A simple, direct assay for T-lymphocyte reactivity to islet antigen(s) in human insulin-dependent diabetes mellitus (IDDM) should facilitate preclinical diagnosis and the evaluation of intervention therapy to avert autoimmune-mediated β-cell destruction. In subjects with preclinical or clinical IDDM, we measured the reactivity of peripheral blood mononuclear cells (PBMCs) incubated over 6 days with either adult human islets or fetal pig proislets, or other fetal pig tissues, and with human insulin. With islets, the stimulation index (SI) of [3H]thymidine uptake by PBMCs exceeded the mean + 2SD of control subjects in 6 of 6 preclinical subjects (SI 8.7 ± 3.7), 7 of 11 clinical subjects (SI 5.2 ± 3.4), and 1 of 12 control subjects (SI 2.7 ± 1.7); with insulin, the responses were less in frequency and magnitude, being 4 of 6 (2.7 ± 1.6), 3 of 11 (2.2 ± 1.1), and 0 of 12 (1.20 ± 0.55), respectively. The mean responses to islets of PBMCs from preclinical and clinical subjects differed significantly from control subjects (P < 0.02 by 2-tailed Kruskal-Wallis test). Secretion of granulocyte macrophage colony–stimulating factor by PBMCs over 6 days was assayed in the preclinical group and generally paralleled the uptake of [3H]thymidine. PBMC reactivity to islets appeared to be at least as sensitive a marker of preclinical IDDM as autoantibodies to a 64,000-Mr protein, presumably the enzyme glutamic acid decarboxylase, in fetal pig proislets. In conclusion, islet-reactive T lymphocytes in subjects with preclinical and clinical IDDM can be identified in bulk culture of PBMCs. Detection of these autoreactive T lymphocytes should be of value in the diagnosis of preclinical IDDM and in monitoring the effects of immunotherapy.

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