Mechanisms of cyclosporine protection against spontaneous diabetes mellitus in the BB/W or rat.

Anti-islet cell-mediated immunity in the Bio-Breeding/Worcester (BB/Wor) rat was studied by measuring the cytotoxic activity of splenic lymphoid cells from diabetes-prone (DP) rats receiving either oral cyclosporine (Cy-A, 10 mg/kg/d) or olive oil vehicle (DP control) from age 40 to 105 d. Splenic cells were incubated with concanavalin A (Con-A) for 16 h, then used as effector cells in cytotoxicity assays with 51Cr labeled cells from a rat islet cell line (RIN) as targets. Lysis of RIN cells (% 51Cr release) by Con-A-activated splenic cells from control DP rats increased from age 40 d (5.4 +/- 1.6%) to 105 d (32.7 +/- 1.8%). This increase was significantly less in Cy-A-treated DP rats (14.5 +/- 3.2%) and remained low at 15 d after stopping Cy-A (14.8 +/- 2.5%). Diabetes developed in control DP rats between 74 and 120 days of age, and in none of the Cy-A-treated DP rats by age 105 d, nor for 15 d after stopping Cy-A. The Con-A-activated splenic cells responsible for lysis of RIN cells also lysed normal rat islet cells and had the functional and phenotypic properties of natural killer (NK) cells. In contrast to the lower Con-A-inducible NK cell cytotoxic activity in Cy-A-treated DP rats, basal NK cell activity and monoclonal antibody-defined NK cell subsets were increased in the Cy-A-treated DP rats. Therefore, Cy-A had inhibited the ability of NK cells to respond to cytotoxic activation despite their increased numbers. To investigate the mechanism(s) of the protective effect of Cy-A, we examined the direct effects of Cy-A in vitro. Cy-A (100 ng/ml) inhibited completely Con-A activation of DP splenic cells cytotoxic to islet cells, and this was accompanied by a similar inhibition of interleukin-2 (IL-2) production. Also Cy-A (300 ng/ml) inhibited partially (approximately 65%) IL-2 activation of DP splenic cells cytotoxic to islet cells. In addition, Cy-A inhibited the cytotoxic effects of DP cells previously activated by Con-A, and 300 ng/ml Cy-A produced a maximum inhibition of 47 +/- 5%.(ABSTRACT TRUNCATED AT 400 WORDS)