Imbalance of the interleukin 2 system in children with IDDM

Abstract

The IL-2 system which involves IL-2 production, IL-2 receptor expression, and response to IL-2, is associated with autoimmune phenomena. Immunological abnormalities including autoimmune phenomena are believed to contribute to the pathogenesis of IDDM. In this study, the production of IL-2, the responses to IL-2 and IL-2 receptor expression by peripheral blood T lymphocytes were compared in IDDM and normal non-diabetic children. The percentage of IL-2 receptor-positive circulating T cells was significantly increased in diabetic children, although IL-2 receptor expression induced by con A stimulation did not differ in the diabetic and control children. IL-2 production was significantly decreased in diabetic children compared with the control children. The response of stimulated T cells to IL-2 did not differ in IDDM and control children. In IDDM, IL-2 production by CD4-positive T lymphocytes within the IL-2 system is thought to be selectively defective. On the other hand, IL-4, which is also produced by CD4-positive T lymphocytes, was increased. Since IL-4 did not suppress IL-2 production, it would seem that the IL-2 producing subset in CD4+HLA-DR+ T cells is decreased in IDDM. These results suggest that in recent onset IDDM, IL-2 receptor-positive circulating T cells require an IL-2 supply.

Decreased Secretion of Th2 Cytokines Precedes Up-regulated and Delayed Secretion of Th1 Cytokines in Activated Peripheral Blood Mononuclear Cells from Patients with Insulin-Dependent Diabetes Mellitus

“…The novel approach demonstrated in this study is supported by data showing IL-2 secretory patterns that differed significantly in the two groups, even though patients and controls were comparable in their peak levels and total production of IL-2. This may also explain why other investigators, who determined the stimulated level of IL-2 as well as IFN-in IDDM patients at earlier time points, reported lower levels of these cytokines [4,7,10,11]. Our results enhance the importance of a comprehensive cytokine analysis, including total secretory capacity and secretory pattern analysis, when compared to the limited peak level determination.…”

“…Previous reports examining the secretion of different cytokines in human IDDM patients were limited mostly to IL-2 determination, providing evidence for defective secretion of IL-2 in in vitro-stimulated PBMC [4][5][6][7]. The plasma levels and stimulated secretion of other cytokines including IFN-, IFN-, TNF-, IL-1 and IL-6 were found comparable in patients and controls [8][9][10].…”

“…They also demonstrate that the failure of IDDM patients to mount an early Th2 response results in an uninhibited late increase in Th1. In contrast to previous reports, where cytokine levels in IDDM patients were sampled only once after stimulation [4][5][6][7][10][11][12], we examined stimulated secretion over time. This enabled us to introduce two innovative parameters: cytokine secretory pattern and total cytokine production, and to provide a more comprehensive analysis of the Th1/Th2 imbalance in IDDM patients.…”

“…An association between decreased T cell/PBMC proliferative response and aberrant secretion of diverse cytokines, including IL-2 and IL-4, has been reported in diabetic patients and prediabetic NOD mice [4][5][6][7]17]. Therefore, we examined whether the aberrant secretory profile of Th1/Th2 cytokines in our IDDM patients was associated with an abnormal PBMC proliferative response.…”

Altered Natural Killer Cells in Type 1 Diabetic Patients

“…One explanation might be impaired secretion of cytokines modulating NK cell function. Interestingly, it was previously suggested that individuals with type 1 diabetes exhibit a deficient production of interleukin-2, a potent NK cell stimulator (35,36). On the other hand, serum levels of interleukin-15 and -12, other molecules implicated in NK cell physiology, were found to be elevated in patients with type 1 diabetes (37,38).…”