Understanding Immunologic Implantation Dysfunction Part 1: Setting the Stage for Selective Immunotherapy with Intralipid and IVIg

10 May
Plant Petri Dish
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It is an unfortunate reality that many IVF programs attach little importance to factors that affect embryo implantation in general, and immunologic implantation dysfunction (IID) in specific (see below). Perhaps the lack of attention given to evaluating IVF patients for factors that adversely affect the receptivity of the uterine lining (endometrium/decidua) is due to the fact that in humans, IVF failure and miscarriage are both four times more likely to be due to embryo “incompetence” than to dysfunctional implantation.Thus, a high measure of IVF success can still be achieved in spite of ignoring less common (and more complex) factors such as IID.

But for the 20% of IVF patients with problems relating to lack of endometrial receptivity, it becomes a different matter altogether. For them, the emotional, physical and financial roller coaster ride goes on and on. Often after “spinning their wheels” and enduring repeated IVF failures, many of them will be advised to move on to egg donation…only to fail there as well. Optimal implantation is not only important for embryo survival; it is also a major factor in determining normal intrauterine growth and development. As such, it is a major determinant of the very quality of life after birth.

Immunologic acceptance of the implanting embryo by the uterus of the mother is both highly complex and magnificent. Not only is it essential for pregnancy to occur, but it also sets the scene for our body’s own cells, tissues and organs to be shielded from attack by our own immune systems. For a moment, consider how, when confrontedby foreign proteins (bacteria, viruses, foreign tissue grafts/transplantation), the body’s immune system goes on the attack, but yet an embryo that is derived from proteins that come from another individual (the sperm or paternal antigen), usually safely implants in the pre-pregnancy uterine lining and then grows into a healthy baby.This phenomenon has come to be referred to as the “immunologic riddle” of pregnancy.

For such a complex arrangement to be foolproof would be without precedent in human biology. To argue that this system can never fail is in my opinion, an absurdity, bordering on arrogance. It can and does go wrong in about 15-20% of women with reproductive failure.When it does, it presents either as failed implantation (presumed by the patient to be infertility), as miscarriage, or (much less frequently) as placental failure and compromised fetal development or intrauterine death. It all depends on the timing, nature and severity of the immune assault.

It is well known that the reason the implanting normal embryo thrives in the womb is that unique immunologic adjustments convert the pre-pregnancy uterine lining (decidua) into a “privileged site” where the embryo and the fetus come to be regarded as the “body’s own” and as such are protected from immune attack. This initial acceptance of the embryo as “self” or “friend” rather than “non-self” or “foe” (in spite of it being composed partially of the father’s “foreign” cells), is one of the miraculous adaptations of nature, and is in large part responsible for our survival as a species.

As soon as implantation begins, the paternal genetic contribution to the embryo (so called DQ alpha genes) initiates asignal to the pre-pregnancy decidual immune system which thereupon determines whether the embryonic “allograft” should be welcomed as “friend” or be rejected as “foe” through immune attack. The process is referred to as “alloimmune recognition.”Given that with the exception of monozygotic twins, interpersonal differences in genotype are inevitable, it follows that maternal and paternal DQ alpha gene combinations will usually also differ in the vast majority of cases. Thus, preservation of the human species required that in spite of such immunogenetic dissimilarities, the immune system of the pre-pregnancy endometrium (decidua) evolutionarily adapt and recognize the embryo as friend rather than foe.

Upon reaching the uterine environment, the genetically “competent” embryo hatches and within 12-24 hours starts sending its root system (trophoblast) into the decidua. The trophoblast has both a villous (root-like) and an extravilous (diffuse) component. The extravilous trophoblast which diffusely permeates the decidua, expresses several so-called “major histocompatibility complex” (MHC) class-1 genes (e.g. histocompatibility leukocyte antigen [HLA]-C, E & G)].These HLA genes, (mainly HLA-G) regulate primarily two types of lymphocytes present in the decidua.These are: a) uterine natural killer cells (NK) and b) cytotoxic lymphocytes (CTL). NK cells comprise approximately 75% of decidual lymphocytes and CTL comprise about 10%. They both play a vital role in regulating the normal implantation process by controlling the penetration and functioning of the trophoblast.

The recognition of proteins as self (“friend”) or non-self (“foe”) is propagated by highly specialized immune lymphocytes known as Regulatory T-cells. These so called Treg cells can “turn-off” immune reactions even once they have been started by conventional immune cells. They play a pivotal role in the immune system’s ability to prevent rejection of an embryo whether due to an autoimmune or alloimmune response. Other immune cells known as “dendritic cells” introduce antigenic proteins to these Treg cells, whose concentration increases when the antigen is recognized as “friend” and decreases when recognized as “foe.” MHC (primarily HLA-G) signaling, through the Treg lymphocyte mechanism working in combination with other regulatory proteins, influences the production and release of so-called cytokines by the NK and CTL cells.

There are 3 varieties of cytokines, two of which play defining roles in the maintenance of implantation:The first is TH-2 cytokines, which encourage growth and expansion of the trophoblast and promote proliferation of blood vessels (angiogenesis). TH-1 cytokines promote destruction (cytolysis) of trophoblastic cells and also cause blood to clot (procoagulant effect).A balance between TH-1 and TH-2 cytokines is essential for normal implantation and development of the placenta (placentation). Over-activity (dominance) of TH-1, the hallmark of NK cell and CTL activation, leads to damage of the trophoblast, implantation dysfunction and reproductive failure.

Part 2 of this post will discuss the diagnosis and treatment of immunologic implantation dysfunction.

81 Comments

  • Rose says:

    Hi dr. Sher,

    I’ve been using IVF+PGD for the last 3 years without success. I have 2 kids, conceived naturally and trying IVF for gender selection. This is a summary of my cycles:
    IVF#1 – all embryos opposite gender, no transfer
    IVF#2 – 1 embryo transferred (FET), m/c around 6 weeks
    IVF#3 – 2 embryo transferred (fresh) – BFN
    IVF#4- all embryos abnormal, no transfer
    IVF#5- 2 embryo transferred(FET), chemical (first beta 79, second 39)
    IVF#6- 2 embryo transferred (fresh) – BFN

    On cycle #5 dexamethasone and lovenox were added and in the last cycle I also had intralipids as my NK cells were reported as elevated. For all the cycles the embryos are tested (aCGH), good quality and the uterine conditions pointed as “perfect”. Don’t know what else can be done. any suggestions/advice?
    Thanks!

    • Geoffrey Sher says:

      Hi Rose,

      Please go to the home page of IVFauthority.com. When you get there look for a “search bar” in the upper right hand column. Then type in the following subjects into the bar, click and this will take you to all the relevant articles I posted there.
      1. “An Individualized Approach to Ovarian stimulation” (posted on November 22nd, 2010)

      2. Ovarian Stimulation for IVF: The most important determinant of IVF Outcome” (Nov. 2103)

      3. “Agonist/Antagonist Conversion Protocol”

      4. “Traveling for IVF from Out of State/Country– The Process at SIRM-Las Vegas” (posted on March, 21st 2012)

      5.“A personalized, stepwise approach to IVF “ (Parts 1 & 2 (posted March, 2012)

      6. “IVF success: Factors that influence outcome”

      7. “Use of the Birth Control Pill in IVF”

      8.”Gender selection”

      Please consider calling 800-780-7437 or 702-699-7437 to arrange a Skype with me so we can discuss your case in detail.

      Finally, perhaps you would be interested in accessing my new book (recently released). It is the 4th edition (and a re-write) of “In Vitro Fertilization: The ART of Making Babies”. The book is available through “Amazon.com” as a down-load or in book form. It can also be obtained from most bookstores.

      Geoff Sher

      P.S: Please go to http://www.youtube.com/watch?v=Vp3GYuqn2eM&feature=youtu.be
      To view a video-tutorial by Linda Vignapiano RN, Clinical Manager at SIRM-Las Vegas.

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