The implementation of a simple, safe and cost-effective treatment protocol is important to improve the pregnancy rate in assisted reproduction. It is particularly important in the case of previous unsuccessful attempts.
It is well known that after placing the embryo into the uterus, the inner membrane (endometrium) releases various substances, proteins, growth factors and they become in contact with the embryo. For the conception in humans, primarily hormonal system regulates endometrium for implantation. Besides, there is evidence suggesting that the maternal immune system also participates in embryo implantation when the egg is fertilized. More than two decades ago, early pregnancy factor was reported to be secreted and influence immune cell function and early events related to development and implantation of the embryo (Clarke, 1992; Morton et al., 1992; Morton, 1998).
Takabatake in 1997, reported that immune cells derived from pregnant mice directly promoted endometrial differentiation in a manner independent of the endocrine system. Later, lymphocytes (some type of immune cells) in the thymus gland derived from non-pregnant mice were also shown to enhance endometrial differentiation to induce embryo implantation, suggesting that some populations of immune cells can affect endometrial differentiation and open the implantation window for the embryo (Fujita et al., 1998). To support this, when endometrial epithelial cells were incubated with autologous peripheral blood mononuclear cells (PBMCs), attachment of BeWo cell spheroids was significantly promoted in endometrial epithelial cell culture. (Kosaka et al., 2003). Furthermore, HCG (basic pregnancy hormone) is able to stimulate chemokine production by PBMC (Kosaka et al., 2002).
Together, these findings suggest that the mother’s immune system supports embryo implantation in the uterus as a complementary pathway and that hormones can induce functional changes in PBMC to facilitate embryo implantation (Fujiwara, 2006).
During implantation of the embryo, maternal immune activation and tolerance are not only limited to the uterus but are also observed in the blood predominantly affecting the innate immune system. Also unexplained female infertility, as well as recurrent pregnancy losses and implantation failure, are thought to be associated with some pathological maternal immune tolerance mechanisms.
There are few effective clinical approaches to infertile patients with repeated failure in IVF. The first scientific clinical research on this subject was published by Yoshioka et al. in 2006 (1). In this therapy, peripheral blood mono-nuclear cells (PBMC) are isolated from the patients and activated by incubation with HCG for two days. Thereafter, PBMC are freshly isolated from the patient again and combined with the cultured PBMC and then these PBMC are administered into the uterine cavity of the patients to induce adequate endometrial differentiation. Three days later, blastocysts are transferred into the uterine cavity. They applied this treatment to patients with repeated failures in IVF therapy and reported that PBMC treatment effectively improved the pregnancy and implantation rates. According to this study clinical pregnancy rate, implantation rate and live birth rate in the PBMC-treated group (41.2, 23.4 and 35.3%; n = 17 respectively) were significantly higher than those in the non-treated group (11.1, 4.1 and 5.5%; n = 18, respectively).
Osamu et al. have shown in 2011 that intrauterine administration of autologous peripheral blood mononuclear cells increases clinical pregnancy rates also in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. (2). Supportive literature on this is given below as 1-2.
In conclusion, intrauterine administration of autologous PBMC may promote implantation and clinical pregnancy rates in patients who had experienced repeated failure of IVF–embryo transfer therapy. Thus, although the precise mechanism remains unknown, intrauterine administration of autologous PBMC may become an effective approach for increasing the pregnancy rate during IVF treatment.
Since recent evidence suggests that some populations of maternal immune cells positively enhance embryo implantation, we offer our patients with repeated implantation failure this supportive treatment to increase their chance of getting pregnant.