CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY Vol. 83, No. 3, June, pp. 230–236, 1997 Article No. II974338 Murine Postthymectomy Autoimmune Oophoritis Develops in Association with a Persistent Neonatal-like Th2 Response Rita Maity,* Rachel R. Caspi,† Sharmila Nair,* Luiz V. Rizzo,† and Lawrence M. Nelson* *Section on Women’s Health, Developmental Endocrinology Branch, NICHD, and †Laboratory of Immunology, NEI, NIH, Bethesda, Maryland 20892 of patients with premature ovarian failure (10). As a Autoimmune oophoritis develops in some patients group, patients with premature ovarian failure have despite evidence of impaired cellular immunity. Here, increased activation of peripheral T lymphocytes (11 – using the murine postthymectomy model of autoim- 13). Curiously, however, despite this evidence of im- mune oophoritis, we investigate the hypothesis that mune activation, these patients have an impaired im- neonatal thymectomy induces autoimmune oophoritis mune response to candida antigen (13). In fact, many by disrupting the normal postnatal balance of T helper patients with autoimmune polyglandular failure type cell regulation. Stimulated CD4 / splenic lymphocytes 1, which can include autoimmune oophoritis, have as- from adult mice sham-operated as neonates produced sociated chronic mucocutaneous candidiasis (14). the expected T helper type 1 (Th1) predominant re- Women with premature ovarian failure are also known sponse normally seen in adult mice (low levels of in- to have reduced NK cell activity in the peripheral blood terleukin-4 and high levels of interferon gamma). In (13, 15). This paradoxical association of organ-specific contrast, cells from adult mice thymectomized as neo- autoimmunity on one hand, and an impaired cellular nates produced an inappropriate neonatal-like Th2- immune response on the other, suggests that these pa- predominant response (high levels of interleukin-4 tients have a basic defect in immune regulation. and low levels of interferon-gamma). Manipulations Murine postthymectomy autoimmune oophoritis pro- that restored the postnatal shift to an adult Th1-domi- vides a useful model to study the immune mechanisms nant pattern ameliorated the autoimmune oophoritis. Thus, neonatal thymectomy abrogates the postnatal involved in the development of autoimmune ovarian shift to a Th1-dominant pattern, and the resulting per- failure (16 – 19). Murine ovarian lymphocytic infiltra- sistent neonatal-like Th2-dominant response is tightly tion is typically well established by 4 weeks after associated with the development of postthymectomy thymectomy (20), and the thecal and stromal location autoimmune oophoritis. These results (i) suggest that of the infiltration is similar to that seen in human auto- the postnatal shift to the normal adult Th1/Th2 bal- immune oophoritis (20). The model also resembles hu- ance is established by a thymus-dependent process man premature ovarian failure in that susceptibility and (ii) raise the possibility that specific genetic de- to the disorder is associated with genes outside the fects, as yet to be determined, might mimic the effect major histocompatibility complex (21 – 23), and, as in of neonatal thymectomy in this model, impair the de- the human disorder, there is an associated reduced NK velopment of normal Th1/Th2 balance, and be a cause cell activity (24). autoimmunity. These results hold implications for the Mice thymectomized on Day 2 to 4 of life, but not pathogenesis and possibly for the therapy of autoim- later, develop a strain-specific constellation of organ- mune polyglandular failure in humans.  1997 Academic specific autoimmunity against the ovary, thyroid, or Press gastric parietal cells (17). It has been proposed that neonatal thymectomy abrogates the development of regulatory CD4 / splenic lymphocytes that normally INTRODUCTION prevent autoimmunity (25 – 28). However, the mecha- nisms of this CD4 / regulation, and the reason why the Autoimmune oophoritis causes young women to de- timing of thymectomy is so critical, are unclear (29). velop amenorrhea, infertility, hot flashes, vaginal dry- Here we investigate the hypothesis that murine neo- ness, and elevated gonadotropins (1, 2), findings nor- natal thymectomy induces autoimmune oophoritis by mally associated with menopause. One percent of disrupting the normal postnatal balance of T helper women develop premature ovarian failure by age 40 cell regulation (30 – 32). T helper cell balance involves (3), and autoimmune oophoritis is a well-established two subsets of murine CD4 / lymphocytes, T helper 1 mechanism of this disorder (4–9). (Th1) and Th2. These cells reciprocally regulate cellu- Indirect evidence suggests that autoimmunity is the mechanism of ovarian failure in a substantial portion lar and humoral immune reactions by secreting distinct 230 0090-1229/97 $25.00 Copyright  1997 by Academic Press All rights of reproduction in any form reserved. AID Clin 4338 / a510$$$141 04-21-97 22:08:23 clinal AP: Clin