MURINE POSTTHYMECTOMY AUTOIMMUNE OOPHORITIS DEVELOPS IN ASSOCIATION WITH A PERSISTENT NEONATAL-LIKE TH2 RESPONSE

Autoimmune oophoritis develops in some patients despite evidence of im paired cellular immunity. Here, using the murine postthymectomy model of autoimmune oophoritis, we investigate the hypothesis that neonatal thymectomy induces autoimmune oophoritis by disrupting the normal post natal balance of T helper cell regulation. Stimulated CD4(+) splenic l ymphocytes from adult mice sham-operated as neonates produced the expe cted T helper type 1 (Th1) predominant response normally seen in adult mice (low levels of interleukin-4 and high levels of interferon gamma ). In contrast, cells from adult mice thymectomized as neonates produc ed an inappropriate neonatal-like Th2-predominant response (high level s of interleukin-4 and low levels of interferon-gamma). Manipulations that restored the postnatal shift to an adult Th1-dominant pattern ame liorated the autoimmune oophoritis. Thus, neonatal thymectomy abrogate s the postnatal shift to a Th1-dominant pattern, and the resulting per sistent neonatal-like Th2-dominant response is tightly associated with the development of postthymectomy autoimmune oophoritis. These result s (i) suggest that the postnatal shift to the normal adult Th1/Th2 bal ance is established by a thymus-dependent process and (ii) raise the p ossibility that specific genetic defects, as yet to be determined, mig ht mimic the effect of neonatal thymectomy in this model, impair the d evelopment of normal Th1/Th2 balance, and be a cause autoimmunity. The se results hold implications for the pathogenesis and possibly for the therapy of autoimmune polyglandular failure in humans. (C) 1997 Acade mic Press.