Azathioprine associated T-cell mutations in insulin-dependent diabetes mellitus

Somatic mutations arise regularly in human T lymphocytes. As these events o ccur at increased frequencies in several autoimmune disorders, presumably b ecause of increased T-cell proliferation, we investigated if this is also t rue for insulin-dependent diabetes mellitus (IDDM). Mutations of the hypoxa nthine guanine phosphoribosyltransferase (hprt) gene measured by 6-thioguan ine (TG) selection were studied in 28 patients (60 determinations) enrolled in a prospective double-blinded placebo-controlled study of azathioprine i mmunosuppression: 17 patients (34 determinations) were receiving azathiopri ne and 11 (26 determinations) placebo. Mean hprt T-cell mutant frequencies (MFs) were elevated in both patient groups, but only in the azathioprine gr oup were elevations large and statistically correlated with the duration of the therapy. These results suggest that the organ-specific antigenic stimu lus of the T-cell proliferation in IDDM does increase mutant cells in the p eripheral blood, but this increase is relatively small. However, azathiopri ne, which is converted to 6-mercaptopurine in vivo, selects and amplifies t he hprt mutants that do arise. Clinical azathioprine resistance may be expl ained by hprt mutations arising in T cells relevant to the underlying autoi mmune process. Monitoring for these mutations should allow more effective u se of this immunosuppressive agent.