone marrow cells from a normal strain of rat (creating chimeras) prevents diabetes [6,12,[19][20][21]. In our study [6], mixed lymphocyte cultures and ConA stimulation assays performed with lymphocytes from the recipient BB rats demonstrated that they had been immunologically reconstituted.…”