Effect of cyclosporine a on serum tumor necrosis factor α in new-onset type I (insulin-dependent) diabetes mellitus

Abstract

Because the etiology of insulin-dependent diabetes mellitus (IDDM) is thought to be autoimmune, several clinical trials have utilized immunosuppression to treat newly diagnosed diabetic patients. In the University of Miami trial, cyclosporine A (CyA) was used to treat one group ( n = 10), while the other received placebo ( n = 13). During the 1-year study, islet β-cell function was better preserved in the CyA group compared to the placebo group, based on the response (C-peptide production) to a physiologic stimulus (meal challenge). Specifically, when measured by regression analysis, the slope defining the rate of decline of β-cell function was significantly lower for the CyA-treated group ( p < 0.05). Cytokine levels were analyzed retrospectively from frozen (−70°C) stored sera from both groups. At time 0, tumor necrosis factor α (TNFα) levels were similar in the Cya (40.1 ± 14.2 pg/mL) and placebo group (38.5 ± 12.1 pg/mL) of IDDM subjects (normal 32.0 ± 5.0 pg/mL). At 1 month, the level of TNFα in the CyA group was significantly lower than that observed in the placebo group (22.3 ± 7.2 versus 53.3 ± 8.9 pg/mL ( P < .05). TNFα levels subsequently fell in the placebo group and were not significantly different between placebo and CyA groups. Soluble interleukin 2 receptor (IL-2R) levels in IDDM patients were significantly higher than in normal subjects at diagnosis of IDDM. For the next 6 months, these levels fell consistently in both the CyA and placebo groups. Serum interleukin 2 (IL-2) levels in IDDM subjects were higher than normal at the time of diagnosis of IDDM, but were not statistically different between groups over the 6-month period. Serum levels of interleukin 6 (IL-6) and γ interferon (γIFN) were similar in IDDM and normal subjects, and not different over 6 months in the CyA and placebo groups of IDDM subjects. TNFα and other cytokines, including IL-1, IL-6, and γIFN have been implicated as possible mediators of islet β-cell destruction in IDDM. In this study, serum TNFα levels fell after 1 month of CyA treatment in newly diagnosed IDDM patients. The effect of CyA to preserve islet β-cell function better in these patients may be related to decreased production of TNFα.