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

10 May
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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.

75 Comments

  • Yasmin says:

    Good Morning Dr. Sher,

    We are fascinated and so impressed with the progress and positive developments your team and yourself have made in helping people have families.

    We remain hopeful to provide our young child with a sibling. We are a couple who are dealing with secondary infertility.
    My query is that if we have been pregnant 3 times – then is it most likely we can rule out IID?

    Brief background
    (2009 – 1st PG naturally – miscarried at 8 weeks , 2010 – 2nd PG through IUI resulting in a natural delivery of a healthy bouncing baby and 2012- 3rd through fresh transfer IVF with PDG – but no heart beat detected at scan) then is it most likely we can rule out IID?

    We ask as we have adopted the approach you have recommended and banked embryos due to maternal advanced age ….I’m no spring chicken at 42!.

    We have over the past 18 months had retrieved a reasonable quantity of eggs resulting in very few good quality embryos.
    We have had 3 transfers of IFV – 1 fresh and 2 FET. The last 2 FET we had CGH done resulting in good quality day 5 BC and day 6 HB transfers. We naturally expected that as the quality of embryo was reasonably good then chances were high – no success. We are now examining problems with implantation and looking at all possibilities. The one issue may be thin lining under 8mm – I see that you recommend vaginal Viagra which we will explore this.

    Thank you also for your informative blog – which you manage to fit into your heavy schedule. We look forward to reading your 4th edition of your book.

    Yasmin and Nick

    • Geoffrey Sher says:

      Firstly,

      I presume you are banking blastocyusts and the the embryos are being karyotyped (CGH or equivalent). If so then you are on the right path. Do not however assume that because you had a baby, you cannot have an immunologic problem. You need to be tested for NK cell activity and you and your husband should be matched for DQal[pha/HLA genetic similarities. I use Reprosource Reproductive Immunonology Laboratories inn Boston, MA because there are very few labs in the U.S.A that can do these tests adequately.

      Please go to the home page of this blog, http://www.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. “Immunologic Implantation Dysfunction” (posted on May, 10th and on May 16th respectively.

      5. “Thyroid Autoimmune Disease and IVF”

      6. “Embryo Implantation………” (Part-1 and Part- 2—-Posted August 2012)

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

      8.“A personalized, stepwise approach to IVF at SIRM”; Parts 1 & 2 (posted March, 2012)

      9. “IVF success: Factors that influence outcome”

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

      11.”Staggered IVF”

      12.“Embryo Banking”

      13.“Array CGH versus metaphase CGH in IVF patients….’

      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.

      Geoff Sher

  • kuba rosa says:

    Hello Dr. Sher,

    What is your specific INTRALIPID protocol at your center? 100 cc 20% INTRALIPID in 500 cc NS a week before tranfer, 100 cc IL in 500 cc NS after positive pregnancy, and 100 cc IL in 500 cc NS every 2-4 weeks for the duration of 20 wks of pregnancy??? Have you had any women with any complications to INTRALIPID? What is the dose of dexamethasone and what period of the duration do you prescribe (how many weeks of pregnancy)? Have you published this protocol for review??? Do you have any references or publications of the protocol? I would greatly appreciate it if you would email me. kuba_rosa@hotmail.com
    Thanks Dr. Sher

    Kuba Rosa

    • Geoffrey Sher says:

      Please call 702-892-9696 on Monday and ask for Linda Vignapiano RN. She will provide you with this information.

      Geoff Sher

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