ORIGINAL ARTICLE: Serial Estimation of Th1:Th2 Cytokines Profile in Women Undergoing In‐Vitro Fertilization‐Embryo Transfer

Abstract

Problem To investigate changes in the ratio of T‐cell subpopulations expressing intracellular T helper1 (Th1) and T helper 2 (Th2) cytokines in women with a history of recurrent failed implantation under going in‐vitro fertilization (IVF)‐embryo transfer. Method of study Twenty‐eight peripheral blood samples were obtained at two time points, from 14 women undergoing IVF treatment; eight women with a history of recurrent failed implantation, who did not get pregnant in the index IVF cycle and six who had one or more previous successful IVF pregnancy and who became pregnant in the index IVF cycle. The proportion of lymphocytes expressing interferon‐gamma (IFN‐γ), tumour necrosis factor‐alpha (TNF‐α), and interleukin 4 (IL‐4) and the Th1:Th2 ratios of IFN‐γ:IL‐4, and TNF‐α:IL‐4 in T helper cells was measured by flow cytometry, in samples obtained before commencing IVF treatment and in samples obtained after ovarian stimulation (on the day of oocyte retrieval). Results In samples collected during oocyte retrieval, women with a history of recurrent failed implantation had a higher IFN‐γ:IL‐4 and TNF‐α:IL‐4 ratio than the control group, (18.6 ± 9.3 versus 6.47 ± 1.68, P = 0.009) and (39.1 ± 15.7 versus 11.53 ± 3.76, P = 0.001) respectively. In women with a history of recurrent failed implantation the ratio of IFN‐γ:IL‐4 and TNF‐α:IL‐4 at oocyte retrieval was higher than pre‐treatment ratios (18.6 ± 9.3 versus 12.01 ± 9.8, P = 0.018) and 39.10 ± 15.7 versus 18.66 ± 11.42, P = 0.010) respectively, showing a Th1 bias. In women with a successful IVF the converse was true; the ratio at oocyte retrieval was significantly lower than pre‐treatment ratios (6.47 ± 1.68 versus 9.37 ± 6.8, P = 0.035) and 11.53 ± 3.76 versus 18.60 ± 12.9, P = 0.027) respectively, representing a Th2 bias. Conclusion Women with a history of unexplained recurrent failed IVF treatment have a Th1 bias and this polarization is more enhanced following hormonal manipulations during IVF treatment. Comparing pre‐treatment ratios of IFN‐γ:IL‐4 and TNF‐α:IL‐4 to ratios obtained at oocyte retrieval may be clinically useful. Women with recurrent failed IVF have increasing ratios.

Immunological status in patients undergoing in vitro fertilisation: responses to hormone treatment and relationship to outcome

“…In support of our findings, previous studies have found a gradual increase of serum macrophage colony-stimulating factor (M-CSF) and granulocyte colonystimulating factor (G-CSF) throughout ovarian stimulation in IVF cycles (Nishimura et al, 1998;Salmassi et al, 2005;Salmassi et al, 2010). IFN-γ, IL-4 and TNF have been studied after lymphocyte activation with PMA/ionomycin before and after ovarian stimulation (Kalu et al, 2008), and IL-10 has been analyzed in serum during IVF treatment (Wu et al, 2001). …”

“…Several observations suggest that Th1 cytokines are harmful to human pregnancy and may lead to pregnancy loss as early as at implantation (Kwak-Kim et al, 2003;Kalu et al, 2008;Hudic and Fatusic, 2009). Furthermore, although less studied, Th17-like immunity has been associated with recurrent miscarriage (Wang et al, 2010a;Wang et al, 2010b).…”

“…Several similar studies indicate a Th1 bias among women with pregnancy losses, whereas successful pregnancies are associated with increased Th2 responses (Piccinni et al, 1998;Makhseed et al, 2001;Kwak-Kim et al, 2003;Kalu et al, 2008;Hudic and Fatusic, 2009). …”

“…Strong mitogenic stimuli such as PMA/ionomycin (Piccinni et al, 1998;Kwak-Kim et al, 2003;Sacks et al, 2003;Kalu et al, 2008) or PHA (Makhseed et al, 2001), as well as trophoblast cell line extracts (Raghupathy et al, 1999;Ginsburg et al, 2005) have previously been used as stimuli, whereas we here wanted to investigate paternal antigen-induced responses during in vitro fertilization (IVF) treatment.…”

Immunogenetic contributions to recurrent pregnancy loss

“…These cells also release IFN-γ to promote inflammation. It has been shown to be elevated in RPL patients [13,72,78,79,124]. Significant associations between RPL and the IFN-γ(+874) polymorphisms have been found [115,119,120].…”