Immune cells in uteroplacental tissues throughout pregnancy: a brief review.

In a brief introduction, this review states why the presence of immune cells at the interface poses problems for an immunologist (Medawar paradigm). Different types of placentation are then discussed, and the various interactions with leukocytes, the extreme being with the equids where a certain degree of 'attack' is often seen. The limits of animal models when dealing with the human situation are emphasized. It is then stated why the various phases of pregnancy are different, and an analysis made of the cellular movements at the implantation, peri-implantation, immediate post-implantation and resorption windows in rodents. Details of the cellular components involved are given, as are hints for the human situation. The Th1/Th2 paradigm is described, with clinical examples, and its limits. Thus, the newly appraised dual role of natural killer (NK) cells is discussed, with examples in rodents and in humans (pre-eclampsia, implantation failure, abortion systems). Clinical data on the IL-12/IL-18/NK tripod and implantation failure in humans are detailed.

Immune cells in uteroplacental tissues throughout pregnancy: a brief review.

In a brief introduction, this review states why the presence of immune cells at the interface poses problems for an immunologist (Medawar paradigm). Different types of placentation are then discussed, and the various interactions with leukocytes, the extreme being with the equids where a certain degree of 'attack' is often seen. The limits of animal models when dealing with the human situation are emphasized. It is then stated why the various phases of pregnancy are different, and an analysis made of the cellular movements at the implantation, peri-implantation, immediate post-implantation and resorption windows in rodents. Details of the cellular components involved are given, as are hints for the human situation. The Th1/Th2 paradigm is described, with clinical examples, and its limits. Thus, the newly appraised dual role of natural killer (NK) cells is discussed, with examples in rodents and in humans (pre-eclampsia, implantation failure, abortion systems). Clinical data on the IL-12 /IL-18/NK tripod and implantation failure in humans are detailed.

Cytokines and implantation.

This review introduces the field of cytokines and implantation and then recalls the specialized role of the uterus and the notion of the 'implantation window'. The role of inflammatory and angiogenic cytokines is presented, as well as the involvement of cytokines such as -interferons in corpus luteum maintenance in non-chorionic gonadotrophin-producing species. -Interferons are reviewed, before dealing with the more in depth analysis of cytokine networks in the pre- and peri-implantation uterus. The emerging involvement of cytokines in controlling uterine vascularization angiogenesis is reviewed, with emphasis on NK activating factors.

Immunological similarities between implantation and pre-eclampsia.

PROBLEM: Cytokines are involved in implantation success and failure. We envisage that they could be similarly involved in pre-eclampsia (PE). MATERIALS AND METHODS: First, we review the primipaternity and primiparity concepts and then why natural killer (NK) cells are involved in implantation. We stress that the common event in all PE is vascular remodelling. RESULTS AND CONCLUSION: We conclude that PE could involve cytokine and/or NK dysfunctions, and propose a working hypothesis.

Role of the endometrial tripod interleukin-18, -15, and -12 in inadequate uterine receptivity in patients with a history of repeated in vitro fertilization-embryo transfer failure.

OBJECTIVE: To document in the endometrium the correlation among the interleukin (IL)-12, -15, and -18 mRNA and the correlation between cytokine levels, vascular status, and endometrial natural killer (NK) cell count in the context of recurrent implantation failure. DESIGN: A pilot study. SETTING: Department of Reproductive Immunology. PATIENT(S): Women who failed to become pregnant after repeated IVF-embryo transfer and fertile control subjects. INTERVENTION(S): Ultrasonic evaluation and endometrial biopsy in luteal phase. MAIN OUTCOME MEASURE(S): Uterine artery Doppler, count of uterine CD56 bright cells/field, and quantification by real-time polymerase chain reaction (PCR) to monitor IL-12 family (IL-12p40, IL-12p35, EBI3, IL-23), the IL-18 system (IL-18, IL-18R, IL18BP), and the IL-15 mRNA ratio. RESULT(S): The uterine artery Doppler and the CD56 bright cell counts were significantly different in fertile and infertile patients. The mean uterine artery pulsatility index correlated significantly negatively with the IL-18/actin ratio suggesting a defect of the cytokine-dependent vascular remodeling pathway. The number of uterine CD56 bright cells was significantly correlated with the IL-15/actin and IL-18/IL-18BP ratios. Thus, IL-18 and IL-15 seems to be involved in the local recruitment and the activation of uterine natural killer (uNK) cells. IL-18 was itself correlated with IL-15 and IL-12, suggesting a local control of uNK cells activation. CONCLUSION(S): The assessment of the tripod IL-12/-15/-18 shows distinct immune-related mechanisms that are involved in the broader context of inadequate uterine receptivity.

Controlled natural in vitro fertilization may be an alternative for patients with repeated unexplained implantation failure and a high uterine natural killer cell count.

Patients with a history of repeated and unexplained implantation failure after IVF-embryo transfer and a high uterine natural killer cell count during estrogen-progestin treatment may benefit from controlled natural IVF-ET.

Reproductive immunology 2003: reassessing the Th1/Th2 paradigm?

We briefly review the history of concepts (some of which are still valid) which have lead to the present situation where pregnancy is viewed as being a Th2 phenomenon. We recall some of the early evidence which has been taken as supporting the general validity of this concept in murine and human pregnancy. We then recall some of the recent data dealing with "newer" cytokines and the role of uterine natural killer (NK) cells at the feto-maternal interface which fit neither with a steady-state concept nor with inflammatory cytokines, being solely "bad guys" as the paradigm would predict, nor with the concept of reduction of NK "activity" being required for successful pregnancy. As an example of the newer complexity, we briefly recall some of our recent micro-array studies in mice, and describe briefly our most recent data in human pointing out the importance of the tripod IL-12/IL-18/NK in successful or failed pregnancy in human, perhaps under IL-15 control. We conclude by a repeated warning against the so-called rationales of lymphocyte alloimmunization for therapy of recurrent spontaneous abortion and improvement of implantation rates.

A new role for natural killer cells, interleukin (IL)-12, and IL-18 in repeated implantation failure after in vitro fertilization.

OBJECTIVE: To investigate the endometrial immunohistochemical staining of interleukin (IL)-12 and IL-18 and to quantify the CD56 bright natural killer (NK) cells in relation to Doppler vascular disorders. DESIGN: Controlled clinical study. SETTING: Research unit of a university hospital. PATIENT(S)": Thirty-five women with repeated implantation failure after ET in IVF and 12 fertile control patients.Ultrasound evaluation and endometrial biopsy on day 20. MAIN OUTCOME MEASURE(S): The balance between IL-12 and IL-18, the number of NK cells, and the vascular status among fertile and implantation failure patients. RESULT(S): The control patients displayed normal vascular parameters, a weak anti-IL-12 staining, a consistent moderate stromal anti-IL-18 staining, and fewer than 15 NK cells/field. This pattern was observed among only 17% (6/35) of the implantation failure group. The remaining patients fit into one of two patterns: [1] 37% (13/35) had more than 40 NK cells/field with a strong anti-IL-12 and/or anti-IL-18 staining, and [2] the remaining 46% (16/35) had a marked local depletion of IL-18 and IL-12. Respectively, 85% and 31% of two groups displayed abnormal vascular parameters. CONCLUSION(S): Distinctions between the different local dysregulations of the cytokine network may provide clues for further exploration and treatment.

Cytokines, implantation and early abortion: re-examining the Th1/Th2 paradigm leads to question the single pathway, single therapy concept.

PROBLEM: Human in vitro fertilization (IVF) embryo transfer is accompanied by a low implantation rate even after a very successful IVF, and there are a certain number of 'idiopathic sterilities' which are due to repeated implantation failures. In the very same vein, the question of improving implantation rates is of prime importance in agricultural research to improve the management of livestock. Preimplantation prenatal diagnosis cannot be accomplished in individuals who have a high rate of implantation failure, whether women undergoing IVF, or animals, during genetic cloning. Implantation cytokine networks need to be known in such a perspective. METHODS: We review the evolution and theories in reproductive immunology, briefly deal with the complexity of implantation as a step by step developmental event, and then present some of our recent data in mice and human. CONCLUSIONS: We conclude that the T helper cell type 1/2 (Th1/ Th2) paradigm, as useful as it has been to explain pregnancy, is no longer sufficient in view of the emerging complexity of the cytokine network at the materno-fetal interface. This is peculiarly true for implantation, which, as a step by step developmentally regulated process, involving inflammatory molecules, cannot fit into such a scheme.

Assessment of leukemia inhibitory factor levels by uterine flushing at the time of egg retrieval does not adversely affect pregnancy rates with in vitro fertilization.

OBJECTIVE: To assess intrauterine levels of leukemia inhibitory factor (LIF) by uterine flushing at the time of egg retrieval and to confirm that the procedure has no detrimental effect on pregnancy rates. DESIGN: Prospective study. SETTING: Assisted reproductive unit of a university hospital. PATIENT(S): Uterine flushing was performed in 148 IVF patients. The first 100 patients were compared with a matched control group. INTERVENTION(S): Uterine flushing at the time of egg retrieval. MAIN OUTCOME MEASURE(S): IVP-ET results, pregnancy rates, and intrauterine LIF levels. RESULT(S): Pregnancy rates were not different in the group of patients with (27%) or without uterine flushing (28%). Leukemia inhibitory factor was detected in 60 patients (46%). Pregnancy rates did not differ between patients' detectable LIF and those in whom LIF was undetectable. Mean levels of LIF were 30.1 +/- 49.3 pg/mL and 28.6 +/- 51.2 pg/mL in pregnant and nonpregnant patients respectively. CONCLUSION(S): The flushing procedure at the time of egg retrieval did not adversely affect pregnancy rates. Leukemia inhibitory factor was detected in 46% of patients at the time of egg retrieval, but no correlation were observed with better pregnancy rates in patients with detectable LIF. Mean LIF levels did not differ in pregnant and nonpregnant women. Access to endoluminal secretions of the endometrium during IVF-ET may represent a new research in human implantation.