Embryo Interaction May Be Key to Diagnosis and Treatment of Immunological Implantation Failure by Geoffrey Sher, M.D.
What is the basis for the diagnosing and treating of immunologic implantation failure with IVIG and corticosteroids?
There have recently been several significant developments in the reproductive immunology arena that promise to soon resolve the raging controversy regarding the issue of immunologic implantation failure with IVF and the role of immunotherapy. Recent recognition of the fact that the implanting embryo engages in a “cross talk” with immune cells in the endometrium (lymphocytes; Natural Killer [NK] cells and T-cells) through the interaction of growth factors known as cytokines (i.e. the cytokine network) to reach a “negotiated settlement” with the embryo (a semi-allograph) allowing it to develop unhindered in the uterus rather than be rejected.
The embryo, upon arrival in the uterus, relays its desire to enter into a “dialogue” with the endometrial immune system, through releasing specific genes known as Human Lymphocyte Antigens (HLA). If the signal is appropriate and is well received by the endometrial NK and T-cells, the cytokine network is established and the “dialogue” is both initiated and propagated thereby.
Cytokines produced by both the embryo and the immune cells of the endometrium, fall in to two categories. TH-1 cytokines tend to destroy the cells of the trophoblast (the root system of the early embryo and of the placenta), and TH-2 cytokines propagate implantation and placentation. A harmonious interaction of TH-1 and TH-2 cytokines is necessary for healthy implantation and for the developing conceptus to survive and thrive. It is perhaps not surprising that clear evidence has recently emerged of TH1 dominance in cases of “unexplained” recurrent pregnancy loss, pregnancy-induced complications (such as pre-eclampsia) that threaten fetal survival and in “unexplained (often repeated) IVF failure. Cases at risk of the latter are women who exhibit local (endometrial) and peripheral (blood) immunologic and immunophenotypic evidence of NK cell hyper activation (NKa) and or cytotoxic T-cells (CTL), prior to undergoing IVF. These findings will hopefully pave the way to a rational discourse. Since THI cytokine dominance in large part originates from increased NKa and CTL activity in the endometrium, it follows that rational treatment must focus upon immunoregulation/modulation of the culpable cells, prior to the embryo’s arrival in the uterus. Currently, immunoglobulin-G (IVIG) and steroid therapy offers the best method for down-regulating NKa and CTL activity in the uterine lining.
It has long been our position at SIRM that the unwillingness on the part of ART practitioners to recognize the entity of immunologic implantation failure and the use of NKa and CTL regulators such as IVIG and corticosteroids has been motivated by an agenda propagated by a few individuals who were desirous aimed at “killing the messengers”. Now, emerging clinical/scientific evidence offers renewed hope that will force a healthy debate on this highly charged, hitherto controversial, but nevertheless very important cause of IVF failure.
Why do we measure HLA-G to determine embryo implantation potential?
Given the pivotal role of HLA-signaling (predominantly HLA-G) in establishing the ground work for a healthy TH-1:TH-2 balance by initiating the cytokine network (and thereby, facilitating normal implantation), it occurred to us and to other researchers that sHLA-G secretion by individual early embryos in culture, might provide insight into embryos subsequent potential for implantation and viability. This led us to measure sHLA-G expression in the media surrounding each embryo, 46 hours following forced fertilization by intracytoplasmic sperm injection (ICSI). Since at SIRM (unlike almost all other IVF programs) we culture each embryo in a separate aliquot of culture medium and inseminate all mature eggs by ICSI, we were well positioned to accurately time and measure early embryo sHLA-G expression. We soon came to recognize (and recently published) our observation that the embryo’s sHLA-G expression provides a reliable measure (unavailable through microscopic assessment anywhere) of its subsequent implantation and pregnancy-generating potential. We have since validated these findings through sHLA-G expression of embryos
transferred to more than 500 women. As a result, we currently offer sHLA-G embryo testing (performed bi-coastally) to all SIRM IVF patients.
What are the barriers to widespread use of sHLA-G embryo testing?
Since in order to evaluate sHLA-G expression of each embryo, one must of necessity culture each fertilized egg separately, the vast majority of IVF programs who culture embryos in groups or batches would not be able to use this method unless they completely change embryo labs. Moreover, the precise timing for the collection of media surrounding each developing embryo (46 hours post-fertilization), an important step in the testing methodology, is hard to effect unless all oocytes are inseminated by ICSI (which provides for precise timing of fertilization). Since most IVF programs do not perform ICSI uniformly on all oocytes, this would be difficult to do, adding a significant additional impediment to the widespread dissemination of this methodology.
What promise does sHLA-G embryo testing hold for the future?
- The emergence of an era where a rational basis can be established for the transfer of few, and in many cases of a single “competent” embryo at a time, while maintaining optimal IVF success rates. (We are soon to launch such a study at SIRM where only 1 sHLA-G +ve embryo will be transferred)
- Measurement of embryo-derived markers such as sHLA-G could help us to better understand and perhaps “interpret” what the embryo is trying to “relate” to the endometrial immune cells…. in the hope of gaining insight in to the subsequent quality of the pregnancy that follows, and
- An opportunity to test and develop new formulations of fertility drugs as well as individualize the protocols of stimulation…. based on the potential to produce “competent “embryos.
Geoffrey Sher, M.D. is the executive medical director for the Sher Institutes for Reproductive Medicine and an executive board member for INCIID. Dr. Sher, founder of SIRM, has been influential in assisting more than 140,000 women have babies following the treatment of infertility in general, and for the births of more than 4,000 IVF babies in specific.