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Due to the expression of paternal antigens by the embryo, pregnancy is considered as a semi-allograft and so immunological dysregulation is considered as one of the important causes in repeated implantation failure (RIF) and recurrent pregnancy loss (RPL). It has been revealed that lymphocytes immunotherapy (LIT) could be an appropriate approach to prevent pregnancy loss in such patients. Various mechanisms have been suggested for effectiveness of LIT such as enhancing expression of anti-paternal cytotoxic antibodies (APCA), progesterone-induced blocking factor (PIBF), anti-idiotypic antibodies (Ab2), and mixed lymphocyte reaction blocking antibodies (MLR-Bf), as well as reduction in the T helper 1/T helper 2 ratio and deviation in the pattern of cytokines production. However, there are controversial results about the beneficial effect of LIT treatment in RIF and RPL patients. In the current study, we reviewed findings of LIT in RIF and RPL patients with a focus on possible mechanisms of alloimmunization in preserving pregnancy. Besides, we highlighted possible reasons for mixed results about the effectiveness of LIT and way of solving the problem. Also, we proposed potential laboratory and clinical criteria to recruit patients for LIT.

Placental growth factor (PlGF) is an angiogenic factor which belongs to vascular endothelial growth factor (VEGF) family. In addition to the angiogenic function of PlGF, in some conditions such as preeclampsia and early pregnancy losses, it can induce inflammatory reactions which could be accompanied with reduced angiogenesis. Hence, it is crucial to investigate inflammatory and angiogenic switching states and understand underlying mechanisms. PlGF is expressed in endometrium, placenta and trophoblast cells and is involved in maturation of uterine NK cells. Up-regulation of PlGF directs VEGF to VEGFR-2 and reinforces angiogenesis. However, when VEGF/VEGFR-2 signaling pathway is impaired, PlGF may shift to severe inflammation and cause tissue damages which could lead to early pregnancy losses. Downregulation of PlGF has also been reported in pregnancy complications. In this review, we discussed the role of PlGF in embryo implantation failure and early pregnancy loss and also possible mechanisms regarding the role of PlGF in angiogenic/inflammatory switching in early pregnancy losses. Furthermore, we summarized the effects of various compounds on PlGF expression and briefly talked about its therapeutic potential that may be an opportunity for prevention of pregnancy loss.

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During embryo implantation, crosstalk between the endometrial epithelium and the blastocyst, especially the trophoblasts, is a prerequisite for successful implantation. During this crosstalk, various molecular and functional changes occur to promote synchrony between the embryo and the endometrium as well as the uterine cavity microenvironment. In the past few years, growing evidence has shown that endometrium-derived exosomes play pivotal roles in the embryonic-maternal crosstalk during implantation, although the exact mechanism of this crosstalk has yet to be determined. The presence of metalloproteinases has been reported in endometrium-derived exosomes, implying the importance of these enzymes in exosome-based crosstalk. Thus, in this review, we describe the potential roles of the metalloproteinases of endometrium-derived exosomes in promoting embryo attachment and implantation. This study could provide a better understanding of the potential roles of exosomal metalloproteinases in embryo implantation and pave the way for developing novel exosome-based regulatory agents to support early pregnancy.

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