Effect of Helper and/or Cytotoxic T-Lymphocyte Depletion on Low-Dose Streptozocin-Induced Diabetes in C57BL/6J Mice

Abstract

The low-dose streptozocin (STZ) model of diabetes has been reported to involve direct STZ beta-cytotoxicity and/or immunologically mediated β-cell destruction. Because the T-lymphocyte dependency of such a model is controversial, we further assessed the role of T-lymphocytes by determining the occurrence and magnitude of hyperglycemia as well as the pancreatic insulin contents in both STZ-injected nude C57BL/6J male mice and STZ-injected euthymic C57BL/6J male mice selectively depleted in helper and/or cytotoxic T-lymphocytes with monoclonal antibodies (MoAbs). The effectiveness of MoAb treatment was assessed in lymph node cells by flow-microfluorometry analysis and in spleen cells by concanavalin A stimulation, allospecific cytotoxic T-lymphocyte activity, and T-lymphocyte lymphokine production. Sixteen days after the first STZ injection, hyperglycemia (plasma glucose > 200 mg/dl) occurred in significantly fewer helper T-lymphocyte-depleted mice (P < .005) or helper and cytotoxic T-lymphocyte–depleted mice (P < .001) than in non–MoAb-treated mice. However, a progressive increase in the number of mice with hyperglycemia ensued in all MoAb-treated groups, and 2 mo after STZ was administered, the prevalence of hyperglycemia, mean plasma glucose levels, and pancreatic insulin contents did not differ significantly from the values obtained in the non–MoAb-treated animals. Similarly, STZ-injected C57BL/6J male nude mice developed hyperglycemia that was associated with a marked decrease in pancreatic insulin contents on a time course comparable with that of STZ-injected euthymic C57BL/6J male mice depleted in helper or in helper and cytotoxic T-lymphocytes by MoAbs. Thus, selective helper T-lymphocyte depletion, either genetic or induced by MoAb treatment, although able to temporarily protect mice from the development of hyperglycemia, did not prevent the ultimate loss of the β-cell mass initiated by the direct toxic effect of STZ.