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Figure 2 | Journal of Ovarian Research

Figure 2

From: Reinterpretation of evidence advanced for neo- oogenesis in mammals, in terms of a finite oocyte reserve

Figure 2

Hypothesis for the restoration of fertility in CT-treated female mice following BMT. (A) Self-tolerance to ovarian antigens during homeostasis. In the steady-state ovary, antigens produced by apoptotic oocytes in atretic follicles [126] constitutively stimulate Treg to suppress an autoreactive T cell response and maintain self-tolerance [127, 128]. Thus, low-level apoptosis protects against autoimmunity [131]. (B) Ovotoxic CT precipitates autoimmunity via increased apoptosis and CY-induced Treg depletion. The ovotoxic CT combination of CY and BU [12, 13] enhances oocyte apoptosis and antigen release, promoting autoimmunity [131]. Moreover, specific effects of CY, namely augmentation of effector T-cell stimulation and reduction of Treg numbers and function [132], stimulate autoimmunity to ovarian antigens. A proportion of oocytes may survive CT-induced damage, but the switch to autoreactivity causes their immune clearance and ovarian failure. (C) Restoration of self-tolerance by BMT. In the mouse with developing autoimmunity to ovarian antigens caused by CT, suppressive Treg function - and therefore self-tolerance - is restored by haematopoietic chimaerism following syngeneic BMT. Consequently, any undamaged primordial follicles avoid immune clearance, sustaining fertility. That beneficial effects on fertility are absent when BMT is postponed from 1 week to 2 months following CT [13] accords with a temporal window for donor Treg to suppress autoimmunity efficiently, beyond which an autoreactive T cell response predominates [132]. (D) Parabiosis. This hypothesis predicts that in the parabiotic system of Eggan et al. [14], where CT-treated female mice were connected to untreated partners (1 d later) by their circulations, priming of an ovarian autoreactive T cell response in the CT-treated mouse would be suppressed by functional Treg infiltrating from the untreated mouse, thereby imposing dominant self-tolerance in both parabionts. The use of superovulation to measure ovarian function [14] may have precluded detection of restoration of fertility in CT-treated mice by parabiosis, and in CT-treated (nonparabiotic) mice by BMT (see section 3.(D)).

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