OBJECTIVE: Fetal-maternal immune adaptation is pivotal for pregnancy success. The human placenta minimizes maternal immunological rejection towards the semi-allogenic fetus. In OD pregnancies, the fetal-placental district is fully allogenic to the mother since the oocyte derives from a donor woman. Placental immunoregulatory functions are mainly mediated by IDO1 and IDO2 enzymes whose activation is the rate-limiting step in catabolism of tryptophan that produces kynurenine which supports maternal immune tolerance. IDO1 and 2 transcription is activated by Interferon-ɣ (IFN-ɣ), Interleukin 18 (IL18) and Tumor Necrosis Factor-α (TNFα) and inhibited by IL18 Binding Protein (IL18-BP). In the present study, we investigated placental expression of IDO1, IDO2, IFN-ɣ IL18, TNFα, and IL18-BP in spontaneous pregnancies (CTRL) and in homologous and heterologous Assisted Reproductive Technology (ART) pregnancies to define differences in the placenta-mediated mechanisms of semi-allogenic or allogenic fetal-maternal acceptance characterizing successful pregnancies.
METHODS: Placentae from CTRL (n=12), homologous (n=15) and heterologous (n=7) ART pregnancies were collected. Placental biopsies were processed for mRNA and protein isolation. IDO1, IDO2 and TNFα gene expressions were evaluated using Real Time PCR. IL18, IL18-BP and IFNɣ protein expression were evaluated using competitive Enzyme-Linked ImmunoSorbent Assay (ELISA).
RESULTS: In heterologous ART placentae, we found a significant IDO1 (p=0.04 and p=0.017), IDO2 (1.48 and 0.91 Fold Increase) and TNFα (1.8 and 2.1 Fold Increase) gene expression increase relative to CTRL and homologous ART pregnancies. No differences were reported in IL18, IL18-BP and IFNɣ protein expression levels (p>0.05) among groups.
CONCLUSION: IDO1, IDO2 and TNFα over-expressions in heterologous ART pregnancies suggest that the OD placenta compensates the presence of an allogenic fetus facilitating maternal acceptance. However, this mechanism is not mediated by IL18, IL18-BP and IFNɣ suggesting an alternative epigenetic regulation of IDO pathway. Further investigations are required.