Two- and three-color cytofluorimetric techniques were used to study the expression patterns of the activation antigen HLA-DR on peripheral blood immunoregulatory T-cells from 25 patients with newly diagnosed insulin-dependent diabetes mellitus (IDDM) and 14 age- and sex-matched control subjects. The mean percentage of total activated (CD3+HLA-DR+) T-cells was significantly elevated in the IDDM group compared with the control group (P < 0.001). In control subjects, basal activation of CD4+ and CD8+ lymphocytes accounted for the low percentage levels of activated T-cells. In contrast, the majority of IDDM patients showed an unbalanced activation of CD4+ and CD8+ lymphocytes with predominant activation of the CD8+ lymphocyte subset. The composition of the activated T-cell fraction was dependent on the composition of the total (activated + nonactivated) T-cell population, as indicated by the positive correlation between the CD4+/CD8+ T-cell ratios in these two cell populations (r = 0.714; P < 0.001). Excessive activation of CD8+ T-cells was attributable to similar increases in the proportions of CD8+ CD45RA+HLA-DR+ (naive) and CD8+CD45RA-HLA-DR+ (memory) cells. Analysis of the CD11b-defined subsets revealed predominant activation of CD8+ CD11b- (cytotoxic) T-cells; CD8+ CD16+ HLA-DR+ natural killer cells were unchanged. The distribution of HLA-DR+ cells among subsets of CD4+ T-cells differed from the pattern in the CD8+ population in that selective activation of CD4+ CD45RA- (memory, helper-inducer) cells accounted for the small increase in activated CD4+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)
The non-specific activation of the immune system by administration of complete Freund's adjuvant was examined in Wistar rats as a possible means of amplification of the specific immune response directed to pancreatic B cells caused by low dose non-diabetogenic multiple injections of streptozotocin. Rats were given intraperitoneally 0.5 ml of complete Freund's adjuvant to induce polyclonal lymphocyte activation and, 1 day later, the animals were given an intraperitoneal injection of 15 mg streptozotocin/kg body weight (group 1). This combined treatment was given twice at weekly intervals. In two further groups, rats were treated with complete Freund's adjuvant alone (group 2) or streptozotocin alone (group 3) with the same doses and at the same times. Only the rats in group 1 developed delayed but severe and persistent hyperglycaemia. In addition, significant complement-dependent cytotoxicity was detected in nine out of 15 rats (60%) in group 1 in islet cells, but not in spleen lymphocytes. The pancreatic insulin content of the rats in group 1 was depleted by up to 3.1 +/- 0.5%. With these experiments, a new animal model for insulin-dependent diabetes is described; complete Freund's adjuvant/streptozotocin diabetes. In many aspects, this model of diabetes parallels the development of insulin-dependent diabetes in man, including the humoral autoimmunity to islet cell antigens.
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