It has been proposed that the development of insulin-dependent diabetes is controlled by the T helper 1 (TH1) versus TH2 phenotype of autoreactive TH cells: TH1 cells would promote diabetes, whereas TH2 cells would actually protect from disease. This proposition was tested by establishing cultures of TH1 and TH2 cells that express an identical diabetogenic T cell receptor and comparing their ability to initiate disease in neonatal nonobese diabetic mice. TH1-like cells actively promoted diabetes; TH2-like cells invaded the islets but did not provoke disease--neither did they provide substantial protection.
Insulin-dependent diabetes mellitus results from T cell-mediated destruction of insulin-producing, pancreatic islet  cells. How this destruction takes place has remained elusive-largely due to the slow kinetics of disease progression. By crossing a transgenic mouse carrying a  cell-specific T cell receptor onto the NOD. scid background, we produced a simplified but robust and accelerated model of diabetes. This mouse produces CD4 ؉ T cells bearing transgenic T cell receptor but is devoid of CD8 ؉ T cells and B cells. More importantly, this mouse develops a rapid diabetes, which has allowed us to record and quantify  cell death. We have determined that  cells within the inf lamed islets die by apoptosis.Nonobese diabetic (NOD) mice naturally develop an insulindependent diabetes mellitus (IDDM) with remarkable similarity to that of human IDDM patients (reviewed in refs. 1-3). As a result, NOD mice have become an invaluable tool for studying the underlying immunobiology of IDDM and the complex genetics that control it (4). Through their study, we now know that IDDM results from the selective destruction of insulin-producing, pancreatic  cells. This destruction is coordinated by  cell antigen-specific, CD4ϩ T cells that produce proinflammatory cytokines (5, 6).How  cells are killed is not well understood. This is due to the fact that  cell death is difficult to detect in vivo, due to the slow kinetics of the inflammatory process and the rapid clearance of dead cells from the host. The lymphocytic infiltration, termed insulitis, takes place over several months; early lesions contain predominantly mild insulitis with little loss of  cells. By the time NOD mice show sustained hyperglycemia, Ͼ90% of the total  cell mass is destroyed, making analysis impossible. Therefore, it has been difficult to establish a reproducible window in which to study  cell death in vivo.As a result, a number of groups have sought to study  cell death in vitro, testing, for example, whether several proinflammatory cytokines can kill  cells (for review see ref. 7). No consensus was reached on how  cells died, but interleukin (IL)-1, alone or in combination with interferon-␥ and tumor necrosis factor (TNF)-␣, could inhibit the glucose-induced secretion of insulin and induced the production of the toxin, nitric oxide, by  cells (8)(9)(10)(11)(12)(13)(14). This led to the speculation that local production of IL-1 may play an important role in inducing  cell death (15). While a number of studies have examined the role of cytokines-notably IL-2, IL-10, IL-12, TNF-␣, and interferon-␥-to enhance islet pathology and speed  cell death in vivo (16-23), they have not provided any direct assessment of how  cells are affected and if they, in fact, die. Moreover, it is difficult to appraise how well these cytokine models reflect the natural disease process.We have taken a different approach to studying  cell death. We believed that to realize how  cells die in IDDM, in a physiologically meaningful way, we needed (i) to perform ...
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