Abstract
The nonobese diabetic (NOD) mouse develops a high incidence of autoimmune diabetes and is believed to be a good model for insulin-dependent diabetes mellitus (IDDM) in humans. We isolated T-lymphocyte lines from islets of newly diabetic NOD mice, some of which are autoreactive to NOD spleen cells. Because autoreactive T-lymphocytes have been implicated in immune suppression, we injected NOD mice with an autoreactive T-lymphocyte line. The injected mice had a marked decrease in incidence of IDDM compared with control mice. Moreover, their islets showed no insulitis at 1 yr of age. We conclude that autoreactive T-lymphocytes can prevent the development of IDDM in NOD mice. This result suggests that 1) islets contain both effector cells capable of damaging pancreatic beta-cells and cells able to regulate this autoimmune response, and 2) development of IDDM depends on the balance between these opposing forces.
Highlights
The nonobese diabetic (NOD) mouse develops a high incidence of autoimmune diabetes and is believed to be a good model for insulin-dependent diabetes mellitus (IDDM) in humans
The proliferative response of the islet-derived T-lymphocyte line PR-3 is shown in Fig. 1, with splenocytes or islets from strains of the following MHC genotypes used as stimulators: NOD {KdAN0DE-Db), BALB/c {KdAdEaDd), B10.BR {KkAkEkDk), and B10.GD (KdAdE-Db), where E~ means no expression of I-E molecules
We show that autoreactive T-lymphocytes are present in NOD islets by isolating such cells as T-lymphocyte lines
Summary
The NOD mouse develops insulitis followed by p-cell destruction leading to IDDM. To study the lymphocytes infiltrating the islet, we isolated islets from newly diabetic female NOD mice and derived T-lymphocyte lines from these islets. Lymphokine production by PR-3 on stimulation by NOD spleen cells or mitogens was determined from mRNA analysis and biological assays; PR-3 produces IL-2 and IFN-7 but not IL-4 These results demonstrate that the PR-3 T-lymphocyte line is composed of autoreactive CD4 T-lymphocytes belonging to the Th1 Tlymphocytes. In an initial in vivo experiment, groups of 15 nondiabetic 5-wk-old female NOD mice received a single injection of 107 PR-3 cells or saline. In the control group, which had received saline, animals first developed IDDM at 90 days of age, and by 210 days, 80% had the disease This is similar to the incidence of IDDM in untreated NOD mice in our colony. Groups of animals received monthly treatments with 107 PR-3 cells, saline, or 107 young NOD splenic T-lymphocytes (Fig. 2). All islets examined from nondiabetic NOD mice treated monthly with the autoreactive PR-3 T-lymphocyte line had no lymphocytes inside or surrounding the islets (Fig. 38)
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