Immunotolerance induced by intratesticular antigen priming: expression of TGF-β, Fas and Fas ligand

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Abstract
The authors have previously reported that an injection of Santigen (S-Ag) into rat testes prior to immunization induces systemic tolerance (designated orchidic tolerance) and protects the animals from experimental autoimmune uveoretinitis (EAU) and that the signal for orchidic tolerance induction emigrates from the testis within a few hours after antigen priming of the testis. In order to understand the mechanism by which the signal or signal carrier is generated, they determined in this study changes in immunoreactivity for transforming growth factor-β (TGF-β), IFN-β, IL-2, Fas and Fas ligand in the testis following an injection of S-Ag. Immunoreactivity for TGF-β increased with time, reaching a maximum in six hours and declining thereafter. The time required for the maximum expression of TGF-β coincided well with the time-dependent profile of orchidic tolerance signal generation within the testis. Little or no immunoreactivity was observed for IFN-γ and IL-2 in normal (control) and S-Ag-injected testes. Immunoreactivity for Fas and Fas ligand was detected both in control and experimental testes and did not change appreciably with time following Ag-priming of the testis. Fas immunoreactivity was found in spermatids and virtually absent in the interstitial tissue, while Fas ligand immunoreactivity was primarily associated with the interstitial cells such as Leydig cells. Fas ligand immunoreactivity was very weak, if any, in the germ cells and Sertoli cells. These results suggest that TGF-β and Fas ligand expressed in MHC-positive interstitial cells may play an important role in the generation of orchidic tolerance induction signal. A preliminary study showed that splenocytes preincubated with testis extracts and S-Ag, when transferred to naive rats, induced systemic tolerance in recipient animals. Inclusion of anti-TGF-β or a carboxyl terminal peptide of Fas in the testis extract reduced the potency of incubated splenocytes to induce systemic tolerance in recipient rats. These results indicate that generation of the orchidic tolerance signal does not require the anatomical structure of the testis but is mediated by molecular entities such as TGF-β and Fas ligand.