EFFECT OF CYCLOSPORINE-A ON SERUM TUMOR-NECROSIS-FACTOR-ALPHA IN NEW-ONSET TYPE-1 (INSULIN-DEPENDENT) DIABETES-MELLITUS

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 beta-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 beta-cell function was significantly lower for the CyA-treated group (p < 0.05). Cytokine levels were analyzed retrospectively from frozen (-70-degrees-C) stored sera from both groups. At time 0, tumor necrosis factor alpha (TNFalpha) 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 TNFalpha 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). TNFalpha 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 gamma interferon (gammaIFN) were similar in IDDM and normal subjects, and not different over 6 months in the CyA and placebo groups of IDDM subjects. TNFalpha and other cytokines, including IL-1, IL-6, and gammaIFN have been implicated as possible mediators of islet beta-cell destruction in IDDM. In this study, serum TNFalpha levels fell after 1 month of CyA treatment in newly diagnosed IDDM patients. The effect of CyA to preserve islet beta-cell function better in these patients may be related to decreased production of TNFalpha.